title: CONCURRENT WHOLE BRAIN RADIOTHERAPY AND SHORT-COURSE CHLOROQUINE IN PATIENTS WITH BRAIN METASTASES: A PILOT TRIAL.
abstract: OBJECTIVE
  The immune modulatory drug chloroquine (CQ) has been demonstrated to enhance survival following radiotherapy in patients with high-grade glioma in a clinical trial, but the efficacy in patients with brain metastases is unknown. We hypothesized that short-course CQ during whole brain radiotherapy (WBRT) would improve response to local therapy in patients with brain metastases.
  
  
  METHODS
  A prospective, single-cohort study was performed combining WBRT with concurrent CQ to assess both the feasibility of and intracranial response to combined therapy in patients with brain metastases. Safety, tolerability and overall survival of this combination was also examined, along with allelic status ofIDO2(indoleamine 2,3-dioxygenase 2), an immune modulatory enzyme inhibited by chloroquine that may affect survival outcomes. CQ therapy (250 mg by mouth daily) was initiated 1 week before WBRT (37.5 Gy in 2.5 Gy daily fractions) in patients with newly diagnosed brain metastases from biopsy-proven, primary lung, breast or ovarian solid tumors (n=20). The primary endpoint was radiologic response 3 months after combined CQ and WBRT therapy. Secondary endpoints included toxicity and overall survival. Patients were stratified byIDO2allelic status.
  
  
  RESULTS
  After a median clinical follow up of 5 months (range, 0.5-31), 16 patients were evaluable for radiologic response which was complete response in two patients, partial response in 13 patients and stable disease in one patient. There were no treatment-related grade≥3 toxicities or treatment interruption due to toxicity. Median and mean overall survival was 5.7 and 8.9 months, respectively (range, 0.8-31). A trend toward increased overall survival was observed in patients with wild-typeIDO2compared to patients with heterozygous or homozygous configurations that ablateIDO2enzyme activity (10.4 mos vs. 4.1 mos.; p=0.07).
  
  
  CONCLUSIONS
  WBRT with concurrent, short-course CQ is well tolerated in patients with brain metastases. The high intracranial disease control rate warrants additional study.
authors.affiliation: Department of Radiation Oncology, Lankenau Medical Center, Wynnewood PA 19096 USA [H.E., A.D.]; Lankenau Institute for Medical Research, Wynnewood PA 19096 USA [A.D., J.B.D., M.C., G.C.P.]; New Link Genetics Corporation, Ames IA 50010 USA [R.M.]; and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia PA 19107 USA [H.B.E., G.C.P.].
authors.forename: Harriet Belding
authors.initials: HB
authors.lastname: Eldredge
authors.forename: Albert
authors.initials: A
authors.lastname: Denittis
authors.forename: James B
authors.initials: JB
authors.lastname: Duhadaway
authors.forename: Michael
authors.initials: M
authors.lastname: Chernick
authors.forename: Richard
authors.initials: R
authors.lastname: Metz
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast
keywords: 3-dioxygenase (IDO); Whole brain radiotherapy; brain metastases; chloroquine; immunomodulation; immunotherapy; indoleamine 2; non-small cell lung cancer (NSCLC)