Lead-In Phase to Randomized Trial of Motexafin Gadolinium and Whole-Brain Radiation for Patients With Brain Metastases: Centralized Assessment of Magnetic Resonance Imaging, Neurocognitive, and Neurologic End Points

2002 ◽  
Vol 20 (16) ◽  
pp. 3445-3453 ◽  
Author(s):  
Minesh P. Mehta ◽  
William R. Shapiro ◽  
Michael J. Glantz ◽  
Roy A. Patchell ◽  
Michael A. Weitzner ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Radiation Therapy ◽  
Brain Metastases ◽  
Response Rate ◽  
Resonance Imaging ◽  
End Points ◽  
Motexafin Gadolinium ◽  
Whole Brain Radiation ◽  
Neurocognitive Tests ◽  
Brain Radiation

PURPOSE: Motexafin gadolinium is a redox mediator that selectively targets tumor cells, is detectable by magnetic resonance imaging (MRI), and enhances the effect of radiation therapy. This lead-in phase to a randomized trial served to evaluate radiologic, neurocognitive, and neurologic progression end points and to evaluate the safety and radiologic response of motexafin gadolinium administered concurrently with 30 Gy in 10-fraction whole-brain radiation therapy for the treatment of brain metastases. PATIENTS AND METHODS: Motexafin gadolinium (5.0 mg/kg/d for 10 days) was administered before each radiation treatment in this prospective international trial. Patients were evaluated by MRI, neurologic examinations, and neurocognitive tests. Prospective criteria and centralized review procedures were established for radiologic, neurocognitive, and neurologic progression end points. RESULTS: Twenty-five patients with brain metastases from lung (52%) and breast (24%) cancer, recursive partitioning analysis class 2 (96%), and an average of 11 brain metastases were enrolled. Neurocognitive function was highly impaired at presentation. Motexafin gadolinium was well tolerated. Freedom from neurologic progression was 77% at 1 year. Median survival was 5.0 months. In 29% of patients, the cause of death was brain metastasis progression. The radiologic response rate was 68%. Motexafin gadolinium’s tumor selectivity was established with MRI. CONCLUSION: (1) Centralized neurologic progression scoring that incorporated neurocognitive tests was implemented successfully. (2) Motexafin gadolinium was well tolerated. (3) Local control, measured by radiologic response rate, neurologic progression, and death caused by progression of brain metastasis, seemed to be improved compared with historical results. A randomized phase III trial using these methods for evaluation of efficacy has just been completed.

Survival and Neurologic Outcomes in a Randomized Trial of Motexafin Gadolinium and Whole-Brain Radiation Therapy in Brain Metastases

2003 ◽  
Vol 21 (13) ◽  
pp. 2529-2536 ◽  
Author(s):  
Minesh P. Mehta ◽  
Patrick Rodrigus ◽  
C.H.J. Terhaard ◽  
Aroor Rao ◽  
John Suh ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Radiation Therapy ◽  
Brain Metastases ◽  
Randomized Trial ◽  
Cancer Patients ◽  
Treatment Benefit ◽  
Motexafin Gadolinium ◽  
Lung Cancer Patients ◽  
Whole Brain Radiation ◽  
Brain Radiation

Purpose: This phase III randomized trial evaluated survival as well as neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). Patients and Methods: Patients were randomly assigned to 30 Gy of WBRT ± 5 mg/kg/d MGd. Survival and time to neurologic progression determined by a blinded events review committee (ERC) were coprimary end points. Standardized investigator neurologic assessment and neurocognitive testing were evaluated. Results: Four hundred one (251 non–small-cell lung cancer) patients were enrolled. There was no significant difference by treatment arm in survival (median, 5.2 months for MGd v 4.9 months for WBRT; P = .48) or time to neurologic progression (median, 9.5 months for MGd v 8.3 months for WBRT; P = .95). Treatment with MGd improved time to neurologic progression in patients with lung cancer (median, not reached for MGd v 7.4 months for WBRT; P = .048, unadjusted). By investigator, MGd improved time to neurologic progression in all patients (median, 4.3 months for MGd v 3.8 months for WBRT; P = .018) and in lung cancer patients (median, 5.5 months for MGd v 3.7 months for WBRT; P = .025). MGd improved neurocognitive function in lung cancer patients. Conclusion: The overall results did not demonstrate significant differences by treatment arm for survival and ERC time to neurologic progression. Investigator neurologic assessments demonstrated an MGd treatment benefit in all patients. In lung cancer patients, ERC- and investigator-determined time to neurologic progression demonstrated an MGd treatment benefit. MGd may improve time to neurologic and neurocognitive progression in lung cancer.

Motexafin gadolinium (MGd) combined with whole brain radiation therapy prolongs time to neurologic progression in non- small cell lung cancer (NSCLC) patients with brain metastases: Pooled analysis of two randomized phase III trials

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2010-2010
Author(s):  
W. R. Shapiro ◽  
M. P. Mehta ◽  
C. Langer ◽  
A. Bezjak ◽  
R. Timmerman ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Brain Metastases ◽  
Pooled Analysis ◽  
Whole Brain Radiation Therapy ◽  
Phase Iii ◽  
Whole Brain ◽  
Motexafin Gadolinium ◽  
Whole Brain Radiation ◽  
Nsclc Patients ◽  
Brain Radiation

2010 Background: In 2 randomized trials, whole brain radiation therapy (RT) plus MGd prolonged time to neurologic progression (TNP) in NSCLC patients (pts) with brain metastases (BM). In this report, results of a pooled analysis from both trials are presented. Methods: In trial 9801, 401 pts with BM from solid tumors were randomized to RT (30 Gy) or RT+MGd, 5 mg/kg qd x 10 days. The subgroup of 251 pts with NSCLC is included in this analysis. In trial 0211, 554 pts with BM from NSCLC were randomized to the same treatments. In both trials, eligibility included a KPS = 70, no liver metastases, and = 1 site of extracranial metastasis. In both trials, a primary endpoint was time to neurologic progression determined by a blinded events review committee (ERC), incorporating data from neurologic exams, neurologic symptom collection, and neurocognitive tests. Results: 805 pts received RT (N=403) or RT+MGd (N=402). Most pts had multiple BM (80%), extracranial metastases (47%) and presented with neurologic deficits (84%). Treatment with MGd was well tolerated, with 93.3% of intended doses administered. Most common MGd-related grade 3+ adverse events were hypertension (4.6%), and fatigue (2.8%). TNP in the RT+MGd group was 15.4 mo, significantly longer than the 9.0 mo for the RT alone group, p=0.016, HR=0.74 (95% CI 0.57–0.95). The results of both studies are consistent, as shown in the table below. Similar results were observed in time to investigator-determined neurologic progression (p=0.015, HR=0.76) and time to neurocognitive progression (memory: HR=0.80, p=0.047, executive function: HR=0.74, p=0.028, all tests combined: HR=0.78, p=0.020). Conclusions: Motexafin gadolinium significantly prolonged time to neurologic progression and neurocognitive progression in NSCLC patients with brain metastases undergoing whole brain radiation therapy in a pooled analysis of 2 randomized phase III trials. [Table: see text] No significant financial relationships to disclose.

Neurocognitive Function and Progression in Patients With Brain Metastases Treated With Whole-Brain Radiation and Motexafin Gadolinium: Results of a Randomized Phase III Trial

2004 ◽  
Vol 22 (1) ◽  
pp. 157-165 ◽  
Author(s):  
Christina A. Meyers ◽  
Jennifer A. Smith ◽  
Andrea Bezjak ◽  
Minesh P. Mehta ◽  
James Liebmann ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Executive Function ◽  
Brain Metastases ◽  
Phase Iii ◽  
Fine Motor ◽  
Whole Brain ◽  
Motexafin Gadolinium ◽  
Whole Brain Radiation ◽  
Neurocognitive Tests ◽  
Brain Radiation

Purpose To report the neurocognitive findings in a phase III randomized trial evaluating survival and neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). Patients and Methods Patients were randomly assigned to receive WBRT 30 Gy in 10 fractions with or without MGd 5 mg/kg/d. Monthly neurocognitive testing for memory, executive function, and fine motor skill was performed. Results Four hundred one patients were enrolled (251 with non–small-cell lung cancer, 75 with breast cancer, and 75 with other cancers); 90.5% patients had impairment of one or more neurocognitive tests at baseline. Neurocognitive test scores of memory, fine motor speed, executive function, and global neurocognitive impairment at baseline were correlated with brain tumor volume and predictive of survival. There was no statistically significant difference between treatment arms in time to neurocognitive progression. Patients with lung cancer (but not other types of cancer) who were treated with MGd tended to have improved memory and executive function (P = .062) and improved neurologic function as assessed by a blinded events review committee (P = .048). Conclusion Neurocognitive tests are a relatively sensitive measure of brain functioning; a combination of tumor prognostic variables and brain function assessments seems to predict survival better than tumor variables alone. Although the addition of MGd to WBRT did not produce a significant overall improvement between treatment arms, MGd may improve memory and executive function and prolong time to neurocognitive and neurologic progression in patients with brain metastases from lung cancer.

Incidence, timing, and treatment of new brain metastases after Gamma Knife surgery for limited brain disease: the case for reducing the use of whole-brain radiation therapy

2011 ◽  
Vol 115 (1) ◽  
pp. 37-48 ◽  
Author(s):  
Stephen Rush ◽  
Robert E. Elliott ◽  
Amr Morsi ◽  
Nisha Mehta ◽  
Jeri Spriet ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Brain Metastases ◽  
Gamma Knife ◽  
Gamma Knife Surgery ◽  
Whole Brain Radiation Therapy ◽  
Leptomeningeal Disease ◽  
Whole Brain ◽  
Whole Brain Radiation ◽  
Brain Radiation

Object In this paper, the authors' goal was to analyze the incidence, timing, and treatment of new metastases following initial treatment with 20-Gy Gamma Knife surgery (GKS) alone in patients with limited brain metastases without whole-brain radiation therapy (WBRT). Methods A retrospective analysis of 114 consecutive adults (75 women and 34 men; median age 61 years) with KPS scores of 60 or higher who received GKS for 1–3 brain metastases ≤ 2 cm was performed (median lesion volume 0.35 cm3). Five patients lacking follow-up data were excluded from analysis. After treatment, patients underwent MR imaging at 6 weeks and every 3 months thereafter. New metastases were preferentially treated with additional GKS. Indications for WBRT included development of numerous metastases, leptomeningeal disease, or diffuse surgical-site recurrence. Results The median overall survival from GKS was 13.8 months. Excluding the 3 patients who died before follow-up imaging, 12 patients (11.3%) experienced local failure at a median of 7.4 months. Fifty-three patients (50%) developed new metastases at a median of 5 months. Six (7%) of 86 instances of new lesions were symptomatic. Most patients (67%) with distant failures were successfully treated using salvage GKS alone. Whole-brain radiotherapy was indicated in 20 patients (18.3%). Thirteen patients (11.9%) died of neurological disease. Conclusions For patients with limited brain metastases and functional independence, 20-Gy GKS provides excellent disease control and high-functioning survival with minimal morbidity. New metastases developed in almost 50% of patients, but additional GKS was extremely effective in controlling disease. Using our algorithm, fewer than 20% of patients required WBRT, and only 12% died of progressive intracranial disease.

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