MGd Plus Whole Brain Radiation Therapy Prolongs Time to Neurologic Progression of NSCLC Brain Metastases

November 1, 2006

Motexafin gadolinium (MGd, Xcytrin) combined with whole brain radiation therapy (WBRT) prolongs time to neurologic progression in non-small-cell lung cancer (NSCLC) patients with brain metastases if treatment starts within 3 weeks of the brain metastasis diagnosis, according to data from a phase III trial.

ATLANTA--Motexafin gadolinium(MGd, Xcytrin) combined withwhole brain radiation therapy (WBRT)prolongs time to neurologic progressionin non-small-cell lung cancer (NSCLC)patients with brain metastases if treatmentstarts within 3 weeks of the brainmetastasis diagnosis, according to datafrom a phase III trial. Minesh P. Mehta,MD, presented the results at the AmericanSociety of Clinical Oncology 42ndAnnual Meeting (abstract 7014).

All patients in the study, known asSMART (Study of Neurologic ProgressionWith Motexafin Gadolinium andRadiation Therapy), had NSCLC withbrain metastases. Patients were randomizedto receive WBRT 30 Gy in 10 fractionsor WBRT plus MGd 5 mg/kg/d for10 days.

Patients were seen monthly for 8months, then every 2 months, for standardizedneurologic examination andtreatstandardizedneurocognitive testing usinga battery of validated tests assessingmemory, verbal fluency, and executivefunction.

The time to neurologic progressionendpoint measured major decline in neurologicfunction, based on prespecifiedevents such as change in level of consciousness,aphasia/dysphasia/dysarthria,hemiparesis, new visual field defects,ataxia, cranial nerve palsy, and neurocognitiveprogression in all domains.

Patients were enrolled from centers inNorth America, Europe, and Australia.Most patients (81%) had multiple brainmetastases; 51% had extracranial metastases,and 84% presented with neurologicdeficits.

Overall, mean time from brain metastasesdiagnosis to randomization forthe MGd arm was 4.3 weeks vs 3.3 weeksfor controls, an imbalance that adverselyaffected outcomes in the MGd arm.

Time to Progression
Dr. Mehta reported that median timeto progression (as measured from randomization)in the intent-to-treat populationof 554 patients was 15.37 months in the MGd group vs 10.03 months inthe WBRT-alone group (HR 0.78,P = .12). Analyses correcting for the imbalancein treatment delay betweenthe two arms (by measuringfrom time of brain metastasisdiagnosis) showed that mediantime to neurologic progressionwas 15.53 months forthose receiving MGd/WBRTvs 10.2 months for controls (HR0.75, P = .05).

"We found that when treatment is delayed,time to neurologic progression isshorter," Dr. Mehta said. When treatment began within 4 weeks or less afterdiagnosis of brain metastasis, addingMGd significantly prolonged time to neurologicprogression (see Table).Dr. Mehta noted that this differencehas implications fordifferences in outcome in differentcountries. He said thatthe proportion of NSCLC patientsnot treated until 4 ormore weeks after brain metastasisdiagnosis ranges from 9.8% inNorth America to 41.3% in the rest ofthe world, including 56.4% in France.Further analysis showed that a major reason for delay of WBRT was use ofchemotherapy as initial treatment forbrain metastasis, Dr. Mehta said. Only1.7% of North American patients receivedsuch treatment vs 17.5% of patientsat other sites, including 21.4% inFrance.

A subgroup analysis of the 348 patientsfrom North American showed amedian time to neurologic progressionof 24.2 months with MGd/WBRT, comparedwith 8.8 months with WBRT alone(HR 0.53, P = .004).

Adverse Effects
The most common adverse effect ofMGd was minor skin discoloration,which affected 66% of patients. Grade3-4 adverse events were uncommon."Motexafin gadolinium was well toleratedand did not compromise the abilityto deliver radiation therapy," he said.

The investigators concluded that MGdprolonged time to neurologic progressionand that this was particularly apparentin patients randomized from NorthAmerican centers, who were more likelythan patients from some other countriesto have begun treatment within 4 weeksafter diagnosis of brain metastases.

"When initiation of RT was delayedbeyond 3 weeks after brain metastasis diagnosis,MGd benefit was lost," Dr.Mehta said.