Combo Chemo Promising for Brain Metastasis

Roxanne Nelson

November 02, 2012

Combination chemotherapy appears to be effective for controlling brain metastasis in women with advanced breast cancer.

The combination of lapatinib plus capecitabine produced responses similar to those seen with whole-brain radiotherapy (WBRT), but without the associated neurologic adverse effects, according to the phase 2 LANDSCAPE study, published online ovember 2 in the Lancet Oncology.

Of the 44 patients who could be evaluated, 29 (65.9%) experienced an objective central nervous system (CNS) response (95% confidence interval [CI], 50.1 to 79.5), and 9 (20%) of these had a reduction in CNS volume of 80% or more. Overall, 37 patients (84%) had a reduction in tumor volume from baseline.

Because "women live longer with advanced cancer, the occurrence of brain metastases is becoming increasingly common," said lead study author Thomas Bachelot, MD, from the Centre Léon Bérard in Lyon, France, in a statement.

He pointed out that currently, 20% to 30% of women with advanced breast cancer develop secondary brain tumors, and those with HER2-positive disease seem to have the highest risk.

"Traditionally, most of these women receive WBRT, which can impair cognitive function," Dr. Bachelot explained. "Delaying such a treatment for those patients is potentially a big advance," he noted.

The median time to radiotherapy was 8.3 months (95% CI, 5.4 to 9.1) and, at the time the analysis was conducted, 36 (82%) patients had received radiation therapy to the brain. This is particularly relevant in a population with short overall survival, Dr. Bachelot noted, because it can help delay the substantial toxicities of radiotherapy.

"This strategy deserves further evaluation to confirm the clinical benefits in terms of survival, cognitive function, and quality of life," he said.

Might Be Valid Option

However, no information on quality of life or neurocognitive function was provided in the study, note Rupert Bartsch, MD, and Matthias Preusser, MD, both from the Medical University of Vienna in Austria, in an accompanying comment. That information would put the results of this trial in context.

"Furthermore, more than 40% of all patients did not present with neurological symptoms at baseline, which raises the question of whether screening for brain metastases was done and raises doubts about the feasibility of extrapolation of [the] findings to the general population of patients with symptomatic brain metastases," they write.

Another issue is treatment toxicity, Drs. Bartsch and Preusser note. Grade 3 or 4 adverse events were seen in about one fifth of patients receiving the combination, and dose reductions were necessary in a sizeable portion of patients.

Lapatinib and capecitabine might already be a valid treatment option. Drs. Rupert Bartsch and Matthias Preusser

However, with "due caution," they agree that for patients with "multiple brain metastases from HER2-positive breast cancer presenting with minimal clinical symptoms and good performance status, primary systemic treatment containing lapatinib and capecitabine might already be a valid treatment option."

Study Details

In this single-group phase 2 open-label multicenter study, Dr. Bachelot and colleagues assessed the therapeutic value of lapatinib plus capecitabine for previously untreated brain metastases in patients with HER2-positive breast cancer. The trial involved 45 such patients.

The study's primary end point was objective CNS response, defined as a "50% or greater volumetric reduction of CNS lesions in the absence of increased steroid use, progressive neurological symptoms, and progressive extra-CNS disease."

Participants were enrolled from April 2009 to August 2010, and received oral lapatinib 1250 mg every day and oral capecitabine 2000 mg/m² from day 1 to day 14 of a 21-day cycle. The median follow-up was 21.2 months.

Of the patients who experienced a response, the median time to the first documented response was 1.8 months (range, 1.1 to 5.8 months).

A total of 42 (96%) patients were evaluable for CNS response, according to Response Evaluation Criteria in Solid Tumors (RECIST); 2 (5%) had a complete response, 22 (52%) had a partial response, 15 (36%) had stable disease, and 3 (7%) had progressive disease.

Overall time to progression was 5.5 months, and was greater in patients who responded to treatment than in those who did not (6.0 vs 2.8 months). At 6 months, overall survival was 90.9% (95% CI, 77.6 to 96.5) and median overall survival for the evaluable patients was 17.0 months (95% CI, 13.7 to 24.9).

Adverse Events

About half the patients (49%) experienced at least 1 grade 3 or 4 adverse event, the most common being diarrhea and hand–foot syndrome. Four patients discontinued treatment because of adverse events and 14 experienced at least 1 serious adverse event. There were no deaths related to drug toxicity.

In addition, 16 patients required a lapatinib dose reduction and 26 required a capecitabine dose reduction.

"The combination of lapatinib and capecitabine — pending further clinical assessment to substantiate the clinical benefits — might change the management of selected patients with brain metastases, allowing delay to WBRT and its side-effects," conclude the authors. "This strategy deserves further assessment to confirm the clinical benefits for patients in terms of survival, cognitive function, and quality of life," they note.

This study was funded by GlaxoSmithKline-France and UNICANCER. Dr. Bachelot and coauthors Véronique Diéras, MD, from the Department of Medical Oncology at the Curie Institute in Paris, France, and Marta Jimenez, MSc, from UNICANCER in Paris, report relationships with GlaxoSmithKline-France.

Lancet Oncol. Published online November 2, 2012. Abstract, Comment