title: Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial.
abstract: OBJECTIVE
  To determine the efficacy of motexafin gadolinium (MGd) in combination with whole brain radiotherapy (WBRT) for the treatment of brain metastases from non-small-cell lung cancer.
  
  
  METHODS
  In an international, randomized, Phase III study, patients with brain metastases from non-small-cell lung cancer were randomized to WBRT with or without MGd. The primary endpoint was the interval to neurologic progression, determined by a centralized Events Review Committee who was unaware of the treatment the patients had received.
  
  
  RESULTS
  Of 554 patients, 275 were randomized to WBRT and 279 to WBRT+MGd. Treatment with MGd was well tolerated, and 92% of the intended doses were administered. The most common MGd-related Grade 3+ adverse events included liver function abnormalities (5.5%), asthenia (4.0%), and hypertension (4%). MGd improved the interval to neurologic progression compared with WBRT alone (15 vs. 10 months; p = 0.12, hazard ratio [HR] = 0.78) and the interval to neurocognitive progression (p = 0.057, HR = 0.78). The WBRT patients required more salvage brain surgery or radiosurgery than did the WBRT+MGd patients (54 vs. 25 salvage procedures, p < 0.001). A statistically significant interaction between the geographic region and MGd treatment effect (which was in the prespecified analysis plan) and between treatment delay and MGd treatment effect was found. In North American patients, where treatment was more prompt, a statistically significant prolongation of the interval to neurologic progression, from 8.8 months for WBRT to 24.2 months for WBRT+MGd (p = 0.004, HR = 0.53), and the interval to neurocognitive progression (p = 0.06, HR = 0.73) were observed.
  
  
  CONCLUSIONS
  In the intent-to-treat analysis, MGd exhibited a favorable trend in neurologic outcomes. MGd significantly prolonged the interval to neurologic progression in non-small-cell lung cancer patients with brain metastases receiving prompt WBRT. The toxicity was acceptable.
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, WI 53792, USA.
authors.forename: Minesh P
authors.initials: MP
authors.lastname: Mehta
authors.forename: William R
authors.initials: WR
authors.lastname: Shapiro
authors.forename: See C
authors.initials: SC
authors.lastname: Phan
authors.forename: Radj
authors.initials: R
authors.lastname: Gervais
authors.forename: Christian
authors.initials: C
authors.lastname: Carrie
authors.forename: Pierre
authors.initials: P
authors.lastname: Chabot
authors.forename: Roy A
authors.initials: RA
authors.lastname: Patchell
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Glantz
authors.forename: Lawrence
authors.initials: L
authors.lastname: Recht
authors.forename: Corey
authors.initials: C
authors.lastname: Langer
authors.forename: Ranjan K
authors.initials: RK
authors.lastname: Sur
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Roa
authors.forename: Marc A
authors.initials: MA
authors.lastname: Mahe
authors.forename: Andre
authors.initials: A
authors.lastname: Fortin
authors.forename: Carsten
authors.initials: C
authors.lastname: Nieder
authors.forename: Christina A
authors.initials: CA
authors.lastname: Meyers
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Smith
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.forename: Markus F
authors.initials: MF
authors.lastname: Renschler
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000556:secondary / Q000628:therapy*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000532:radiotherapy / Q000556:secondary / Q000628:therapy*; D003072:Cognition Disorders / Q000175:diagnosis / Q000209:etiology; D003131:Combined Modality Therapy / Q000379:methods; D016371:Cranial Irradiation / Q000379:methods*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008665:Metalloporphyrins / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D016016:Proportional Hazards Models
chemical_list: D000970:Antineoplastic Agents; D008665:Metalloporphyrins; C437683:motexafin gadolinium