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In Reply:

¹ Duke University, Durham, NC
² National Cancer Institute, Bethesda, MD

We appreciate the issues raised by Drs M. Raphael Pfeffer, Mark L. Levitt, and Dan Aderka regarding the efficacy of gefitinib for patients with recurrent glioblastomas.¹ Drs Pfeffer, Levitt, and Aderka raised concerns that the conclusion in the abstract stated that gefitinib "has activity" and that this does not reflect the fact that a minority of patients achieved a 6-month progression-free survival.

We agree that gefitinib has limited efficacy at the doses used in the current trial in a patient population not selected for target expression and pathway activation. In fact, our initial manuscript concluded, "Gefitinib is well tolerated and has modest activity in patients with recurrent glioblastoma." In the review process, we were advised to alter the manuscript: "In your revision addressing the issues raised by the reviewer, we agree that the word ‘modest’ is perhaps either too subjective or overly optimistic; it might be better to say that the drug ‘has activity’ and let further trials quantify it." The published manuscript reflects this change.

We remain confident that gefitinib does have activity in a subset of patients. At this time, we still have two patients with well controlled disease on this trial after 72 and 99 weeks. Although the extent of surgical resection has a benefit in patients with glioblastomas,² the durable stability of disease seen in the minority of patients suggests gefitinib may benefit these patients. Given our current understanding of the role of EGFR amplification and EGFR and PTEN mutations in glioblastoma, and the role of PTEN in resistance to EGFR inhibition^3,4 gefitinib represents a novel therapy that at higher doses and perhaps in combination with other therapies may offer benefit in a defined population of glioblastoma patients.

Clearly, physicians and patients in consultation with their caregivers should read fully the results and discussion of any manuscript before adoption of a therapy. Further preclinical and clinical studies will likely be required to optimally use gefitinib in patients with glioblastoma.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Rich JN, Reardon DA, Peery T, et al: Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22:133-142, 2004[Abstract/Free Full Text]

2. Lacroix M, Abi-Said D, Fourney DR, et al: A multivariate analysis of 416 patients with glioblastoma multiforme: Prognosis, extent of resection, and survival. J Neurosurg 95:190-198, 2001[Medline]

3. She QB, Solit D, Basso A, et al: Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3'-kinase/Akt pathway signaling. Clin Cancer Res 9:4340-4346, 2003[Abstract/Free Full Text]

4. Bianco R, Shin I, Ritter CA, et al: Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 22:2812-2822, 2003[CrossRef][Medline]

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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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Rich, J. N. Articles by Dancey, J. E. Search for Related Content PubMed Articles by Rich, J. N. Articles by Dancey, J. E. Related Articles Related Article Related Correspondence