Top

Published in:

01-09-2013 | Original Research

Concurrent whole brain radiotherapy and short-course chloroquine in patients with brain metastases: a pilot trial

Authors: Harriet B. Eldredge, Albert DeNittis, James B. DuHadaway, Michael Chernick, Richard Metz, George C. Prendergast

Published in: Journal of Radiation Oncology | Issue 3/2013

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 were 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 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 vs. 4.1 months; 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.

Gavrilovic IT, Posner JB (2005) Brain metastases: epidemiology and pathophysiology. J Neurooncol 75(1):5–14PubMedCrossRef

Delattre JY et al (1988) Distribution of brain metastases. Arch Neurol 45(7):741–744PubMedCrossRef

Nussbaum ES et al (1996) Brain metastases. Histology, multiplicity, surgery, and survival. Cancer 78(8):1781–1788PubMedCrossRef

Posner JB (1978) Neurologic complications of systemic cancer. Dis Mon 25(2):1–60PubMedCrossRef

Videtic GM et al (2009) American College of Radiology appropriateness criteria on multiple brain metastases. Int J Radiat Oncol Biol Phys 75(4):961–965PubMedCrossRef

Lagerwaard FJ et al (1999) Identification of prognostic factors in patients with brain metastases: a review of 1,292 patients. Int J Radiat Oncol Biol Phys 43(4):795–803PubMedCrossRef

Lutterbach J, Bartelt S, Ostertag C (2002) Long-term survival in patients with brain metastases. J Cancer Res Clin Oncol 128(8):417–425PubMedCrossRef

Gaspar L et al (1997) Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37(4):745–751PubMedCrossRef

Sperduto CM et al (2008) A validation study of a new prognostic index for patients with brain metastases: the Graded Prognostic Assessment. J Neurosurg 109(Suppl):87–89PubMed

10.

Sperduto PW et al (2010) Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys 77(3):655–661PubMedCrossRef

11.

Kim EL et al (2010) Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells. Neuro Oncol 12(4):389–400PubMedCrossRef

12.

Briceno E, Calderon A, Sotelo J (2007) Institutional experience with chloroquine as an adjuvant to the therapy for glioblastoma multiforme. Surg Neurol 67(4):388–391PubMedCrossRef

13.

Sotelo J, Briceno E, Lopez-Gonzalez MA (2006) Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 144(5):337–343PubMedCrossRef

14.

Hou DY et al (2007) Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res 67(2):792–801PubMedCrossRef

15.

Metz R et al (2007) Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor IDO inhibitory compound D-1MT. Cancer Res 67:7082–7087PubMedCrossRef

16.

Katz JB et al (2008) Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev 222:206–221PubMedCrossRef

17.

Munn DH, Mellor AL (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117(5):1147–1154PubMedCrossRef

18.

Smith C et al (2012) IDO Is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov 2(8):722–735PubMedCrossRef

19.

Andrews DW et al (2004) Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 363(9422):1665–1672PubMedCrossRef

20.

Kondziolka D et al (1999) Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 45(2):427–434PubMedCrossRef

21.

Eisenhauer EA et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247PubMedCrossRef

22.

Ben-Zvi I et al (2012) Hydroxychloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol 42(2):145–153PubMedCrossRef

23.

Munshi A et al (2008) Unusual intensification of skin reactions by chloroquine use during breast radiotherapy. Acta Oncol 47(2):318–319PubMedCrossRef

24.

Rustogi A, Munshi A, Jalali R (2006) Unexpected skin reaction induced by radiotherapy after chloroquine use. Lancet Oncol 7(7):608–609PubMedCrossRef

25.

Borgelt B et al (1981) Ultra-rapid high dose irradiation schedules for the palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 7(12):1633–1638PubMedCrossRef

26.

Davey P et al (2008) A phase III study of accelerated versus conventional hypofractionated whole brain irradiation in patients of good performance status with brain metastases not suitable for surgical excision. Radiother Oncol 88(2):173–176PubMedCrossRef

27.

Haie-Meder C et al (1993) Results of a randomized clinical trial comparing two radiation schedules in the palliative treatment of brain metastases. Radiother Oncol 26(2):111–116PubMedCrossRef

28.

Murray KJ et al (1997) A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiat Oncol Biol Phys 39(3):571–574PubMedCrossRef

29.

Antonadou D et al (2002) Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol 20(17):3644–3650PubMedCrossRef

30.

DeAngelis LM et al (1989) The combined use of radiation therapy and lonidamine in the treatment of brain metastases. J Neurooncol 7(3):241–247PubMedCrossRef

31.

Eyre HJ et al (1984) Randomized trial of radiotherapy versus radiotherapy plus metronidazole for the treatment metastatic cancer to brain. A Southwest Oncology Group study J Neurooncol 2(4):325–330

32.

Komarnicky LT et al (1991) A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases (RTOG-7916). Int J Radiat Oncol Biol Phys 20(1):53–58PubMedCrossRef

33.

Phillips TL et al (1995) Results of a randomized comparison of radiotherapy and bromodeoxyuridine with radiotherapy alone for brain metastases: report of RTOG trial 89–05. Int J Radiat Oncol Biol Phys 33(2):339–348PubMedCrossRef

34.

Mehta MP et al (2009) Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial. Int J Radiat Oncol Biol Phys 73(4):1069–1076PubMedCrossRef

35.

Scott C et al (2007) Improved survival, quality of life, and quality-adjusted survival in breast cancer patients treated with efaproxiral (Efaproxyn) plus whole-brain radiation therapy for brain metastases. Am J Clin Oncol 30(6):580–587PubMedCrossRef

36.

Suh JH et al (2006) Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. J Clin Oncol 24(1):106–114PubMedCrossRef

37.

Jensen PB, Sehested M (1997) DNA topoisomerase II rescue by catalytic inhibitors: a new strategy to improve the antitumor selectivity of etoposide. Biochem Pharmacol 54(7):755–759PubMedCrossRef

38.

Sorensen M, Sehested M, Jensen PB (1997) pH-dependent regulation of camptothecin-induced cytotoxicity and cleavable complex formation by the antimalarial agent chloroquine. Biochem Pharmacol 54(3):373–380PubMedCrossRef

39.

Amaravadi RK et al (2011) Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res 17(4):654–666PubMedCrossRef

Title: Concurrent whole brain radiotherapy and short-course chloroquine in patients with brain metastases: a pilot trial
Authors: Harriet B. Eldredge
Albert DeNittis
James B. DuHadaway
Michael Chernick
Richard Metz
George C. Prendergast
Publication date: 01-09-2013
Publisher: Springer Berlin Heidelberg
Published in: Journal of Radiation Oncology / Issue 3/2013
Print ISSN: 1948-7894
Electronic ISSN: 1948-7908
DOI: https://doi.org/10.1007/s13566-013-0111-x

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objective

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2013

Timing and duration of 5-HT3 receptor antagonist therapy for the prophylaxis of radiotherapy-induced nausea and vomiting: a systematic review of randomized and non-randomized studies

Patient surveillance after cancer treatment by Johnson et al.

Report on revision of the Chinese 1992 staging system for nasopharyngeal carcinoma

Lack of association between COX-2 staining level and biochemical recurrence following salvage radiation therapy for recurrent prostate cancer

Assessment of intact cervix motion using implanted fiducials in patients treated with helical tomotherapy with daily MVCT positioning

A review of low-level ionizing radiation and risk models of leukemia

Keynote webinar | Spotlight on antibody–drug conjugates in cancer