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The addition of motexafin gadolinium to whole brain radiation therapy significantly prolongs time to neurologic progression in non-small cell lung cancer patients with brain metastases, according to pooled data from two randomized phase III trials.
Time to neurologic progression was 15.4 months compared with 9 months for those given radiation alone, said Dr. William R. Shapiro of the Barrow Neurological Institute, Phoenix.
Motexafin gadolinium (Xcytrin, Pharmacyclics Inc) selectively localizes in tumors and induces apoptosis by inhibiting thioredoxin reductase. The agent is in development for treating brain metastases in patients with non-small cell lung cancer (NSCLC), and a new drug application was filed with the U.S. Food and Drug Administration in April 2007 by the manufacturer, which sponsored the analysis.
The pooled data were derived from the phase III PCI-P120-9801 trial of patients with brain metastases from any solid tumor, and from the Study of Neurologic Progression with Motexafin Gadolinium And Radiation Therapy (SMART) trial of patients with brain metastases from NSCLC, and comprised a total of 805 patients. The PCI-P120-9801 was sponsored by Schering Plough, and SMART was sponsored by Pharmacyclics, which also sponsored the pooled data analysis.
Pooling data was necessary to derive statistical power. "Trials in brain metastases pose challenges because survival is short and a large percentage of patients die from systemic disease or medical complications," Dr. Shapiro said.
The primary end point was time to neurologic progression or death with evidence of neurologic progression, as determined by a blinded, centralized events review committee. Secondary end points were time to neurologic progression and time to neurocognitive progression.
Patients received whole brain radiation therapy of 30 Gy delivered in 10 fractions with or without motexafin gadolinium 5 mg/kg per day for 10 days.
Time to neurologic progression improved as determined by the review committee and by individual investigator, with P values of .016 and .015.
Time to neurocognitive progression also improved with motexafin gadolinium, with a P value equal to .02.
Skin discoloration occurred in 74%. "Patients turned a nice olive green, but this usually went away after 24 hours," Dr. Shapiro said. Other adverse effects were urine discoloration (41%), nausea and vomiting (32%), fatigue (30%), and hypertension (23%). For most, adverse events were grade 1 and 2.
Importantly, Dr. Shapiro added, motexafin gadolinium did not interfere with whole brain radiation therapy. Most patients (93%) received the full 10 days of motexafin gadolinium, and 99% received full radiation treatments.
However, there was no overall survival benefit. Dr. Shapiro observed that in the study of metastatic brain tumors, survival is not a good end point because lung cancer patients often die before they deteriorate neurologically.
Shapiro W.R. et al. 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. Abstract 2010.
Commentary |
Treatment of patients with brain metastases has been based on a foundation of surgery and radiotherapy. Additional interventions such as chemotherapy have not been particularly effective. Motexafin gadolinium (MGd), a radiosensitizer, has prolonged time to neurologic progression in two randomized phase III trials for patients with non-small cell lung cancer metastatic to the brain. This pooled analysis makes clear that time to neurologic progression and neurocognitive progression are significantly prolonged with MGd and whole-brain radiotherapy in patients with NSCLC metastatic to the brain. Other studies will be needed to determine if similar benefits are noted in patients with brain metastases and other histologies such as breast cancer and melanoma. — Henry S. Friedman, M.D.
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