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In Reply

Department of Medical Oncology, Bellaria-Maggiore Hospital, Azienda Unità Sanitaria Locale of Bologna, Bologna, Italy

We thank Drs Chamberlain and Glantz for their interest in our article on the incidence and outcome of pseudoprogression after concurrent chemoradiotherapy in glioblastoma (GBM) patients in which, for the first time, a correlation was found with O⁶-methylguanine-DNA methyltransferase (MGMT) methylation status.¹ In the study, 208 patients were treated with combined radiotherapy and temozolomide (TMZ), but MGMT methylation status was only assessable in 103 patients; the remaining 105 patients had insufficient histologic material or MGMT was not assessable at methylation-specific polymerase chain reaction. However, as shown by Hegi et al,² patients whose samples are not assessable for MGMT methylation do not seem to characterize a specific subset with a different survival; data collected from these patients therefore do not result in any bias. We do not agree with the authors’ claim that there is a potential logical correlation between MGMT gene promoter methylation and MGMT protein expression: given that MGMT, an inducible enzyme, may be upregulated after chemotherapy or radiotherapy, the concept of low/high MGMT expression should be avoided in this context.

Drs Chamberlain and Glantz appropriately raised the question concerning the concept of adjuvant treatment in GBM, developed in the 1970s with a goal of increasing the cure rate after the complete excision of tumors such as breast cancer, the underlying rationale being to treat microscopic disease when the tumor bulk was at a minimum. However, GBM patients rarely received "true" adjuvant treatment and, in the European Organisation for Research and Treatment of Cancer (EORTC) National Cancer Institute of Canada trial, only 49% of patients underwent complete resection.³ In our protocol, like those for metastatic disease in other solid tumors, treatment was scheduled up to disease presence, or given in 12 cycles when no disease was found during magnetic resonance (MR) imaging or a complete response was achieved. Furthermore, the proposed administration of 12 cycles was included in the Canadian recommendations for the treatment of GBM, at least for patients who showed continuous improvement on therapy,⁴ and this schedule has been suggested as a standard arm in the new experimental protocols of the major international cooperative groups, such as EORTC and Radiation Therapy Oncology Group (ie, EORTC 26052-22053/Radiation Therapy Oncology Group 0525 trial, comparing standard treatment with dose-intensive TMZ in patients with newly diagnosed GBM).

Moreover, Drs Chamberlain and Glantz stated that the standard 5 days every 28 days postradiotherapy TMZ schedule does not have a long-term effect on MGMT tumor content. However, as shown by the references made, the few data available concerning this finding are reported in a study evaluating MGMT inactivation in peripheral-blood mononuclear cells treated with TMZ,⁵ but whether this also applies to tumor cells remains to be demonstrated.⁶ To date, no data are available on the advantages of a prolonged/alternative schedule versus the standard schedule of 5 days very 28 days.

The authors suggest that histology is the valid method for identifying pseudoprogression; yet, as they state, only a small percentage of patients with suspected pseudoprogression undergo surgery because the tumor mass, which can be controlled by corticosteroids, tends to diminish quite rapidly. Moreover, it is difficult to define the role of necrosis given that, in the histologic setting, it is often present concomitantly with neoplastic cells. Lastly, the role of new imaging tools such as spectroscopic MR imaging, MR scan, MR perfusion and diffusion, or [¹⁸F]fluorodeoxyglucose positron emission tomography in discriminating disease progression and pseudoprogression have recently been reviewed.⁷ A few of our patients underwent repeat surgery, and others underwent brain functional imaging; however, due to the sporadic nature of this treatment option and the bias in patient selection, no conclusion can be drawn regarding the role of these diagnostic modalities, which should be tested in prospective trials.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Brandes AA, Franceschi E, Tosoni A, et al: MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol 26:2192-2197, 2008[Abstract/Free Full Text]

2. Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from TMZ in glioblastoma. N Engl J Med 352:997-1003, 2005[Abstract/Free Full Text]

3. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant TMZ for glioblastoma. N Engl J Med 352:987-996, 2005[Abstract/Free Full Text]

4. Mason WP, Maestro RD, Eisenstat D, et al: Canadian recommendations for the treatment of glioblastoma multiforme. Curr Oncol 14:110-117, 2007[CrossRef][Medline]

5. Tolcher AW, Gerson SL, Denis L, et al: Marked inactivation of O⁶-alkylguanine-DNA alkyltransferase activity with protracted TMZ schedules. Br J Cancer 88:1004-1011, 2003[CrossRef][Medline]

6. Stupp R, Hegi ME: Methylguanine methyltransferase testing in glioblastoma: When and how? J Clin Oncol 25:1459-1460, 2007[Free Full Text]

7. Brandes AA, Tosoni A, Spagnolli F, et al: Disease progression or pseudoprogression after concomitant radiochemotherapy treatment: Pitfalls in neurooncology. Neuro Oncol 10:361-367, 2008[Abstract/Free Full Text]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Brandes, A. A. Articles by Tosoni, A. Search for Related Content PubMed Articles by Brandes, A. A. Articles by Tosoni, A. Social Bookmarking                            What's this?