In Reply (to previous coment on Temodar)
Al Musella's Comments: (This is his personal views and are not necessarily the views of the Musella Foundation!)
Posted on: 09/01/2007
Journal of Clinical Oncology, Vol 25, No 23 (August 10), 2007: pp. 3550-a-3551
© 2007 American Society of Clinical Oncology.
Multidisciplinary Oncology Center, University of Lausanne Hospitals, Lausanne, Switzerland
Monika E. Hegi
Laboratory for Tumor Biology and Genetics, Department of Neurosurgery, and National Center for Competence in Research Molecular Oncology at Swiss Institute for Experimental Cancer Research, University of Lausanne Hospitals, Lausanne, Switzerland
We thank Drs Friedman and Maxwell for their interest in our editorial.1 They object to our proposal of conducting separate trials for patients with and without MGMT promoter methylation and argue that even in cells with unmethylated promoter, MGMT expression may be lacking on immunohistochemical analysis. This observation, however, does not argue against our statement, but it emphasizes the importance of assessing MGMT on a genetic level rather than by immunohistochemistry. MGMT may be an inducible protein, upregulated in the tumor tissue as response to DNA damage induced by alkylating agent chemotherapy and radiation.
Although we will not argue the fact that an occasional patient may benefit from alkylating agent chemotherapy even in the absence of MGMT promoter methylation, multivariate analysis of our randomized and the preceding phase II trial incontestably showed that MGMT status was the strongest independent prognostic factor in patients treated with temozolomide and radiotherapy (TMZ/RT), and the main predictor for treatment benefit with combined-modality therapy.2,3 It is thus only logical to reserve alkylating agent chemotherapy to patients who are most likely to derive a benefit. Rather than wasting time and resources on treatment with only a small chance for a measurable benefit, alternative strategies for the other patients need to be developed. In any event, MGMT promoter methylation in the patients receiving alkylating agent chemotherapy is such a strong prognostic factor that analysis of the MGMT status is required in order to adequately analyze any clinical trial of malignant glioma.
Friedman and Maxwell appropriately point out that cytotoxic drugs when used as single agents rarely have a major therapeutic impact, and that combination treatments should be developed. We entirely concur with this conclusion. In our trial of temozolomide for newly diagnosed glioblastoma, this agent was therefore combined with concomitant radiotherapy leading to a meaningful improvement in survival (but not a cure).4 Further improvement may be achieved by the addition of other cytotoxic or targeted agents. At the recent American Society of Clinical Oncology annual meeting, we presented our initial results with the addition of the integrin inhibitor cilengitide to the established combination of TMZ/RT.5 Again, the importance of MGMT status was confirmed, suggesting that separate strategies according to this molecular marker may be appropriate.
The main challenge in the development of combination regimens, as advocated by Friedman and Maxwell, is the lack of active agents with proven efficacy. New agents with promising results from uncontrolled phase I/II trials may not translate into the expected improvement in outcome when appropriately tested in randomized controlled trials. The recent experience with erlotinib or enzastaurin are just two examples, although these agents, if used in the adequate patient population or in combination, may still be of value.6
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: Monika E. Hegi, Oncomethylome Sciences, Brussels, Belgium (C) Stock Ownership: None Honoraria: None Research Funding: Monika E. Hegi, Oncomethylome Sciences, Brussels, Belgium Expert Testimony: None Other Remuneration: None
- Stupp R, Hegi ME: Methyl-guanine methyltransferase testing in glioblastoma: When and how? J Clin Oncol 25:1459-1460, 2007[Free Full Text]
- Hegi ME, Diserens AC, Godard S, et al: Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 10:1871-1874, 2004[Abstract/Free Full Text]
- Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997-1003, 2005[Abstract/Free Full Text]
- Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005[Abstract/Free Full Text]
- Stupp R, Goldbrunner R, Neyns B, et al: Phase I/IIa trial of cilengitide (EMD121974) and temozolomide with concomitant radiotherapy, followed by temozolomide and cilengitide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol 25:75s, 2007 (suppl; abstr 2000)
- van den Bent M, Brandes A, Rampling R, et al: Randomized phase II trial of erlotinib (E) versus temozolomide (TMZ) or BCNU in recurrent glioblastoma multiforme (GBM): EORTC 26034. J Clin Oncol 25:76s, 2007 (abstr 2004)
- The Fallacy of Single-Agent Chemotherapy for Cancer
Henry S. Friedman and Jill Maxwell
JCO 2007 25: 3550 [Full Text]
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