RTOG Protocol No: 9305	Protocol Status:
	Opened:	February 14, 1994
	Closed:	June 30, 2000

Title:

A Phase III Study Comparing Stereotactic External Beam Irradiation Followed by Conventional RT with BCNU to Conventional RT with BCNU for Supratentorial Malignant Glioma

Patient Population:
- Glioblastoma multiforme, histopathologically confirmed
- Supratentorial, well-circumscribed lesions, <4 cm
- Age >18
- KPS >60
- No prior irradiation
- Hgb >10, absolute neutrophils >1500, platelets >100,000
- BUN <25, creatinine <1.5, bilirubin <2.0, SGOT <2 x normal

Objectives:

1. To determine if the use of radiosurgery given prior to conventional radiotherapy with BCNU improves upon the overall survival of conventional radiotherapy plus BCNU.

2. To determine and compare the frequency and severity of toxicities of these approaches.

3. To compare the effect of treatment regimens on neurologic function and quality of life.

Schema:

S T R A T I F Y

Age 1. > 18 to < 50 2. > 50 Performance Status 1. Karnofsky 90-100 2. Karnofsky 60-80

R A N D O M I Z E

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).

Study Chairs:	Luis Souhami, M.D. (Radiation Oncology)	Patients Entered as of:
	Lucia Zamorano, M.D. (Neurosurgery)	6/30/00	203
	Jan C. Buckner, M.D. (Medical Oncology)

Reference: Souhami L, Scott C. Randomized Prospective Comparison Of Stereotactic Radiosurgery (SRS) Followed By Conventional Radiotherapy (RT) With BCNU To RT With BCNU Alone For Selected Patients With Supratentorial Glioblastoma Multiforme (GBM): Report Of RTOG 93-05 Protocol. Proc Am Soc Thera Rad Oncol (ASTRO, pp. 94-95, 2002.

Purpose/Objective: RTOG 9305 was a prospective randomized trial evaluating upfront SRS followed by RT with BCNU to RT with BCNU to compare survival, patterns of failure, toxicity and quality of life between the two arms, in selected patients (pts) with GBM.

Materials/Methods: Between February 1994 and September 2000, 203 selected pts with GBM were entered on this phase III trial. Eligible pts were > 18 years of age, KPS > 60, with histological proof of a unifocal (< 4 cm) GBM. Pts were stratified by age and KPS. Pts were randomly assigned to receive: 1) 60 Gy/ 30 fractions/2 Gy once daily plus BCNU 80 mg/m2 days 1, 2, 3 of RT then q 8 weeks for a total of 6 cycles (Arm 1), or 2) SRS (15-24 Gy) followed by the same RT and BCNU (Arm 2). A total of 186 pts enrolled were analyzable (4 pts in Arm 1 and 17 in Arm 2 excluded). The primary reason for ineligibility on the SRS arm was due to the tumor being too large at time of SRS. The pretreatment patient characteristics, including age, KPS, RTOG RPA class and pre/post surgery tumor size, were well balanced between the arms. The Spitzer Quality of Life index was used to measure general quality of life (QOL) and the Mini Mental Status Examination (MMSE) was used for cognitive functioning. We used the standard error of measurement (SEM) to determine clinically meaningful change in the scores.

Results: At a median follow-up time of 44 months, the median survival for Arm 1 was 14.1 months (95% CI: 11.0, 14.9) and it was 13.7 months (95% CI: 11.3, 15.2) for arm 2, P = 0.5328. The 24 and 36 months survival rates were 22% and 16% vs 18% and 8% for Arm 1 and 2, respectively. Similarly, there was no difference in survival between the arms when analyzed by RTOG RPA classes III or IV (median survivals of 14.7 and 14.2 for Arms 1 and 2, respectively). Compliance was very good for conventional RT and chemotherapy but 18% of the SRS pts had unacceptable deviations.

Five pts died on Arm 1 due to chemotherapy toxicity compared to two pts on the Arm 2. Acute and late grade 3 RT-related toxicities were more frequent on Arm 2 and there were no grade 4 toxicities.

The patterns of failure were similar between the arms with more than 90% of the pts presenting a component of local failure.

QOL deterioration (Spitzer index) at the end of therapy, compared to baseline, was similar between the arms (40% on Arm 1 and 50% on Arm 2, P = 0.4606). Using the MMSE only, approximately 30% of the pts, in each arm, had a cognitive decline in that timeframe. There was no difference in quality-adjusted survival between the two arms.

Conclusions: As used in this trial, the results show that the use of upfront SRS followed by RT and BCNU does not lead to an improved survival nor changes patterns of failure in this group of selected pts with GBM. Furthermore, there was no difference in general QOL and cognitive functioning between the arms.