Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases.

BACKGROUND AND PURPOSE: Chloroquine (CLQ), an antimalarial drug, has a lysosomotropic effect associated with increased radiationsensibility, which is mediated by the leakage of hydrolytic enzymes, increased apoptosis, autophagy and increased oxidative stress in vitro. In this phase II study, we evaluated the efficacy and safety of radiosensibilization using CLQ concomitant with 30 Gray (Gy) of whole-brain irradiation (WBI) to treat patients with brain metastases (BM) from solid tumors. METHODS: Seventy-three eligible patients were randomized. Thirty-nine patients received WBI (30 Gy in 10 fractions over 2 weeks) concomitant with 150 mg of CLQ for 4 weeks (the CLQ arm). Thirty-four patients received the same schedule of WBI concomitant with a placebo for 4 weeks (the control arm). All the patients were evaluated for quality of life (QoL) using the EORTC Quality of Life (QoL) Questionnaire (EORTC QLQ-C30) (Mexican version) before beginning radiotherapy and one month later. RESULTS: The overall response rate (ORR) was 54% for the CLQ arm and 55% for the control arm (p=0.92). The progression-free survival of brain metastases (BMPFS) rates at one year were 83.9% (95% CI 69.4-98.4) for the CLQ arm and 55.1% (95% CI 33.6-77.6) for the control arm. Treatment with CLQ was independently associated with increased BMPFS (RR 0.31,95% CI [0.1-0.9], p=0.046).The only factor that was independently associated with increased overall survival (OS) was the presence of< 4 brain metastases (RR 1.9, 95% CI [1.12-3.3], p=0.017). WBI was associated with improvements in cognitive and emotional function but also with worsened nausea in both patients groups. No differences in QoL or toxicity were found between the study arms. CONCLUSION: Treatment with CLQ plus WBI improved the control of BM (compared with the control arm) with no increase in toxicity; however, CLQ did not improve the RR or OS. A phase III clinical trial is warranted to confirm these findings.

Clinical features and prognostic factors in patients with carcinomatous meningitis secondary to breast cancer.

Prognosis in patients with carcinomatous meningitis (CM) is poor, and numerous prognostic factors for response and survival have been described, but remain controversial. In general, series are small and involve a heterogeneous type of solid neoplasms. The purpose of this study was to describe a series of patients with breast cancer-associated CM to determine the clinical features and prognostic factors associated with survival. We conducted a retrospective study on 49 patients diagnosed between January 2003 and December 2007 at the Instituto Nacional de Cancerología in Mexico City. CSF cytopathology samples were re-reviewed to confirm the diagnosis. Overall survival (OS) for patients with breast cancer with CM was 7 weeks. Factors independently associated with better OS included absence of encephalopathy at diagnosis (11 weeks versus 1 week; p = .036), low CSF protein content (15 versus 5 weeks; p = .022), and nontriple-negative receptor status in the primary breast cancer tumor (13 versus 3 weeks; p = .015). According to multivariate analysis, patients were divided into favorable and poor prognostic groups, with OS of 14 weeks and 2 weeks, respectively (p < .001). These factors can identify a subgroup of patients who are candidates for an intensive management approach.