RTOG Protocol No: 9513	Protocol Status:
	Opened:	October 1, 1997
	Closed:	April 15, 1998

Title: A Phase II Study of Topotecan Plus Cranial Radiation For Glioblastoma Multiforme

Patient Population:
- Histology-confirmed glioblastoma multiforme
- Tumor supratentorial in location
- Therapy begins within five weeks of surgery (but within one week after registration)
- No prior chemotherapy, radiotherapy to the head and neck, or radiosensitizer
- Age > 18 years
- Karnofsky Performance Status > 50%
- Neurologic functional status 0, 1, or 2
- Hemoglobin > 10 g/dL, absolute neutrophil count > 1500/mm³, platelets > 100,000/mm³
- BUN < 25 mg/dL and creatinine < 1.5 mg/dL
- Bilirubin < 1.5 mg/dL and SGPT or SGOT < twice normal range
- Normal chest x-ray
- Signed study-specific informed consent

Objective:

1. To compare survival of GBM patients receiving topotecan and radiotherapy with appropriately matched patients treated in prior RTOG studies.

2. To assess tumor response in patients with measurable disease post-operatively.

3. To determine progression-free survival.

4. To determine acute and late treatment-related toxicities.

Schema:

* 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 (margin of 2.5 cm if no edema is present)

** 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.

Study Chairs:	David Macdonald, M.D. (Medical Oncology)	Total Patients Entered: 87
	Barbara Fisher, M.D. (Radiation Oncology)

Reference: Fisher B, Won M, et al. Phase II Study of Topotecan plus Cranial Radiation for Glioblastoma Multiforme: Results of Radiation Therapy Oncology Group RTOG 95-13. Int J Radiat Onco Biol Phys, 53:980-986, 2002.

Purpose: A Phase II trial was conducted by the Radiation Therapy Oncology Group (RTOG) to compare the survival of patients with glioblastoma multiforme treated with topotecan combined with standard cranial radiotherapy (RT) for matched patients treated in prior RTOG studies. A secondary objective was to document the acute and late toxicities of this combination of chemotherapy and RT.

Methods and Materials: Eighty-seven patients with histologically confirmed glioblastoma multiforme received standard cranial RT (60 Gy/30 fractions in 6 weeks) plus topotecan 1.5 mg/m2 per day i.v. for 5 d/wk every 3 weeks for 3 cycles. Eighty-four patients were evaluated, of whom 60 (71%) were > 50 years, 44 (52%) were men, and 61 (73%) had a Karnofsky performance status of > 80. Twenty-nine percent of patients had undergone biopsies, 48% partial resections, and 21% gross total resections. Two resections were unspecified as to the extent of tumor removal. Fourteen percent of patients were recursive partitioning analysis Class III, 46% were Class IV, 35% were Class V, and 5% were Class VI.

Results: The median survival was 9.3 months. Sixty-seven patients (80%) had progression. The 1-year survival rate was 32%. One patient remained alive without recurrence. RTOG 9513 patients were matched with patients in an RTOG clinical trial database from previous clinical trials. The matching variables were age, Karnofsky performance status, mental status, and prior surgery. No statistically significant difference was found between the survival of the study patients and that of the matched patients from the RTOG database. Fifty-four percent of patients had Grade IV acute toxicity. The toxicity was primarily hematologic. Four patients had Grade III late central nervous system toxicities.

Conclusion: Topotecan administered at a dose of 1.5 mg/m2 per day i.v. for 5 d/wk every 3 weeks for 3 cycles given concurrently with standard cranial RT for glioblastoma does not produce a statistically significant survival advantage over previously tested therapies. Other methods of administration of topotecan or other camptothecins may provide more effective radiosensitization.