title: A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104.
abstract: OBJECTIVE
  To compare 1-year survival and acute toxicity rates between an accelerated hyperfractionated (AH) radiotherapy (1.6 Gy b.i.d.) to a total dose of 54.4 Gy vs. an accelerated fractionation (AF) of 30 Gy in 10 daily fractions in patients with unresected brain metastasis.
  
  
  METHODS
  The Radiation Therapy Oncology Group (RTOG) accrued 445 patients to a Phase III comparison of accelerated hyperfractionation vs. standard fractionation from 1991 through 1995. All patients had histologic proof of malignancy at the primary site. Brain metastasis were measurable by CT or MRI scan and all patients had a Karnofsky performance score (KPS) of at least 70 and a neurologic function classification of 1 or 2. For AH, 32 Gy in 20 fractions over 10 treatment days (1.6 Gy twice daily) was delivered to the whole brain. A boost of 22.4 Gy in 14 fractions was delivered to each lesion with a 2-cm margin.
  
  
  RESULTS
  The average age in both groups was 60 years; nearly two-thirds of all patients had lung primaries. Of the 429 eligible and analyzable patients, the median survival time was 4.5 months in both arms. The 1-year survival rate was 19% in the AF arm vs. 16% in the AH arm. No difference in median or 1-year survival was observed among patients with solitary metastasis between treatment arms. Recursive partitioning analysis (RPA) classes have previously been identified and patients with a KPS of 70 or more, a controlled primary tumor, less than 65 years of age, and brain metastases only (RPA class I), had a 1-year survival of 35% in the AF arm vs. 25% in the AH arm (p = 0.95). In a multivariate model, only age, KPS, extent of metastatic disease (intracranial metastases only vs. intra- and extracranial metastases), and status of primary (controlled vs. uncontrolled) were statistically significant (at p < 0.05). Treatment assignment was not statistically significant. Overall Grade III or IV toxicity was equivalent in both arms, and one fatal toxicity at 44 days secondary to cerebral edema was seen in the AH arm.
  
  
  CONCLUSIONS
  Although a previous RTOG Phase I/II report had suggested a potential benefit in patients with limited metastatic disease, a good Karnofsky performance status, or neurologic function when treated with an AH regimen, this randomized comparison could not demonstrate any improvement in survival when compared to a conventional regimen of 30 Gy in 10 fractions. Therefore, this accelerated hyperfractionated regimen to 54.4 Gy cannot be recommended for patients with intracranial metastatic disease.
authors.affiliation: Medical College of Wisconsin, Milwaukee 53226, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Murray
authors.forename: C
authors.initials: C
authors.lastname: Scott
authors.forename: H M
authors.initials: HM
authors.lastname: Greenberg
authors.forename: B
authors.initials: B
authors.lastname: Emami
authors.forename: M
authors.initials: M
authors.lastname: Seider
authors.forename: N L
authors.initials: NL
authors.lastname: Vora
authors.forename: C
authors.initials: C
authors.lastname: Olson
authors.forename: A
authors.initials: A
authors.lastname: Whitton
authors.forename: B
authors.initials: B
authors.lastname: Movsas
authors.forename: W
authors.initials: W
authors.lastname: Curran
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000532:radiotherapy* / Q000556:secondary; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011832:Radiation Injuries / Q000453:epidemiology; D016019:Survival Analysis; D013997:Time Factors