Should concomitant and adjuvant treatment with temozolomide be used as standard therapy in patients with anaplastic glioma?

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Abstract

Malignant gliomas are devastating tumors associated with poor prognosis. Standard treatment has been surgery followed by radiotherapy while the role of chemotherapy has remained controversial. Concomitant and adjuvant treatment with temozolomide has recently been shown to improve survival in patients with glioblastoma. While it seems intuitive to apply this regimen to patients with anaplastic gliomas which have traditionally been considered more chemosensitive, chemotherapy has not been shown to prolong life in patients with anaplastic gliomas. Despite promising preclinical and early clinical results, there is currently not enough level 1 evidence to justify concomitant and adjuvant temozolomide as standard therapy for patients with newly diagnosed anaplastic gliomas. Further investigation is needed to better define the role of chemotherapy in patients with anaplastic gliomas. Trials evaluating chemoradiotherapy as well as targeted therapeutic agents are the subject of further research.

Introduction

An estimated 18,500 new cases of primary central nervous system (CNS) tumors will be diagnosed in 2005 which will account for an estimated 12,760 deaths [1]. Gliomas comprise approximately half of primary CNS tumors. The World Health Organization (WHO) classifies gliomas into four grades. Grades I and II are low-grade tumors with typically a long natural history, while Grades III and IV are rapidly growing, malignant tumors, with a substantially shorter clinical course [2].

Anaplastic gliomas correspond to WHO Grade III. Histologically, these tumors have nuclear atypia and mitotic activity. In contrast to glioblastoma (GBM), WHO Grade IV, these tumors are usually not associated with necrosis. Anaplastic gliomas are believed to be either of astrocytic, oligodendrocytic, or a mixed lineage.

Overall prognosis for patients with anaplastic gliomas is poor. Patients with anaplastic astrocytomas (AA) have a median survival time of less than 3 years from diagnosis. Important prognostic factors include age at diagnosis, performance status, extent of resection, measures of tumor cell proliferation (not universally agreed upon as a prognosticator), and gene alterations (preliminary findings). Prognosis for patients with anaplastic oligodendroglioma (AO) is better than that of AA. The median survival for patients with AO is approximately 5 years. Prognostic factors associated with AO include age at diagnosis, location and extent of surgical resection, performance status, and the presence of chromosomal deletions. Overall prognosis for patients with anaplastic oligoastrocytoma (AOA) lies between that of AA and AO, depending on the dominant histological cell type and the other prognostic factors outlined above.

Because these tumors infiltrate the brain parenchyma diffusely with ill-defined borders, treatment is challenging and a cure is rarely achieved. Standard treatment for patients with anaplastic gliomas has been maximal surgical resection followed by adjuvant radiotherapy (RT) [3]. The addition of chemotherapy has been controversial. Adjuvant treatment with BCNU, a nitrosourea, has been justified by trials and meta-analysis showing a small long-term survival benefit in patients with anaplastic gliomas treated with surgery followed by alkylating chemotherapy plus RT compared to surgery followed by RT alone, and smaller trials putatively demonstrating the benefit of multi-agent chemotherapy regimens [3], [4]. Treatment with these agents is clearly associated with increased toxicity, but the clinical benefit, especially in terms of survival, is not as obviously discerned. Confounding this assessment is the observation that these trials and analysis were predominantly comprised of patients with GBM, and less than 20% of patients had anaplastic gliomas. Due to the increased toxicity and marginal survival benefit, the use of chemotherapy in patients at initial treatment has not been adopted universally. This review will discuss current issues surrounding the controversial role of chemoradiotherapy and the emerging role of temozolomide in anaplastic gliomas; to appreciate the issues involved, it is instructive to first review the role of chemoradiotherapy in GBM.

Section snippets

Chemoradiotherapy for GBM

The debate over the role of chemoradiotherapy in anaplastic gliomas has been further ignited by the results of a phase III cooperative group trial published by Stupp and colleagues in 2005 conducted by the European Organization for Research in the Treatment of Cancer (EORTC) brain and RT groups and National Cancer Institute of Canada (NCIC), EORTC 22981/26981, NCIC CE.3 [5]. This trial showed a significant survival benefit in patients with GBM treated with combination RT and temozolomide, an

Anaplastic astrocytoma

The revolutionary results of the trials described above have given rise to a paradigm shift in favor of chemoradiotherapy in the treatment of malignant gliomas. The applicability of this treatment regimen to anaplastic gliomas has been the subject of further contention. Based on observations from previous trials, anaplastic gliomas have been regarded as more chemosensitive than GBM and intuitively, one would expect that they should respond better than GBM to chemotherapy regimens. A study by

Differences in chemotherapy

One obvious difference between the trials is the timing of chemotherapy. EORTC 22981/26981 administered concomitant and adjuvant temozolomide in contrast to RTOG 9402 and EORTC 26951 trials that utilized sequential chemoradiotherapy. A small body of evidence suggests that concomitant temozolomide with RT may have a synergistic effect. In a study done by Wedge et al., the potentiation of radiation cytotoxicity by temozolomide was observed in vitro with U373MG glioblastoma cell line [16]. Further

Role of 1p and 19q deletions

Molecular genetics have garnered much attention in oligodendrogliomas due to the role of 1p and 19q chromosomal deletions. Allelic loss of 1p and 19q is thought to be an early genetic alteration in the transformation and progression of oligodendrogliomas and has been found in a high proportion of oligodendrogliomas and some oligoastrocytomas [21], [22]. Deletions in 1p and 19q have been associated with longer progression-free survival and chemo- and radiosensitivity in several studies [23], [24]

Salvage effect

The effect of salvage therapy in patients treated in the RT-alone arms of the RTOG 9402 and EORTC 26951 trials has been offered as a possible explanation for the lack of a statistically significant survival benefit observed in these trials. In RTOG 9402, 57% of patients treated with RT alone received salvage chemotherapy with PCV or temozolomide at recurrence. In addition, 43% of patients treated with RT alone were treated with second surgery at recurrence compared to 20% in the PCV plus RT

O6-methylguanine-DNA methyltransferase (MGMT)

Although the findings of EORTC 22981/26981 showed an increase in survival in patients receiving concomitant and adjuvant temozolomide for GBM, a large proportion of these patients only marginally benefited from this regimen. This observation might be explained by the role of O6-methylguanine-DNA methyltransferase (MGMT), an enzyme responsible for DNA repair. Alkylating agents act by adding a methyl group at specific sites in DNA, leading to interstrand cross-linking. If this methylation lesion

Could alkylators be harmful in Grade III anaplastic gliomas?

Yet another question that arises from these clinical observations is whether alkylators may in fact produce a decrement in survival in anaplastic gliomas. Retrospective comparisons of patients with Grade III AA treated with various therapies in RTOG protocols indeed suggest such a possibility [45]. How could this possibly be? In a recent review of the molecular make-up of gliomas, Ohgaki et al., point out that secondary GBM which evolve through malignant transformation of Grades II and III

Mismatch repair and p53 deficiency

Although the findings of Hegi and colleagues showed a survival benefit associated with temozolomide among patients with a methylated MGMT promoter region, the overall survival curves for RT plus temozolomide and RT alone were similar for the first 9 months of follow-up. Therefore, the pathways involved in resistance do not rely solely on MGMT. Epigenetic silencing of the MGMT promoter region, resulting in lack of MGMT expression, does not always result in cell death. Persistence of the methyl

Continuous scheduling

Because MGMT functions as a suicide enzyme that is consumed in the DNA repair process, de novo synthesis is required for sustained activity. Thus, continuous chemotherapy regimens, which deplete MGMT levels, may lead to an increased cytotoxicity. This mechanism may be another explanation for the survival benefit found in EORTC 22981/26981 where a 42-day continuous schedule of temozolomide during RT in the treatment arm was used. In contrast, patients in the combination treatment arm of RTOG

MGMT inhibitors

Specific inhibitors of MGMT have been developed and represent another avenue to overcome resistance. The compound mentioned in the trial described above, O6-benzylguanine (BG) inactivates MGMT by acting as an alternate substrate [57], [58], [59]. BG has been tested in early clinical trials in patients with gliomas [56], [60], [61]. It is associated with increased myelotoxicity and requires a drastic reduction in the dose of BCNU [62], [63], [64]. Another MGMT inhibitor, O6

Conclusion

Historically, the benefit of chemoradiotherapy in the treatment of anaplastic gliomas has been disputed. This debate has been fueled further by the recent findings of EORTC 22981/26981, demonstrating a significant survival benefit in patients with GBM treated with concomitant and adjuvant temozolomide. It may seem logical to apply this regimen to anaplastic gliomas as they have been previously thought to be more chemosensitive than GBM; however, several trials have failed to show a survival

Malika L. Siker is a resident in radiation oncology at Medical College of Wisconsin, Milwaukee, WI.

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    Malika L. Siker is a resident in radiation oncology at Medical College of Wisconsin, Milwaukee, WI.

    Arnab Chakravarti is at Massachusetts General Hospital in the Department of Radiation Oncology.

    Minesh P. Mehta has studied medicine and surgery at the University of Zambia (1981). His research interests are primarily in the areas of tomotherapy, incorporating advanced imaging in radiotherapy treatment planning, CNS malignancies, lung cancer, pediatric neoplasms, stereotactic radiosurgery, radiosensitization, combined modality therapies, altered fractionation, cost-effectiveness, and outcomes research. He is the PI for an NIH-funded Tomotherapy Program Project Grant. Within the context of CNS neoplasms, his particular expertise is in setting up and running multi-disciplinary clinics, conducting national multimodality protocols, participating in national organizational strategies for managing these tumors and developing radiosurgery systems and protocols. In addition, within this context, he developed 3-D/conformal techniques as well as interstitial brachytherapy expertise. He is running numerous multimodality clinical trials at the national level for both adult and pediatric CNS neoplasms. Current major thrust areas include developing molecularly-targeted agents as radiosensitizers for CNS tumors, such as the EGFR pathway, PKC, angiogenesis, etc. He is the PI for an ongoing international Phase III trial of Motexafin-Gadolinium, a novel radiosensitizer, being evaluated in brain metastases patients. He is engaged in clinical trials combining Temozolomide with radiation therapy for CNS tumors. In addition, he is working with topoisomerase I inhibitors as radiosensitizers, for thoracic neoplasms, particularly small cell lung cancer. For the latter, he has developed a unique hyperfractionated, accelerated regimen, which has been tested in a national trial. As far as pediatric neoplasms are concerned, his major research focus has been on medulloblastoma. Outcomes research, with specific emphasis on cost-effectiveness, quality of life and neurocognitive function has been another important area of activity.

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