Gefitinib in Recurrent Glioblastoma

Correspondence

95% CI 1.02 to 1.34; the Breslow-Day test for heterogeneity has P ⫽ .12, and the random-effects analysis for a significant effect has P ⫽ .20. Several points need to be considered when assessing the validity of a meta-analysis: (1) is there evidence that support the hypothesized effect, and did the hypothesis precede rather than follow the analysis? In our case, the hypothesis was based on the preceding in vitro evidence that epithelial cells that contain TGFBR1*6A grow more rapidly than cells that contain TGFBR1 when treated with transforming growth factor ␤, one of the most potent naturally occurring inhibitors of cell growth.4,5 (2) Is the magnitude of the effect large? Our metaanalysis of 12 case-control studies shows that overall cancer risk is increased by 19% for TGFBR1*6A heterozygotes and 70% for TGFBR1*6A homozygotes. Breast cancer risk is increased by 38% for TGFBR1*6A carriers, which is in the same range as the increased breast cancer risk observed in women who take hormone replacement therapy.6 TGFBR1*6A homozygotes have a 102% increased risk of colorectal cancer and 169% increased risk of ovarian cancer, a non-negligible effect. (3) Is there a publication bias? We addressed this issue in the first meta-analysis to the best of our ability using the funnelplot analysis suggested by Egger et al.7 We didn’t find any evidence of publication bias.1 Our second meta-analysis of 12 studies included five additional unpublished studies, and only three studies showed an association between TGFBR1*6A and cancer,2 further ruling out a publication bias as an explanation for our results. In summary, our data are in line with those recently reported by Lohmueller et al3 in their meta-analysis of genetic-association studies. Although there was significant heterogeneity in our meta-analyses, evidence for heterogeneity disappeared after we removed the first positive study. Thus, there is only limited evidence of heterogeneity across the 12 studies, and population-specific effects seem unlikely to explain the association between TGFBR1*6A and cancer. Boris Pasche, Virginia Kaklamani, Nanjiang Hou, and Alfred Rademaker Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine, Department of Preventive Medicine, and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL ■ ■ ■

Authors’ Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. Kaklamani VG, Hou N, Bian Y, et al: TGFBR1*6A and Cancer Risk: A Meta-Analysis of Seven Case-Control Studies. J Clin Oncol 21:3236-3243, 2003 2. Pasche B, Kaklamani VG, Hou N, et al: TGFBR1*6A and Cancer: A Meta-Analysis of 12 Case-Control Studies. J Clin Oncol 22:756-758, 2004 3. Lohmueller KE, Pearce CL, Pike M, et al: Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 33:177-182, 2003

4. Pasche B, Kolachana P, Nafa K, et al: T beta R-I(6A) is a candidate tumor susceptibility allele. Cancer Res 59:5678-5682, 1999 5. Chen T, de Vries EG, Hollema H, et al: Structural alterations of transforming growth factor-beta receptor genes in human cervical carcinoma. Int J Cancer 82:43-51, 1999 6. Nelson HD, Humphrey LL, Nygren P, et al: Postmenopausal Hormone Replacement Therapy: Scientific Review. JAMA 288:872-881, 2002 7. Egger M, Davey SG, Schneider M, et al: Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629-634, 1997

DOI: 10.1200/JCO.2004.99.064

Gefitinib in Recurrent Glioblastoma TO THE EDITOR: We received the American Society of Clinical Oncology e-mail alert referring to the early release of a paper by Rich et al1 on the use of gefitinib (Iressa; AstraZeneca, Wilmington, DE) for recurrent glioblastoma multiforme with great excitement, because this is a group of patients for whom no effective therapy currently exists. Our interest was further spiked by the conclusion of the abstract, which states that gefitinib has activity in patients with recurrent glioblastoma. The results presented do not justify this conclusion. The paper states that the primary end point of the study was 6-month progression-free survival (PFS), and the study was designed to differentiate between a 6-month PFS rate of 15% and 30% with type I and type II error rates of 0.091. In fact, none of the patients on the study responded to therapy, and the actual PFS was 13.2%. The authors noted that this is better than the results from a phase II randomized study where another ineffective agent (procarbazine) was compared with temozolamide, and had a 6-month PFS of 8%. The authors carried out subgroup analyses of this phase II study and showed that the most significant factor for eventfree survival was extent of surgical resection. Historical controls in studies of glioblastoma multiforme are problematic because of the effect of new surgical techniques, including navigation and intraoperative mapping, which have increased the neurosurgeon’s ability to resect recurrent tumors. The abstract’s conclusion that gefitinib has activity in glioblastoma multiforme is likely to cause unjustified demand for this drug from patients and their advocates, who are not capable of analyzing the actual results of the study, particularly when the American Society of Clinical Oncology considers the paper to be important enough to warrant early publication and an e-mail alert. M. Raphael Pfeffer, Mark L. Levitt, and Dan Aderka Chaim Sheba Medical Center, Tel Hashomer, Israel ■ ■ ■

Authors’ Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. 2755

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REFERENCE 1. Rich JN, Reardon DA, Peery T, et al: Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22:133-142, 2004

DOI: 10.1200/JCO.2004.99.299

IN REPLY: 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 progressionfree 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 resis-

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tance to EGFR inhibition3,4 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. Jeremy N. Rich, Henry S. Friedman, and James B. Powell Jr Duke University, Durham, NC

Janet E. Dancey National Cancer Institute, Bethesda, MD ■ ■ ■

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 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 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 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

DOI: 10.1200/JCO.2004.99.044

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