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. 2013 Sep 1;2(3):10.1007/s13566-013-0111-x.
doi: 10.1007/s13566-013-0111-x.

CONCURRENT WHOLE BRAIN RADIOTHERAPY AND SHORT-COURSE CHLOROQUINE IN PATIENTS WITH BRAIN METASTASES: A PILOT TRIAL

Harriet Belding Eldredge  1 , Albert Denittis, James B Duhadaway, Michael Chernick, Richard Metz, George C Prendergast
Affiliations

CONCURRENT WHOLE BRAIN RADIOTHERAPY AND SHORT-COURSE CHLOROQUINE IN PATIENTS WITH BRAIN METASTASES: A PILOT TRIAL

Harriet Belding Eldredge et al. J Radiat Oncol. .

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 of IDO2 (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 by IDO2 allelic 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-type IDO2 compared to patients with heterozygous or homozygous configurations that ablate IDO2 enzyme 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.

Keywords: 3-dioxygenase (IDO); Whole brain radiotherapy; brain metastases; chloroquine; immunomodulation; immunotherapy; indoleamine 2; non-small cell lung cancer (NSCLC).

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Conflict of interest statement

Conflict of interest Statement

George C. Prendergast reports a conflict of interest as an inventor and a compensated scientific advisor, grant recipient and shareholder in New Link Genetics Corporation, which has licensed IDO2 technology patented by the Lankenau Institute for Medical Research. James B. DuHadaway and Richard Metz report related conflicts as inventors and shareholders in New Link Genetics Corporation. Harriett Belding Eldredge, Albert DeNittis and Michael Chernick declare that they have no conflict of interest.

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