Dose-dense temozolomide: is it still promising?

Abstract

Glioblastoma (GBM) has proven to be incurable despite recent progress on its standard of care using temozolomide (TMZ) as the main trunk of initial therapy for newly diagnosed GBM. One of the main reasons accounting for the dismal prognosis is attributed to lack of active therapeutic regimens at recurrence. Since TMZ is the most active cytotoxic agent against GBM, and the standard dosing of TMZ has shown favorable safety profile in clinical trials, re-challenge with TMZ in increased dose density schedules for recurrent tumors that have evaded from prior standard TMZ therapy appears to be a rational approach and has been intensively exploited. A number of phase II clinical trials using different alternating scheduling of dose-dense TMZ (ddTMZ) have shown superior efficacy over the standard TMZ or historical controls with other alkylating agents including nitrosoureas and procarbazine. One ddTMZ schedule, consisting of a 21-days on/7-days off regimen was applied to newly-diagnosed GBM as the adjuvant monotherapy after completion of combined radiation and TMZ and failed to demonstrate survival benefit in a large phase III trial (RTOG 0525). Thus its role in TMZ-pretreated, recurrent GBM should be carefully pursuit in randomized trials, e.g., planned JCOG 1308 trial comparing a 7-days on/7-days off ddTMZ regimen used upfront at the first relapse followed by bevacizumab on progression versus bevacizumab alone, investigating whether insertion of ddTMZ prior to bevacizumab could bestow better outcome in the recurrent setting. In this article, mode of action, past trials, and future directions of ddTMZ therapy are discussed.

Fig. 1

Molecular pathways of temozolomide (TMZ)-induced deoxyribonucleic acid (DNA) methylation and cytotoxic effects. TMZ preferentially methylates O⁶ positions of guanine residues in DNA (m), forming O⁶-methylguanine (O⁶-MG). At DNA replication, O⁶-MG mismatches to thymine (T) instead of cytosine (C), which is then repaired by the mismatch repair (MMR) system that removes the mismatched thymines. However, the O⁶-MG lesions remain in DNA, leading to repetition of MMR which then results in DNA double strand breaks and finally in cell death. A DNA repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT) specifically removes methyl adducts from O⁶-MG and repairs DNA to normal, thereby becomes inactivated itself and degraded through the ubiquitin system (suicide enzyme). MGMT proficient cells are thus resistant to TMZ. Alternatively, tumor cells may also become resistant if MMR system is deficit or inactivated, because of lack of DNA double strand break. Modified from the reference (Nagane, 2010).

Fig. 2

Approaches to deplete MGMT. Interferon (IFN)-β has been shown to suppress MGMT mRNA expression, thereby an enhanced efficacy may be expected by combining IFN-β with TMZ which has been tested in JCOG 0911 trial. O⁶-benzylguanine and PaTrin-2 are potent substrates for MGMT to be used for MGMT depletion. Since temozolomide (TMZ) induces O⁶-methylguanine (O⁶-MG), a major substrate for MGMT, dose intensified TMZ may generate a higher amount of O⁶-MG, leading to MGMT consumption and sensitization of cells to TMZ. CDDP: cis-diamminedichloro-platinum (II), JCOG: Japan Clinical Oncology Group, MGMT: methylguanine-DNA methyltransferase, mRNA: messenger RNA.

Fig. 3

A representative case of successful dose-dense temozolomide (ddTMZ) treatment after failure to standard adjuvant TMZ. A male, 64-year-old patient with multiple left parieto-temporal glioblastomas (GBMs) underwent subtotal resection of the temporal lesion, followed by radiotherapy concomitant with TMZ. After he received adjuvant TMZ for 2 cycles, the parietal lesion progressed (A–D), which was treated with 7-days on/7-days off ddTMZ, leading to shrinkage of the tumor (E, G, H) and reduction of brain edema (F). Gadolinium-enhanced T₁-weighted axial (A, E), coronal (C, G), and sagittal (D, H) images and fluid-attenuated inversion recovery (FLAIR) images (B, F) taken prior to ddTMZ (A-D) and 4 months after initiation of ddTMZ (E–H) are shown.