Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: Report of Radiation Therapy Oncology Group 93-05 protocol
Souhami L.  IJROBP 2004;60: 853-860

Conventional treatment of glioblastoma multiforme (GBM) cures less than 5% of patients. We investigated the effect of stereotactic radiosurgery (SRS) added to conventional external beam radiation therapy (EBRT) with carmustine (BCNU) on the survival of patients with GBM.

Methods and materials: A total of 203 patients with supratentorial GBM (tumor ?40 mm) were randomly assigned either to postoperative SRS followed by EBRT (60 Gy) plus BCNU (80 mg/m2 Days 1–3 every 8 weeks for six cycles) or to EBRT with BCNU alone. The dose of radiosurgery was tumor size–dependent and ranged from 15 Gy for largest to 24 Gy for smallest tumors. RT and BCNU were identical in both arms.

Results: At a median follow-up time of 61 months, the median survival in the radiosurgery group was 13.5 months  as compared with 13.6 months  for the standard treatment group. There were also no significant differences in 2- and 3-year survival rates and in patterns of failure between the two arms. Quality of life deterioration and cognitive decline at the end of therapy, compared with baseline, were comparable and there was no difference in quality-adjusted survival between the arms.

Conclusions: Stereotactic radiosurgery followed by EBRT and BCNU does not improve the outcome in patients with GBM nor does it change the general quality of life or cognitive functioning.   see survival curve

RTOG 93-05

A PHASE III TRIAL COMPARING THE USE OF RADIOSURGERY FOLLOWED BY CONVENTIONAL RADIOTHERAPY WITH BCNU TO CONVENTIONAL RADIOTHERAPY WITH BCNU FOR SUPRATENTORIAL GLIOBLASTOMA MULTIFORME

Arm 1:60 Gy/30 fractions/2 Gy once daily, BCNU 80 mg/m2 i.v. days 1,2,3 of RT then q 8 weeks for a total of 6 cycles.
Arm 2: Radiosurgery followed by 60 Gy/ 30 fractions/2 Gy once daily, BCNU 80 mg/m2 i.v. days 1,2,3 of RT then q 8 weeks for a total of 6 cycles

 

Arm 1: For the first 46 Gy/23 fractions, the treatment volume should include the volume of contrast enhancing lesion and surrounding edema on pre-operative CT/MRI scan plus a 2 cm margin. After 46 Gy the tumor volume should include the contrast enhancing lesion (without edema) on the presurgery CT/MRI scan plus a 2.5 cm margin.

Arm 2: Radiosurgery dose will be prescribed to the isodose surface (>= 50% to <= 90% of the maximum dose) which encompasses the margin of the tumor. Radiosurgery doses will be tumor size dependent. Conventional radiotherapy will begin within one week of the date of radiosurgery.

BCNU will be given to both arms for a total of 6 cycles (maximum dose = 1440 mg/m2).

Considering that 90% of recurrences in malignant gliomas are located within 2 cm of the enhancing edge of the original tumor on CT scans and that the occurrence of multicentric disease or metastatic spread is rare treatments that irradiate a localized tumor to a high dose with a minimal irradiation of adjacent normal brain tissues are an attractive alternative that may improve the therapeutic ratio.

Interstitial brachytherapy has been shown to improve local control and survival in selected patients with malignant gliomas. Gutin et al.12 from the University of California, San Francisco, treated 41 patients with recurrent malignant gliomas (18 glioblastoma multiforme) using stereotactic interstitial implants. The median survival times were 52 weeks and 153 weeks for patients with glioblastoma multiforme and anaplastic astrocytoma, respectively. Despite the prolonged median survivals, the high incidence of focal radiation necrosis with 41% of the patients requiring reoperation is of concern. Gutin et al.13 have also recently reported their experience in a non-randomized trial on the use of brachytherapy as a boost to external irradiation in patients with newly diagnosed high grade gliomas. Of the 101 evaluable patients with unifocal, well-circumscribed lesions, 63 received the combined approach. From the authors' analysis, it appears that a brachytherapy boost may improve median survival of some patients with glioblastoma multiforme but its value for anaplastic astrocytomas remains uncertain. Nearly 50% of the patients in the combined modality treatment group required reoperation for tumor progression and/or necrosis.

1.5 Another possible approach to higher dose treatment is stereotactic external beam irradiation (SEBI), also called "radiosurgery". The term radiosurgery has been used to describe a variety of radiotherapy techniques characterized by the accurate delivery of high doses of radiation, usually in a single session, to stereotactically defined small intracranial targets (usually <= 40 mm in maximum diameter) in such a way that the dose fall-off outside the targeted volume is very sharp. Radiosurgery is a relatively simple, non-invasive treatment technique, usually performed on an out-patient basis. Reviews articles dealing with the physical and clinical aspects of radiosurgery have been published. Since a large number of patients are not eligible for brachytherapy because of tumor location, radiosurgery may prove to be an excellent alternative to brachytherapy as a way to deliver a boost following external beam radiotherapy for patients with malignant gliomas.

The maximum tolerable dose (MTD), based on overall toxicity, was determined to be 24 Gy for <= 20 mm tumors (investigators decided not to escalate the dose despite a lack of bad CNS toxicity at 24 Gy), 18 Gy for 21-30 mm tumors, and 15 Gy for 31-40 mm tumors.

6.1.1 Conventional Radiotherapy must begin within 5 weeks of surgery. (2/14/95) One treatment of 2.0 Gy will be given daily 5 days per week for a total of 60.0 Gy. All portals shall be treated during each treatment session. This conventional external beam irradiation regimen will be identical for both arms. For those patients receiving radiosurgery, conventional radiotherapy must begin within one week from the date of radiosurgery.

6.1.3 Localization, Simulation, and Immobilization

The patient shall be treated in the supine or other appropriate position for the location of the lesion. A head-holding device that is transparent to x-rays must ensure adequate immobilization during therapy and ensure reproducibility. The target volume for both the initial volume and the conedown volume shall be based on the preoperative CT/MRI. The initial target volume shall include the contrast enhancing lesion and surrounding edema (if it exists) demonstrated on CT/MRI plus a 2.0 cm margin. If no surrounding edema is present, the initial target volume in both treatment arms should include the contrast enhancing lesion plus a 2.5 cm margin.

Arms 1 and 2: For the first 46 Gy/23 fractions the treatment volume should include the volume of contrast enhancing lesion and surrounding edema on preoperative CT/MRI scan plus a 2 cm margin. After 46 Gy the tumor volume should include the contrast enhancing lesion (without edema) on the presurgery CT/MRI scan plus a 2.5 cm margin.

6.1.4 Treatment Planning

Treatment plans may include a wedge pair of fields, rotation, or multiple field techniques. Straight opposed lateral fields are not recommended and should be avoided. CT or MRI guided treatment planning is necessary to assure accuracy in the selection of field arrangements. Inability to achieve field placement as defined by the protocol will result in variation scores at headquarters reviews. Isodose distribution for the initial target volume and conedown target volume are required on all patients, including those treated with parallel opposed fields. The inhomogeneity across the target volume should be kept to a minimum. The minimum dose to the target volume should be kept within 5-10% of the dose at the center of the volume (see Appendix VI).

6.2 Radiosurgery

6.2.1 Radiosurgery must be performed within 5 weeks of surgery. (2/14/95) Only those patients whose tumors are <= 40 mm, as measured by a post-operative CT/MRI, are eligible to enter the study. Conventional radiotherapy must begin within one week from the date of radiosurgery.

6.2.2 Total Dose Determination

6.2.2.1 The total dose will depend on the size of the target volume and will be defined as follows:

Maximum Tumor Diameter

<=20 mm
21-30 mm
31-40 mm

 Dose(1/31/96)

24 Gy
18 Gy
15 Gy

6.2.4 Target Volume Determination

6.2.4.1 Target volume and isocenter determination will be based on a CT scan with contrast or MRI with the patient's head in a stereotactic frame. The imaging study used to deliver the radiosurgical treatment must be the same imaging study used to determine the post-operative tumor size.

6.2.4.2 Stereotactic CT slice thickness may not exceed 5 mm.

6.2.4.3 The target volume will include the enhancing portion of the biopsied or residual primary brain tumor without margin. Surrounding areas of edema will not be considered part of the target volume.

6.2.4.4 The target volume (mm3) will be determined on serial CT or MRI images.

6.2.5 Dose Prescription and Dosimetry Requirements

6.2.5.1 The dose will be prescribed to the isodose surface (50% to 90%) which encompasses the margin of the tumor, as defined by the imaging studies. For multiple isocenters, the maximum dose must be normalized to 100% and dose prescribed to the 50% to 90% isodose surface. The 100% (maximum) dose will be recorded for each patient. The prescription dose shall be delivered to the 50% to 90% (maximum = 100%) isodose surface, and is defined as the minimum dose to the target volume. This minimum dose shall be established by an examination of the dose distribution on each axial level on which the target volume has been defined, and/or by the target dose-volume histogram.

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