Could BEP Reduce the Risk of Brain Metastasis in Testicular Cancer?

Brain metastases are common among patients with poor-prognosis advanced non-seminomatous germ-cell tumors (GCTs) and might be more frequent among men who undergo dose-dense chemotherapy than those administered BEP (bleomycin, etoposide and cisplatin), according to a retrospective analysis of relapse events from the phase III GETUG 13 tumor marker–based personalized chemotherapy trial. The findings were published in the European Journal of Cancer.

“Brain metastases develop often, early, and frequently as the only site of relapse in the course of poor-prognosis GCT,” noted lead study author Yohann Loriot, MD, PhD, of the Institut Gustave Roussy and University of Paris-Saclay, Villejuif, in France. “These data suggest that dose-dense chemotherapy is better able to eradicate cancer cells in most tumor sites than BEP does.”

The findings spotlight the importance of early detection and optimal treatment of brain metastases in patients diagnosed with high-risk GCT, perhaps by integrating systematic brain MRI imaging following chemotherapy, the authors argued.

The GETUG 13 study enrolled 254 patients treated at cancer centers in the United States, France, and Slovakia. Patients were initially treated with BEP (intravenous cisplatin [20 mg/m2 per day for 5 days], etoposide [100 mg/m2 per day for 5 days], and intramuscular or intravenous bleomycin [30 mg per day on days 1, 8, and 15]), and subsequent treatment was based on tumor marker response. Between days 18 and 21, human chorionic gonadotropin (hCG) and alfa-fetoprotein concentrations were reassessed and those patients who had experienced a decline in hCG and alfa-fetoprotein continued BEP therapy for three additional cycles. Patients with an unfavorable decline were randomly assigned (1:1) to receive either BEP or a dose-dense regimen of intravenous paclitaxel, BEP, and oxaliplatin, followed by cisplatin and ifosfamide plus mesna and bleomycin, with supportive granulocyte-colony stimulating factor (lenograstim) therapy.

The authors analyzed relapse events among study patients. At a median follow-up of 4.1 years, 43% (109 of 254 patients) had experienced tumor marker or radiographic disease progression and 15 patients had died. Multivariate analyses found that death was associated with marker progression, radiographic progression, or both, within the first year after treatment initiation. Overall survival among patients experiencing relapse was not associated with treatment regimen.

Brain was the predominant site of metastasis (54%; 19 of 35 patients), the researchers reported. Among the 58 patients who had experienced unfavorable marker declines after day 18 of BEP treatment, 40% of those subsequently treated with cisplatin, bleomycin, and etoposide experienced brain metastasis, compared with 57% of those treated with dose-dense chemotherapy. Patients who had extravisceral metastases at baseline or mediastinal primary tumors were at higher risk of developing brain metastases, suggesting a distinct tumor biology, the authors noted.

“The current analysis suggested that among patients who experience a progression, the site may be more likely to be in the brain in patients treated with dose-dense chemotherapy (29% of progressions) than those treated with BEP (12% of progressions),” the authors noted.

It is not clear if this might be due to the reduced cerebral penetrance of cytotoxic chemotherapy agents or a more aggressive biology for GCT tumor cells that metastasize to the brain.

Brain MRI can detect small brain metastases and would hasten detection, the authors emphasized.

The analysis was retrospective and exploratory, the authors cautioned. But they noted that GETUG 13 was the largest clinical trial of patients with poor-prognosis GCT yet published.