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Motexafin Gadolinium Slows Neurologic Deterioration from Brain Metastases: Presented at WCLC

By Norra MacReady

SEOUL, SOUTH KOREA -- September 10, 2007 -- Adding motexafin gadolinium (MGd) to whole brain radiation therapy (WBRT) for brain metastases of non-small cell lung cancer (NSCLC) can slow neurocognitive deterioration, according to data pooled from two randomised trials.

The analysis also showed performance on a simple memory test to be a good predictor of the patient's survival prognosis, according to Markus F. Renschler, MD, Adjunct Clinical Associate Professor, Stanford Cancer Center, Stanford University School of Medicine, Stanford, California, United States.

Dr. Renschler, an investigator for Pharmacyclics, Sunnyvale, California, the company that makes MGd, presented the findings here at the 12th World Conference on Lung Cancer (WCLC).

Motexafin gadolinium is a novel anticancer agent that targets tumours selectively and induces apoptosis by inhibiting the enzyme thioredoxin reductase.

There is a strong correlation between neurocognitive function and the volume, though not number, of brain lesions, explained Dr. Renschler. In other words, "the biggest enemy in your brain is the tumour, it's not the radiation therapy."

The analysis combined data from two international phase 3 clinical trials. The first (protocol 9801) involved 401 patients with brain metastases from any solid tumour. Only data from the 251 patients with NSCLC were included in this report. The second (protocol 0211), or the Study of Motexafin Gadolinium and Radiation Therapy (SMART), followed 554 patients, all with brain metastases from NSCLC.

All patients in both protocols received WBRT alone, for a total dose of 30 Grey in 10 fractions, or WBRT plus MGd, in a daily dose of 5 mg/kg for 10 days. At the time their metastases were diagnosed, and before undergoing either therapy, the patients completed a battery of five tests of memory, verbal fluency, and executive function. Depending on the protocol, they were re-tested monthly for 6 or 8 months, and then at 2- or 3-month intervals, until they showed evidence of neurological symptom progression.

Of the 805 patients in the two studies, 402 received MGd plus WBRT, and 403 underwent WBRT alone. At baseline, 77% of the patients had some degree of neurological deficit, with the deficits balanced across the treatment arms. Memory was the most frequently impaired function.

In protocol 9801, the median time to neurological progression for patients in the control arm was 7.4 months, while no progression was seen among those receiving MGd during the 15 months of follow-up specified in the study design (hazard ratio [HR] = 0.61, P =.048).

In the SMART study, the median time to neurological progression was 15.4 months among patients receiving MGd, compared with 10 months in the control group (HR = 0.78).

These findings did not reach statistical significance (p=0.12), but that was because some of the European investigators gave their patients additional chemotherapy during the study, Dr. Renschler explained. In an analysis of only North American patients, MGd was associated with a median time to progression of 24.2 months, compared with 8.8 months in the control group (HR = 0.53, P =.004).

In the pooled analysis, use of MGd was associated with a favourable HR of 0.80 in memory deterioration, compared with WBRT alone (P =.047), an HR of 0.74 for decline in executive function (P =.028), and an HR of 0.78 for deterioration in all tests combined (P =.02).

The most common adverse effect of MGd was skin and urine discoloration due to the drug's dark-green colour. Other than that, it was well-tolerated, Dr. Renschler said.

In general, impaired performance on more than three tests was a significant predictor of shorter survival (P =.014), with performance on the immediate memory portion of the Hopkins Verbal Learning Test having the single greatest predictive value (P <.001). This consists of reading a list of 12 words to the patient, then having him repeat back as many words as he remembers. The test is done three times, with three different lists of words.

"This [test] is something doctors can do in their practice, and it correlates with survival better than histology or any other kind of test," Dr. Renschler concluded.

[Presentation title: Decreased Neurocognitive Progression With Motexafin Gadolinium (MGd) Plus Whole Brain Radiation Therapy (WBRT) in Non-Small Cell Lung Cancer (NSCLC) Patients With Brain Metastases: Pooled Analysis of Two Randomized Phase 3 Trials. Abstract B1-07]

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