RTOG Protocol No: 9508	Protocol Status:
	Opened:	January 31, 1996
	Closed:	June 15, 2001

Title:

A Phase III Trial Comparing Whole Brain Irradiation With Versus Without Stereotactic Radiosurgery Boost For Patients With One To Three Unresected Brain Metastases

Patient Population:
- Histologically confirmed systemic malignancy
- A diagnostic contrast enhanced MRI of brain demonstrating 1-3 parenchymal brain metastases
- Single brain metastasis is eligible only if surgery is refused or if surgery deemed inappropriate by the treating physician.
- Well circumscribed lesions, with maximum tumor diameter < 4.0 cm (per lesion). If multiple lesions are present and one lesion is at the maximum diameter, the other(s) must not exceed 3.0 cm in maximum diameter.
- No metastases to brain stem, midbrain, pons, or medulla or within 10 mm of the optic apparatus (optic nerves and chiasm).
- No prior cranial irradiation
- Age > 18 years
- Karnofsky performance status > 70.
- Hgb > 8, absolute neutrophil count > 1000, platelets > 50,000
- Study-specific consent form

Objectives:

1. To determine if the delivery of stereotactic radiosurgery (SRS) boost treatment(s) after conventional whole brain radiation therapy improves upon the overall survival of radiotherapy alone in patients with 1-3 unresected brain metastases.

2. To compare site(s) of recurrence and cause of death between such patients receiving or not receiving SRS boost treatment(s) after whole brain radiation therapy.

Schema:

S T R A T I F Y

Number of Metastases 1. Single 2. 2-3 Extent of Extracranial Disease 1. None 2. Present

REGISTER R A N D O M I Z E

Arm 1: Whole brain RT to 37.5 Gy/15 fractions/2.5 Gy once daily, 5 days/week followed by radiosurgery to all (1-3) metastase(i)s Arm 2: Whole brain RT to 37.5 Gy/15 fractions/2.5 Gy once daily, 5 days/week

Arm 1: All patients will receive whole brain radiation therapy delivered to 37.5 Gy in 15 daily fractions of 2.5 Gy followed by stereotactic radiosurgery (SRS) to all (1-3) known metastase(i)s. SRS dose will be tumor size dependent (See Section 6.2.2) and will be prescribed to the isodose surface (> 50% to < 90% of the maximum dose [maximum = 100%]) which encompasses the margin of the tumor.

Arm 2: All patients will receive whole brain radiation therapy delivered to 37.5 Gy in 15 daily fractions of 2.5 Gy.

Study Chairs:	David W. Andrews, M.D.	Total Patients Entered: 333
	Paul W. Sperduto, M.D.
	Louisa Thoron, M.D.
	Adam E. Flanders, M.D.
	Michael Schell, Ph.D.

Reference: Sperduto P, Scott C, et al. Stereotactic Radiosurgery With Whole Brain Radiation Therapy Improves Survival In Patients With Brain Metastases: Report Of Radiation Therapy Oncology Group Phase III Study 95-08. Int J Radiat Oncol Biol Phys 54:3, 2002

Purpose/Objective: To determine if stereotactic radiosurgery (SRS) after conventional whole brain radiation therapy (WBRT) improves overall survival when compared to WBRT alone in patients with 1–3 brain metastases. Secondary objectives include a comparison of sites of recurrence and cause of death.

Materials/Methods: Between 1/96 and 6/01, 333 patients from 34 institutions were randomized to receive WBRT + SRS or WBRT alone. The WBRT was given at 250cGy/fraction to 3750 cGy in 3 weeks. The SRS dose was based on tumor size and was delivered within one week of completion of WBRT. The study was designed to detect a 50% improvement in median survival time (MST) with 80% statistical power for all patients and a 75% improvement in MST in patients with solitary metastases. Central radiology review of local control and salvage therapy analyses will be presented.

Results: There was a statistically significant survival advantage with WBRT + SRS for the following patients: solitary brain metastases (MST 6.5 vs 4.9 months, P=0.04), RPA class I (MST 11.6 vs 9.6 months, P=0.05), age < 50 (9.9 vs 8.3 months, P=0.04) and patients with non-small cell lung cancer or any squamous cell carcinoma (5.9 vs 3.9 months, P=0.05). Also, patients with initial KPS of 90–100 appeared to benefit (10.2 vs 7.4 months) without reaching statistical significance (p=0.07). Furthermore, all patients in the WBRT + SRS group were more likely to have a stable or improved performance status (KPS) at 3 months (50% vs 33%, P=0.02) and at 6 months (43% vs 27%, P=0.03). There was no significant difference in cause of death but there was a significant difference in local control as reported by the treating institution (82% vs 71% at one year for WBRT + SRS vs WBRT alone, respectively (p=0.01). Toxicities were comparable between the two treatment groups.

Conclusions: WBRT + SRS provided a survival advantage compared to WBRT alone in each of the following patient categories: 1) solitary brain metastasis; 2) RPA class I ; 3) age < 50; 4) non-small cell lung cancer or any squamous cell carcinoma. Furthermore, all subsets of patients in the WBRT + SRS group were more likely to have a stable or improved performance status than those in the WBRT alone group. Systemic disease remained the primary cause of death (>2/3) in both groups and improved systemic therapies are needed.