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Journal of Clinical Oncology, Vol 22, No 7 (April 1), 2004: pp. 1345 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.604
In Reply:
Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX We appreciate Dr Weil's interest in our article describing the biologic and clinical results of our trial of adenovirus-mediated p53 gene therapy.1 Consistent with the goals of a phase I trial, the primary objects of the reported study were to determine the maximum-tolerated dose of this new biologic therapeutic agent and to define its toxicity profile. In addition, we were also able to determine that the adenoviral vector was capable of delivering the p53 gene to tumor cells and that the gene was transcribed and translated into functional p53 protein.1 Because this was a phase I trial, therefore, and as implied in the paper, overemphasis or overreading of outcome data should be avoided. Clearly, conclusions about efficacy based on data from only 15 patients, who were treated at varying doses of the agent, must be viewed cautiously. We agree with Dr Weil that extent of resection and age could certainly have influenced the survival of our patients. We also agree that comparing the outcome obtained in our study with that of historical data (ie, Wong et al2) provides only a framework for understanding our data. This comparison was included at the suggestion of our reviewers simply to provide a context in which to interpret our study and was not presented as nor meant to be a statistically rigorous assessment. Nevertheless, long-term survival in this population of previously treated patients with recurrent tumors is rare. Thus, the fact that one of our patients is still alive without recurrence more than 4 years after treatment (including an additional 1 year from acceptance of the paper) is certainly compelling. We appreciate Dr Weil's insight that the outcome of our patients may have been a function of genetics. As we describe in the paper, data from our group and others indicate that tumors composed of cells harboring wild-type p53 alleles may be more resistant to exogenously delivered p53 than are tumors containing mutant-p53 alleles.3-5 In addition to arising in older patients and having EGFR alterations, the so called de novo glioblastoma multiforme described by Dr Weil are typically p53 wild-type.6 Although most of our patients were younger than 55 years, many had tumors expressing wild-type p53 alleles, which may explain some of the recurrences. Importantly, data from our laboratory have shown that combining Ad-p53 with radiation or chemotherapy may overcome the resistance of these wild-type p53 cells to Ad-p53 alone.4,5 Future trials that include only tumors composed of cells harboring mutant p53 alleles or trials that combine Ad-p53 with adjuvant therapies would be of interest. Finally, as described in the Materials and Methods section, the post resection injections were evenly distributed throughout the resection cavity. A grid was laid in the resection cavity that created multiple 1 cm x 1 cm squares. The injections were made into the center of these squares to a depth of about 1 to 2 cm. Because the majority of recurrent tumors have T2-signal changes around the entire tumor mass (enhancing zone on T1-weighted images), the goal was to achieve equal distribution throughout the peritumoral zone of T-2 signal change. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Lang FF, Bruner JM, Fuller GN, et al: Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: Biological and clinical results. J Clin Oncol 21:2508-2518, 2003
2. Wong ET, Hess KR, Gleason MJ, et al: Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572, 1999
3. Gomez-Manzano C, Fueyo J, Kyritsis AP, et al: Adenovirus-mediated transfer of the p53 gene produces rapid and generalized death of human glioma cells via apoptosis. Cancer Res 56:694-699, 1996 4. Lang FF, Yung WK, Raju U, et al: Enhancement of radiosensitivity of wild-type p53 human glioma cells by adenovirus-mediated delivery of the p53 gene. J Neurosurg 89:125-132, 1998[Medline]
5. Shono T, Tofilon PJ, Schaefer TS, et al: Apoptosis induced by adenovirus-mediated p53 gene transfer in human glioma correlates with site-specific phosphorylation. Cancer Res 62:1069-1076, 2002 6. Kleihues P, Burger PC, Collins VP, et al, in Kleihues P and Cavenee WK (eds): Pathology & Genetics of Tumours of the Nervous System, pp 29-39. Lyon, France, IARC Press, 2000 Related Article
Related Correspondence
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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