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Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4860-4861 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.1839
In ReplyHasbro Children's Hospital/Brown Medical School, Providence, RI
Montefiore Medical Center, Bronx, New York, NY
Children's Hospital of Pittsburgh, Pittsburgh, PA
Keck School of Medicine, University of Southern California, Los Angeles, CA
Dana-Farber Cancer Institute and Children's Hospital, Boston, MA
Dana-Farber Cancer Institute and Children's Hospital, Boston, MA
IWK Health Centre Halifax, Nova Scotia, Canada
Memorial Sloan Kettering Cancer Center, New York, NY We appreciate the comments of Serra et al regarding our recent report1 and the opportunity this affords to further elaborate on our approach and conclusions. Our study was initiated in 1992 with participation by 116 institutions of the Pediatric Oncology Group and Children's Cancer Group, legacy groups of the current Children's Oncology Group. Our methodology was similar to that reported by their group during the similar time period,2 including use of the same antibodies. However, antigen retrieval methodology was specifically selected in consideration of the fact that tissue came from multiple treatment sites and we could not be sure of fixation. Essentially all of the resections were subjected to prolonged fixation as well as prolonged decalcification. The immunoperoxidase protocol we used was carefully developed by Rosier et al.3 The consensus protocol provides a well validated approach, but there are alternative methods to perform immunoperoxidase stains that yield valid results. Because this study did not use the consensus protocol does not mean that the results are invalid. We recognize that use of trypsin and microwaving may alter antigeniticity and antigen expression. This should perhaps have been further elaborated on in the article. In addition to use of normal adrenal (Children's Cancer Group) or normal kidney (Pediatric Oncology Group), we used an internal control for p-glycoprotein (Pgp) expression that eliminated need for a separate vimentin tissue control. The internal control is the osteoclast, which constitutively expresses Pgp.4 If the osteoclasts were not staining in a given preparation, the case was graded as uninterpretable. The only cases that were included in this analysis were those that showed intact antigenicity as determined by osteoclast staining for Pgp. We find the data portrayed in the Table by Serra et al (regarding percent exclusion due to vimentin negativity) of interest. We are not aware that it has been published previously; it appears that you may be suggesting a standardization step has not been used in your published manuscripts. It remains possible that some of the technical issues and differences in tissue sources may explain the discrepant results between the present and the prior studies. We remain convinced that our study demonstrates that Pgp does not have utility as a prognostic factor in osteosarcoma, at least in the context of a multi-institutional study. In this setting, the analysis must be sufficiently robust that it can be used on tissue from multiple institutions. If methodology cannot be sufficiently standardized to be clinically useful in a cooperative group setting, then the use of Pgp as a basis for prognostication in any malignancy must be questioned. As noted by Serra et al, the proportion of Pgp-positive patients was not explicitly stated in the text. This was an oversight. Tumors from 45 patients (of 139) were C-494 positive. Clinical characteristics and outcomes of those with specimens were indistinguishable from the entire cohort suggesting that this is a representative sample. The primary reasons that samples were not available to include were: irretrievable specimens from biopsies performed before referral to the medical center or insufficient support for institutions to prepare specimens specifically for this study. Although we had hoped for a more complete collection of biopsy specimens, none of the reasons noted would tend to bias the study. Our group has sought to understand the apparent event-free survival advantage for patients receiving both ifosfamide and muramyl tripeptide phosphatidylethanolamine (MTP-PE).5 We did not analyze data by treatment arm because statistical significance is not achievable with such small cohorts. For purposes of this report, we specifically analyzed the impact of ifosfamide because Pgp does not influence cellular efflux of this agent. Theoretically, ifosfamide could have improved overcome for those with Pgp-mediated treatment resistance. This was not noted in our study. Finally, we did not intend to disparage the methodology or honesty of our colleagues. It does remain an advantage of any prospective study that the outcome is unknown when specimens are collected. We continue to believe that such an approach is optimal and would have referenced the authors' article6 if it had been published at the time of our submission. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Schwartz CL, Gorlick R, Teot L, et al: Multiple drug resistance in osteogenic sarcoma: INT0133 from the Children's Oncology Group. J Clin Oncol 25:2057-2062, 2007 2. Baldini N, Scotlandi K, Barbanti-Brodano G, et al: Expression of P-glycoprotein in high-grade osteosarcomas in relation to clinical outcome. N Engl J Med 333:1380-1385, 1995 3. Rosier RN, Teot LA, Hicks DG, et al: Multiple drug resistance in osteosarcoma. Iowa Orthop J 15:66-73, 1995[Medline] 4. Posl M, et al: P-glycoprotein expression in high grade central osteosarcoma and normal bone cells: An immunohistochemical study. Gen Diagn Pathol 142:317-325, 1997[Medline] 5. Meyers PA, Schwartz CL, Krailo M, et al: Osteosarcoma: A randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol 23:2004-2011, 2005 6. Serra M, Pasello M, Manara MC, et al: May P-glycoprotein status be used to stratify high-grade osteosarcoma patients? Results from the Italian/Scandinavian Sarcoma Group 1 treatment protocol. Int J Oncol 29:1459-1468, 2006[Medline] Related Correspondence
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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