Glioblastoma multiforme (GBM) is 1 of the most aggressive neoplasms of the central nervous system. GBMs usually follow an aggressive course, and patients have a median survival of 8 months to 10 months.1 These tumors have a diffusely infiltrating nature. Therefore, all local therapies, such as surgery and radiation, are inherently palliative. Recently, there has been some improvement in the survival of patients with GBM with the use temozolamide along with postoperative radiotherapy.2 One of the important mechanisms of benefit from using radiotherapy and temozolamide is the radiopotentiation produced by temozolamide.3 When temozolamide was administered concurrently with radiotherapy and was continued after radiotherapy as adjuvant therapy, a large randomized trial demonstrated a small but significant survival benefit of 2.5 months compared with radiotherapy alone (median survival, 14.6 months vs 12.1 months). The benefit of temozolomide was maintained for 2 years after diagnosis, although only 27% of patients remained alive at that time.2
Some other agents also have been investigated in GBM with limited success. Recent studies have assessed the role of irinotecan (CPT-11) and bevacizumab (Avastin) as a novel combination for recurrent GBM.4 Fifty-one patients with recurrent, high-grade glioma were treated with this combination and were assessed in a very recent study. In that trial, the median progression-free survival was 13.4 months for patients with anaplastic gliomas and 7.6 months for patients with GBM.5
Loss of the phosphatase and tensin homolog (PTEN) gene, which is common in GBM, results in activation of the mammalian target of rapamycin (mTOR), thereby increasing messenger RNA translation of several key proteins required for cell-cycle progression. CCI-779 is an inhibitor of mTOR. In a phase 2 study, 43 patients with recurrent GBM received CCI-779 up to a weekly dose of 250 mg until the occurrence of unacceptable toxicity, tumor progression, or patient withdrawal. In that study, there were no episodes of grade 4 hematologic toxicities, and no toxic deaths were reported. One patient was progression free at 6 months. Of the patients in that study who were assessable for response, there were 2 partial responses, and 20 patients had stabilization of disease. The median time to disease progression was 9 weeks, and CCI-779 was tolerated well at that dose schedule.6
The other agent that has been assessed for its role in GBM is imatinib mesylate, an inhibitor of the receptor tyrosine kinase platelet-derived growth factor receptor, the proto-oncogene product c-kit, and the fusion protein Bcr-Abl. In a phase 1/2 study, the maximum tolerated dose and the dose-limiting toxicity of imatinib mesylate when administered for 8 days in combination with temozolomide to patients with malignant glioma (MG) were assessed. Patients with MG who had not failed on prior temozolamide were eligible to receive temozolamide at a dose from 150 mg/m2 daily to 200 mg/m2 daily on Days 4 through 8 plus imatinib mesylate administered orally on Days 1 through 8 of each 4-week cycle. Among patients with GBM who had stable disease at enrollment (n = 28), the median progression-free survival was 41.7 weeks, and the overall survival was 56.1 weeks. Imatinib doses up to 1000 mg daily for 8 consecutive days were tolerated well when combined with standard temozolamide dosing for patients with MG.7 It is readily apparent that, despite the promise demonstrated by several available agents, long-term disease control remains elusive.
Chloroquine is used commonly used in the treatment of malaria, a disease caused by infection with the parasite Plasmodium.8 Although chloroquine appears to possess diverse pharmacologic activity, its plasmodicidal activity results from augmentation of parasite oxidative stress. There are several decades of clinical experience with the use of chloroquine for the treatment of various parasitic and immune-mediated disorders, although its mechanism of action still is being revealed.8, 9
Chloroquine appears to augment oxidative stress in metabolically active mammalian cells, including human astroglial cells. It has been suggested that chloroquine may augment oxidative stress induced by radiotherapy in the treatment of GBM.6 The other main actions of chloroquine responsible for most intracellular actions are 1) molecular intercalation of chloroquine into DNA and 2) inhibition of lysosomic enzymes, particularly phospholipase A2. Configurational changes in nucleic acids render neoplastic cells more susceptible to the cytotoxic effects of radiotherapy as well as chemotherapy.10–12 The lysosomotropic properties of chloroquine are the most important for many of the biologic effects of this drug, including radiosensitisation. Because of its weak base properties, chloroquine accumulates in several intracellular organelles and raises intravesicular pH.13 Chloroquine could damage cells in which lysosomal permeability has been increased by radiation and, thus, could cause the release of proteolytic enzymes, which damage cellular proteins, including plasma membrane-associated proteins (Figs. 1, 2). Furthermore, chloroquine could sequester important cell membrane constituents, such as ceramides, in lysosomes, thus limiting plasma membrane repair.14
Interesting clinical data about clinical experience with chloroquine as adjuvant in the treatment of GBM are emerging. Sotelo and colleagues conducted a randomized, double-blind, placebo-controlled trial among patients with pathologically confirmed GBM. Of 18 patients with GBM who underwent standard treatment with surgery, chemotherapy, and radiotherapy, 9 patients received an additional 150-mg dose of chloroquine daily starting 1 day after surgery and continued through the observation period. Follow-up in that study ranged from 24 months to 50 months, and survival was the main outcome measure. Survival was significantly longer in chloroquine-treated patients than in the control group (33 months vs 11 months, respectively; P = .0002). At the end of the observation period, 4 patients (46%) who received chloroquine were alive: Two patients had evidence of tumor remission after 2 years; and, in the other 2 patients, tumor recurrence developed after 2 years and 4 years in remission, respectively. No control patients survived for >22 months after surgery.15
In another relevant study, 41 patients with GBM received chloroquine as an optional adjuvant administered concurrently with conventional surgery, chemotherapy, and radiotherapy. Eighty-two contemporary patients with GBM who did not receive chloroquine were included in that analysis as a control group. Radiotherapy was divided into 30 doses of 60 grays. Chemotherapy with 6 courses of carmustine was given starting 3 months after surgery. Patients who were treated with chloroquine took the drug for 12 months to 18 months at a daily dose of 150 mg starting on Day 15 after their surgery. Survival in the patients who received chloroquine was 25 ± 3.4 months compared with 11.4 ± 1.3 months in the control group (P = .000; odds ratio, 0.4; 95% confidence interval, 0.26-0.6); the difference remained significant after regression analysis for possible clinical confounders.16
A critical feature is the need for protracted use of chloroquine in GBM therapy. Fortunately, there has been relatively good experience of use of chloroquine for prolonged periods as well in chronic diseases. Daily doses of chloroquine up to 500 mg daily for prolonged periods are tolerated well in patients with human immunodeficiency virus-1/acquired immunodeficiency syndrome or rheumatoid arthritis.17 Although this prolonged administration of chloroquine does result in certain side effects, it would be of limited importance in a disease like GBM, in which the median survival is approximately 1 year to 1.5 years.
The use of chloroquine as adjuvant therapy for patients with GBM needs to be tested in large prospective trials. This would be a highly cost effective strategy for patients who cannot afford temozolamide. In addition, it may benefit patients on chemoradiation who are receiving temozolamide in view of the consequent chemosensitization. Therefore, chloroquine has the potential to open new frontiers in the treatment of glial neoplasms, because it has the unique features of a well studied side-effects profile, it is inexpensive, and it is easily available. Harnessing its potential for achieving therapeutic gain would be the real challenge.