Tumori, 95: 329-337, 2009
Three-dimensional conformal radiotherapy, temozolomide chemotherapy, and high-dose fractionated stereotactic boost in a protocol-driven, postoperative treatment schedule for high-grade gliomas Luigi Pirtoli1, Giovanni Rubino2, Stefania Marsili3, Giuseppe Oliveri4, Marta Vannini2, Paolo Tini1, Clelia Miracco5, and Riccardo Santoni6 1
Section of Radiological Sciences, Department of Human Pathology and Oncology, University of Siena, Siena; Units of 2Radiotherapy, 3Medical Oncology, and 4Neurosurgery, Azienda Ospedaliera Universitaria Senese, Siena; 5Section of Pathologic Anatomy, Department of Human Pathology and Oncology, University of Siena, Siena; 6Radiation Therapy Unit, Department of Biopathology and Diagnostic Imaging, Tor Vergata University, Rome; 1-5Istituto Tumori Toscano (ITT), Siena, Italy
ABSTRACT
Aims and background. No available scientific report deals with high-dose (≥70 Gy) radiotherapy plus temozolomide chemotherapy (TMZ CHT) in high-grade gliomas. The survival results of a protocol-driven, postoperative treatment schedule are reported here to contribute to the discussion on this issue. Methods and study design. Uniform criteria were prospectively adopted for case selection during the period 1993-2006 in the management of 123 patients, and we progressively introduced three-dimensional conformal radiotherapy (3D-CRT, 60 Gy), TMZ CHT and a high-dose (70 Gy) stereotactic boost (HDSRT) in the treatment schedule. Palliative radiotherapy was delivered by whole brain irradiation (WBI, 50 Gy) for bulky tumors, whereas radical irradiation was performed with 3D-CRT throughout the study period. Two periods of accrual are considered: 36 patients were treated before 31 December 1999 (29.25%) and 87 (70.75%) after 1 January 2000. This subdivision was due to the implementation of HDSRT hardware and TMZ CHT from January 2000. Results. The median overall survival was 13 months and the 1-, 2- and 3-year survival rates were 53%, 19.5% and 11.6%, respectively. The differences in survival related to the treatment variables were highly significant, both in univariate and multivariate analysis. The median survival and 1-, 2- and 3-year survival rates in the palliative WBI group were 9.75 months and 37%, 2%, and 0%, respectively; in the 3D-CRT group 17.25 months and 64%, 34%, and 15%, respectively; in the TMZ CHT concomitant with radiotherapy group 20 months and 61%, 39%, and 21%, respectively; in the TMZ CHT concomitant with and sequential to radiotherapy group 25.75 months and 84%, 54%, and 26%, respectively, and in the HDSRT group 22 months and 72%, 48%, and 37%, respectively. No symptomatic radiation necrosis occurred in any of the groups. Conclusions. The results reported here are generally better than those reported in the literature. The selection of patients on the basis of favorable prognostic factors and suitability to the currently available, aggressive postoperative treatment resources can be the mainstay for improving therapeutic results. In particular, the new treatment option reported here (HDSRT in association with TMZ CHT) proved to be safe and effective in obtaining a relatively favorable outcome. Introduction In the last decades there has been no evidence-based demonstration of an improvement in the therapeutic results obtained with radiation therapy in high-grade
Key words: high-grade glioma, radiotherapy, high-dose boost, chemotherapy, temozolomide. Correspondence to: Prof Luigi Pirtoli, Section of Radiological Sciences, Department of Otolaryngology, Orthopedics and Radiological Sciences, University of Siena, Viale Bracci, 53100 Siena, Italy. Tel +39-0577-585700; fax +39-0577-586131; e-mail
[email protected] Received September 17, 2008; accepted November 21, 2008.
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gliomas (HGG). The current standard of postoperative treatment is based, in fact, on a radiation dose of 60 Gy in 6 weeks, in line with the results of prospective studies published between 1979 and 19931-5. This dose level has been defined as “surprisingly standard across the world”6. Recent prospective data based on the use of high boost doses to small-volume tumors, delivered with stereotactic irradiation (HDSRT) and hypofractionation7,8, have failed to demonstrate better survival rates. Therefore, the current guidelines state that, “The recommended dose is 60 Gy in 2-Gy fractions”9. However, the sophisticated imaging resources and radiotherapy techniques currently available allow the administration of higher doses to selected volumes, and interesting survival data and acceptable toxicity rates have been reported after the analysis of retrospective series10,11. The outstanding results of temozolomide chemotherapy (TMZ CHT), concurrently and sequentially delivered with standard-dose irradiation12, point to a new opportunity for the optimization of the postoperative treatment schedule integrating CHT with high-dose irradiation using 3-dimensional conformal radiotherapy (3D-CRT) and HDSRT in selected patients. The results obtained with high-dose (≥70 Gy) RT plus TMZ CHT at the Department of Siena of the Istituto Toscano Tumori (ITT) are reported here. One hundred twenty-three patients with histologically proven HGG were consecutively referred for treatment at the Radiotherapy Unit of the University Hospital of Siena between 1993 and 2006. Uniform protocol criteria were prospectively adopted during this time interval for the postoperative management of these patients, and 3D-CRT, TMZ CHT and HDSRT were progressively introduced. The entire series of 123 patients is reported here, with particular emphasis on the selection of patients for more or less aggressive treatment regimens based primarily on tumor size.
Material and methods One hundred twenty-three patients affected by HGG were treated postoperatively between April 1993 and June 2006. For the purposes of the present study 2 periods of accrual are considered: 36 patients (29.25%) were treated before December 1999 and 87 (70.75%) were treated after this date. This subdivision was due to the implementation of RT hardware and TMZ CHT from January 2000. The considerable increase in patient accrual in the second period is attributable to the progressive, formal actuation, since 2000, of an interdisciplinary staff (GOM, Gruppo Oncologico Multidisciplinare), composed of 3 of the authors (GR, SM, GO), for patient recruitment. The patients’ features at presentation are listed in Table 1. Computed tomography (CT) or magnetic resonance imaging (MRI) was performed in 95 (77.25%) and 86 patients (70%), and in 91 (74%) and 61
L PIRTOLI, G RUBINO, S MARSILI ET AL Table 1 - Main features of the 123 patients at presentation No. pts (%)
Variables M F
74 (60%) 49 (40%)
Age
