Originally published as JCO Early Release 10.1200/JCO.2008.18.0372 on October 14 2008

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In Reply:

James J. Vredenburgh, Jeremy N. Rich, David A. Reardon, Annick Desjardins, Henry S. Friedman

Duke University Medical Center, Durham, NC

Drs Garfield and Hercbergs provide interesting speculation about combining propylthiouracil (PTU) with inhibitors of vascular endothelial growth factor (VEGF) for the treatment of glioblastoma multiforme. Our trial¹ of bevacizumab and irinotecan was the first study published utilizing an anti-VEGF treatment for malignant gliomas. There was considerable hesitation on the part of regulatory agencies regarding anti-VEGF therapy and malignant gliomas, given the risk of intracerebral hemorrhage. The combination of irinotecan and bevacizumab was chosen because of US Food and Drug Administration approval for use in colorectal cancer, and irinotecan has been used to treat recurrent glioma. All of the patients had experienced treatment failure after receiving an alkylating agent, so it was thought that a different class of chemotherapy—a topoisomerase-1 inhibitor—might be efficacious. Clearly, the bevacizumab provided the vast majority of benefit and was responsible for the dramatic results we obtained. Our clinical trial of irinotecan and bevacizumab is just the beginning of the investigation into antiangiogenic therapy and the inhibition of multiple signaling pathways in an attempt to improve the survival of patients with glioma.

Drs Garfield and Hercbergs provide sound scientific rationale for why PTU or methimazole may be synergistic with anti-VEGF therapy, by inhibiting VEGF, insulin-like growth factor 1 receptor, epidermal growth factor, as well as _vβ₃ integrin. The authors reference a recently presented trial of 19 patients with recurrent glioblastoma treated with PTU and high-dose tamoxifen.² The patients who became hypothyroid, as indicated by sustained elevation of thyroid-stimulating hormone, had improved survival compared with patients who did not become hypothyroid. The authors failed to mention their previously published trial of a phase I/II study published in 2003, in which PTU-induced chemical hypothyroidism with high-dose tamoxifen prolonged survival in recurrent high-grade glioma.³ Both studies have small patient numbers, and produced similar results. It is unclear whether the hypothyroidism is responsible for the purported benefit or if it is just selection bias. The reported follow-up is short in both studies; and clinical deterioration secondary to hypothyroidism may be a more common occurrence if PTU or methimazole is combined with bevacizumab, given the improved survival with bevacizumab.

We appreciate the insight provided by Drs Garfield and Hercbergs and agree that a clinical trial of PTU or methimazole with an anti-VEGF agent is indicated.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

NOTES

published online ahead of print atwww.jco.org on October 13, 2008

REFERENCES

1. Vredenburgh JJ, Desjardins A, Herndon JE, et al: Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722-4729, 2007[Abstract/Free Full Text]

2. Hercbergs, AA, Suh J, Reddy C, et al: Early onset propylthiouracil-induced hypothyroidism is associated with improved survival in recurrent high grade glioma. Presented at the American Association of Cancer Research Annual Meeting, San Diego CA, April 12-16, 2008

3. Hercbergs AA, Goyal LK, Suh JH, et al: Propylthiouracil-induced chemical hypothyroidism with high-dose tamoxifen prolongs survival in recurrent high grade glioma: A phase I/II study. Anticancer Res 23:617-626, 2003[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 Google Scholar Google Scholar Articles by Vredenburgh, J. J. Articles by Friedman, H. S. Search for Related Content PubMed Articles by Vredenburgh, J. J. Articles by Friedman, H. S. Related Articles Related Correspondence Social Bookmarking                            What's this?