Motexafin gadolinium (MGd) combined with prompt whole brain radiation therapy (RT) prolongs time to neurologic progression in non-small cell lung cancer (NSCLC) patients with brain metastases: Results of a phase III trial.
Reviewer: John P. Plastaras, MD, PhD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 4, 2006
Presenter: Minesh P. Mehta Presenter's Affiliation: University of Wisconsin, Madison, WI Type of Session: Scientific
Motexafin gadolinium (MGd) is a radiosensitizer that is MRI-detectable and selectively localizes in tumors. It can induce redox stress and is an inhibitor of thioredoxin reductase, an enzyme whose overexpression is correlated with poor prognosis in NSCLC.
A subgroup analysis of a randomized trial showed that there was a time to neurologic progression (TNP) benefit from the addition of MGd to whole brain radiation (WBI) for metastatic NSCLC only (p=0.048)
That subgroup analysis prompted this randomized phase III trial of MGd in patients with intracranial NSCLC metastasis
Materials and Methods
Phase III study design:
International (34% USA, 29% Canada, Europe, Australia, etc.)
550 patients with NSCLC diagnosed with brain metastasis randomized to:
WBI (30 Gy in 10 fractions) vs. WBI + MGd, 5 mg/kg daily for 10 days
Criteria: KPS >=70. No liver metastasis or greater than 2 extracranial sites of metastasis
Primary: Time to neurologic progression (TNP) as assessed centrally
Secondary: TNP as assessed by physician, Time to neurocognitive progression
MGd was well-tolerated with >92% of intended doses given
most common adverse events were skin and urine discoloration
Analysis of TNP by intent to treat as measured from time from randomization showed a benefit from MGd that did not reach statistical significance
15.4 months (95% CI 10.7-24.2) for WBI + MGd vs. 10 months (95% CI 7.4-13.5) for WBI (p=0.12, HR 0.78)
Analysis of TNP as measured from time from diagnosis of brain metastasis showed a significant benefit from MGd (p=0.05)
It turned out that more patients in North America were randomized promptly after diagnosis of brain metastasis for planned WBI, however in the other geographic sites, there was a delay that was attributed to the practice of treating brain metastasis with chemotherapy before WBI (3% in North America vs. 32% in the rest of the world)
In the subset of North American patients (n=348), TNP was significantly delayed by MGd (8.8 months vs. 24.2 months, HR 0.53, p=0.004
In the subset of patients where WBI was initiated within 3 wks of diagnosis (n=378), TNP was significantly prolonged by MGd (HR 0.59, p=0.006)
In patients with a delay, the benefit from MGd disappeared
MGd significantly prolonged TNP in NSCLC patients with brain metastasis when combined with prompt WBI.
Once again, the study of MGd combined with WBI is plagued by a non-significant primary endpoint result, but a very intriguing subset analysis
There was a clear benefit of MGd in the subset of North American patients and promptly treated patients
The unanticipated, routine use of chemotherapy that delayed WBI initiation in non-North American sites hampered this study. This could have been prevented by mandating an interval between diagnosis and initiation of treatment, but it is difficult to predict all possible scenarios during study design.
This agent is being tested as a radiosensitizer in other CNS malignancies such as glioblastoma multiforme and pediatric tumors
Mar 14, 2011 - Surgical resection and whole brain radiation therapy of gastrointestinal brain metastases is associated with prolonged survival and improved quality of life, but survival is still lower compared to metastases arising from other tumors, according to a review published online Feb. 11 in Cancer.