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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 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.

SUBMITTER: Eldredge HB

PROVIDER: S-EPMC3810973 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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

Eldredge Harriet Belding HB Denittis Albert A Duhadaway James B JB Chernick Michael M Metz Richard R Prendergast George C GC

Journal of radiation oncology 20130901 3

<h4>Objective</h4>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.<h4>Methods</h4>A prospective, single-cohort study was performed combining WBRT with concurrent CQ to as ...[more]

PMID: 24187608

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Project description:Maintenance of quality of life is the primary goal during treatment of brain metastases (BM). This is a protocol of an ongoing phase III randomised multicentre study. This study aims to determine the exact additional palliative value of stereotactic radiosurgery (SRS) over whole brain radiotherapy (WBRT) in patients with 4-10 BM.The study will include patients with 4-10 BM from solid primary tumours diagnosed on a high-resolution contrast-enhanced MRI scan with a maximum lesional diameter of 2.5 cm in any direction and a maximum cumulative lesional volume of 30 cm3. Patients will be randomised between WBRT in five fractions of 4 Gy to a total dose of 20 Gy (standard arm) and single dose SRS to the BMs (study arm) in the range of 15-24 Gy. The largest BM or a localisation in the brainstem will determine the prescribed SRS dose. The primary endpoint is difference in quality of life (EQ5D EUROQOL score) at 3 months after radiotherapy with regard to baseline. Secondary endpoints are difference in quality of life (EQ5D EUROQOL questionnaire) at 6, 9 and 12 months after radiotherapy with regard to baseline. Other secondary endpoints are at 3, 6, 9 and 12 months after radiotherapy survival, Karnofsky ? 70, WHO performance status, steroid use (mg), toxicity according to CTCAE V4.0 including hair loss, fatigue, brain salvage during follow-up, type of salvage, time to salvage after randomisation and Barthel index. Facultative secondary endpoints are neurocognition with the Hopkins verbal learning test revised, quality of life EORTC QLQ-C30, quality of life EORTC BN20 brain module and fatigue scale EORTC QLQ-FA13.Worldwide, most patients with more than 4 BM will be treated with WBRT. Considering the potential advantages of SRS over WBRT, i.e. limiting radiation doses to uninvolved brain and a high rate of local tumour control by just a single treatment with fewer side effects, such as hair loss and fatigue, compared to WBRT, SRS might be a suitable alternative for patients with 4-10 BM.Trial registration number: NCT02353000 , trial registration date 15th January 2015, open for accrual 1st July 2016, nine patients were enrolled in this trial on 14th April 2017.

Project description:Treatment of glioblastoma xenografts with chloroquine results in macroautophagy/autophagy inhibition, resulting in a reduction of tumor hypoxia and sensitization to radiation. Preclinical data show that EGFRvIII-expressing glioblastoma may benefit most from chloroquine because of autophagy dependency. This study is the first to explore the safety, pharmacokinetics and maximum tolerated dose of chloroquine in combination with radiotherapy and concurrent daily temozolomide in patients with a newly diagnosed glioblastoma. This study is a single-center, open-label, dose-finding phase I trial. Patients received oral chloroquine daily starting one week before the course of chemoradiation (temozolomide 75 mg/m2/d) until the end of radiotherapy (59.4 Gy/33 fractions). Thirteen patients were included in the study (n = 6: 200 mg, n = 3: 300 mg, n = 4: 400 mg chloroquine). A total of 44 adverse events, possibly related to chloroquine, were registered including electrocardiogram QTc prolongation, irreversible blurred vision and nausea/vomiting resulting in cessation of temozolomide or delay of adjuvant cycles. The maximum tolerated dose was 200 mg chloroquine. Median overall survival was 16 months (range 2-32). Median survival was 11.5 months for EGFRvIII- patients and 20 months for EGFRvIII+ patients. A daily dose of 200 mg chloroquine was determined to be the maximum tolerated dose when combined with radiotherapy and concurrent temozolomide for newly diagnosed glioblastoma. Favorable toxicity and promising overall survival support further clinical studies.Abbreviations: AE: adverse events; CQ: chloroquine; DLT: dose-limiting toxicities; EGFR: epidermal growth factor receptor; GBM: glioblastoma; HCQ: hydroxychloroquine; IDH1/2: isocitrate dehydrogenase (NADP(+)) 1/2; MTD: maximum tolerated dose; CTC: National Cancer Institute Common Toxicity Criteria; MGMT: O-6-methylguanine-DNA methyltransferase; OS: overall survival; po qd: per os quaque die; SAE: serious adverse events; TMZ: temozolomide; WHO: World Health Organization.

Dataset Information

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

Publications

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

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