title: Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Medical Oncology Department, Instituto Nacional de Cancerología de México(INCan), San Fernando N22 Colonia Sección XVI, Tlalpan Mexico City, Mexico. ogar@servidor.unam.mx.
authors.forename: Luis L
authors.initials: LL
authors.lastname: Rojas-Puentes
authors.forename: Marcelino
authors.initials: M
authors.lastname: Gonzalez-Pinedo
authors.forename: Alejando
authors.initials: A
authors.lastname: Crismatt
authors.forename: Alette
authors.initials: A
authors.lastname: Ortega-Gomez
authors.forename: Carlos
authors.initials: C
authors.lastname: Gamboa-Vignolle
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Nuñez-Gomez
authors.forename: Yusmiren
authors.initials: Y
authors.lastname: Dorantes-Gallareta
authors.forename: Claudia
authors.initials: C
authors.lastname: Arce-Salinas
authors.forename: Oscar
authors.initials: O
authors.lastname: Arrieta
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000401:mortality / Q000556:secondary* / Q000628:therapy*; D059248:Chemoradiotherapy / Q000009:adverse effects / Q000379:methods*; D002738:Chloroquine / Q000627:therapeutic use*; D016371:Cranial Irradiation / Q000009:adverse effects / Q000379:methods*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011788:Quality of Life; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*
chemical_list: D011838:Radiation-Sensitizing Agents; D002738:Chloroquine