Chloroquine as an Adjunctive Therapy for Glioblastoma

Abstract & Commentary

By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: Based upon preclinical in vitro and in vivo studies that exhibit a more prolonged susceptibility of glioma cells to chemotherapy with the adjunctive chloroquine, a small but randomized placebo-controlled trial was conducted. The addition of daily chloroquine for one year after surgery was associated with a trend for reduced deaths in patients who received chemotherapy and radiation when compared to similarly treated patients but without chloroquine. These intriguing findings warrant large-scale investigation.

Source: Sotelo J, et al. Adding chloroquine to conventional treatment for glioblastoma multiforme. Ann of Intern Med. 2006; 144:337-343.

Patients with glioblastoma multiforme continue to have a very poor prognosis despite the common use of aggressive combination therapy with surgery, chemotherapy, and radiation. Most recent studies, for example, report a median survival of approximately one year after therapy.1,2 The infiltrative nature of this tumor combined with the presence of inherently resistant or readily acquired chemo- and/or radiotherapy resistant cells, make it a particularly challenging cancer to effectively treat. The development of resistant clones may be facilitated by the high rate of mutagenesis in glial cells exposed to ionizing radiation or chemotherapy.3,4

Sotelo and colleagues at the National Institute of Neurology and Neurosurgery in Mexico have previously shown that cultured glioblastoma cells exposed to chloroquine or quinacrine in vitro maintain sensitivity to carmustine for longer duration and, in a rat model of malignant glioma, both chloroquine and quinacrine potentiate the antineoplastic effect of carmustine.5

Based on these experimental findings, their group conducted a preliminary, open-label, non-randomized trial on patients with glioblastoma multiforme who were being treated by conventional methods but with added chloroquine. For comparison, concurrently treated patients who were treated with conventional therapy alone (no added chloroquine) were followed. Survival was found to be significantly longer for the chloroquine-treated patients.6

Encouraged by these preliminary findings the current study was conducted. It was a double-blind, placebo-controlled trial to evaluate the effect of chloroquine as adjuvant therapy for people with glioblastoma multiforme who were otherwise treated by conventional surgery, radiation and chemotherapy. The study period extended for 40 months from October 2000 through January 2004. To be enrolled, patients younger than 60 years with good performance status (Karnofsky scores of 70 or greater) and with MRI evidence that the tumor was restricted to one hemisphere were invited to participate. Thirty patients who met these criteria were enrolled and were treated by a standardized regimen of ablative surgery, four courses of carmustine and radiation (60 Gy administered over 30-32 treatments. In addition, 15 patients were randomized to receive 150 mg of chloroquine daily starting on day five after surgery for 12 months. The other 15 patients received placebo.

The chloroquine was well tolerated. There were no differences with regard to hematological toxicity when compared to placebo-treated patients. Furthermore, though of theoretical concern, no patients developed any signs of chloroquine-induced retinopathy. No patient from either group discontinued treatment or was lost to follow-up.

Median survival was 24 months for the patients in the chloroquine-treated group and 11 months for controls. At the end of the observation period, six patients treated with chloroquine had survived 59, 45, 30, 27, and 20 months respectively, whereas 3 patients from the control group had survived 32, 25, and 22 months respectively. Although the findings did not reach statistical significance (most certainly because the number of subjects enrolled was small), the rate of death with time was approximately half as large in patients receiving chloroquine as in patients receiving placebo (hazard ratio, 0.52 [95% confidence interval, 0.21-1.26]; P = 0.139).

Commentary

Every once in a while, significant advances occur from insightful extension and investigation of theoretically sound ideas. Certainly, for the treatment of glioblastoma multiforme, advances have been slow to come and are sorely needed. Thus, the group of investigators from Mexico, aware that antimalarial drugs such as chloroquine and quinacrine are strong DNA-intercalating agents with demonstrated antimuagenic activity, postulated that concurrent treatment would be associated with more sustained efficacy of adjuvant chemo- and radiation therapy by virtue of their inhibition of mutation-associated resistance. The results would seem to support this notion. Of course, the observed advantage of chloroquine treatment in this study could have been due to chance alone, as the study was too small to reach statistical confidence. Chloroquine, inexpensive and available generically, is an unlikely candidate for a large-scale pharma-supported clinical trial. Nonetheless, the potential for a meaningful clinical advance is high, and hopefully the cooperative groups will take note and proceed to a definitive, multi-site trial.

References

1. Lopez-Gonzales MA. Brain tumors in Mexico: characteristics and prognosis of glioblastoma. Surg Neurol. 2000;53:157-162.

2. Grossman SA, Batara JF. Current management of glioblastoma multiforme. Semin Oncol. 2004;31:635-644.

3. Kanazawa T, et al. Current and Future Gene Therapy for Malignant Gliomas. J Biomed Biotechnol. 2003;2003:25-34.

4. Souhami L, et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys. 2004;60:853-860.

5. Reyes S, et al. Quinacrine enhances carmustine therapy of experimental rat glioma. Neurosurgery. 2001;49:969-973.

6. Briceno E, et al. Therapy of glioblastoma multiforme improved by the antimutagenic chloroquine. Neurosurg Focus. 2003;14:e3.