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In Reply:

Memorial Sloan-Kettering Cancer Center, New York, NY

David J. Samson, Jerome Seidenfeld, Naomi Aronson

Technology Evaluation Center, Blue Cross and Blue Shield Association, Chicago, IL

Harinder Garewal

Arizona Cancer Center and VA Medical Center, Tucson, AZ

Harold J. Burstein

Dana-Farber Cancer Center, Boston, MA

Daniel D. Von Hoff

Translational Genomics Research Institute, Phoenix, AZ

Mark R. Somerfield

American Society of Clinical Oncology, Alexandria, VA

Dr Nagourney strenuously objects that the American Society of Clinical Oncology’s (ASCO’s) Technology Assessment Working Group did not adequately distinguish between assays measuring tumor growth inhibition versus cell death. The Working Group’s report and accompanying systematic review described and considered each type of test. We evaluated the evidence from published clinical trials that tested whether performance of these assays improves patient outcomes compared with empirical selection of chemotherapy regimens based on published clinical trials. The Working Group concluded that available evidence is insufficient to recommend routine use of these assays. Because the number of available chemotherapeutic agents has increased enormously over the past few years, the Working Group emphasized that the rationale for these assays has never been stronger. The Working Group’s statement should encourage evaluation of these assays in prospective clinical trials that measure the impact of chemotherapy sensitivity and resistance assays (CSRAs) on patient outcomes and treatment recommendations.

Dr Nagorney is simply mistaken in suggesting that diagnostic accuracy indices (sensitivity, specificity, and positive and negative predictive values) are sufficient for establishing a test’s utility. As outlined by the Institute of Medicine,¹ tests are clinically useful only if the information they produce leads to patient management changes that improve outcomes, such as longer survival, better quality of life, or fewer adverse events. Clinical utility can be determined by mapping a causal chain from diagnostic accuracy through changes in management to impact on outcomes.² There is a lack of clarity about how CSRA results influence management decisions and there is insufficient evidence documenting their effect on patient outcomes.³ Similarly, one of the articles that Dr Nagourney cites on gene expression profiles in childhood leukemia concludes, "If patients are found to have a gene-expression profile that is predictive of a poor response to one or several chemotherapeutic agents, should those agents be omitted from their treatment? Not yet."⁴

Well-designed and rigorously conducted randomized controlled trials are the foundation for progress in oncology and all of medicine. Indeed, medical science has most often gone astray when technologies were adopted without careful and rigorous testing in the controlled setting. Two recent examples of therapies that were prematurely adopted are autologous bone marrow transplantation for the treatment of metastatic breast cancer^5,6 and the use of post menopausal hormone replacement therapy.⁷ The breast cancer example reminds us that better tumor response does not necessarily lead to better survival or quality of life. Just as Dr Nagourney is an ardent proponent of an exciting technology that he has helped to develop, so too many championed these technologies. Nevertheless, they were found to be ineffective when prospectively evaluated. Premature adoption of interventions or diagnostic tests undermines the public’s faith in our profession and thereby impedes further progress.

Dr Nagourney laments that there have been repeated unsuccessful efforts to evaluate these assays through the cancer cooperative groups. The reasons underlying this lack of success merit close scrutiny—especially given that many other efficacious therapies have been successfully developed and evaluated using this mechanism. The federally funded cooperative groups are terribly underfunded and indeed are unable to conduct all important clinical trials. Pharmaceutical manufacturers, those who manufacture test kits, and those who develop and offer testing services such as CSRAs routinely provide funds for the conduct of clinical trials. For example, the estrogen receptor assay and more recently the Her-2 neu test, were evaluated in the context of multicenter controlled trials. Thus, Dr Nagourney is not restricted to the cooperative group setting. The ASCO Working Group considered evidence from studies irrespective of sponsorship.

Dr Fruehauf argues that focus on drug resistance assays "...may have been a more reasonable topic for an extensive review... ." As noted above, the ASCO Working Group considered any study of assay-guided therapy, by either sensitivity assays or resistance assays, that met the specified inclusion criteria. The majority of the articles identified from the literature searches concerned technical aspects of sensitivity and resistance assays, and few focused on assessment of clinical outcomes of using assays, the basis for the Working Group’s inclusion criteria.

Dr Fruehauf states that the articles that the ASCO Working Group reviewed were selected by the Blue Cross and Blue Shield Association (BCBSA). The ASCO Working Group developed criteria for selecting articles for inclusion in its own, independent systematic review; the articles were not selected by the BCBSA.

Dr Fruehauf speculates that the "Special Article" was not subjected to peer review by the Journal. ASCO guidelines and technology assessments do not undergo the regular peer review process by the Journal of Clinical Oncology. However, in accordance with ASCO policies and procedures, the manuscript underwent an intensive, multilayered review. After approval by members of the Working Group, "external reviewers," defined as either content area experts or community oncologists who were not members of the ASCO Working Group, provided extensive comments and feedback. Subsequently, the document was reviewed by the ASCO Health Services Committee and by the ASCO Board of Directors before publication.

Dr Fruehauf notes that "some members of the ASCO panel withdrew from authorship." Actually, one member of the original Working Group chose to resign based on a self-identified conflict of interest. This took place before the Working Group began its actual work. One member of the Working Group who did not participate in the manuscript review until very late in the technology assessment process, requested that his name be removed from the list of Working Group members in Appendix A (he was not among the article’s authors) because he disagreed with the conclusions. This should have been made explicit in the final version of the manuscript.

Finally, Dr Fruehauf suggests that it may be time to consider whether "...assay-directed therapy can prolong patient survival?" We could not agree more that this is the critical issue. We share Dr Fruehauf’s hope that the proposed trial of assay-directed therapy in platinum-resistant epithelial ovarian carcinoma can be successfully completed and we look forward to those results. The Working Group is supportive of an evaluation of this concept in the trial setting, and is committed to updating its assessment as new information becomes available. The literature will be reviewed on an annual basis to determine whether an update of the technology assessment is warranted.

Dr Wieand suggests that designs other than randomized comparisons of assay-guided and empiric therapy could assess the clinical utility of CSRAs. He described an approach in which 2-year survival probabilities are compared for two groups of patients, one receiving drug A and the other receiving drug B. Both groups would provide assay results to both drugs and Dr Wieand argues that a certain pattern of results could justify use of CSRAs.

The key problem with this kind of design is a lack of external validity. Two-drug direct comparisons are not relevant to the way CSRAs are used in practice. Specifically, a large number of drugs are typically tested on samples from individual patients, and each patient is treated with a combination of drugs on the basis of consideration of the assay results. It remains unclear precisely how assay findings are to be translated into a selected regimen. Designs that pit two agents against each could ignore many others that patients could end up receiving. Again, this makes it critical to conduct randomized trials comparing assay-guided versus empiric therapy.

Dr Castro fully acknowledges that there is insufficient clinical trial evidence to support the routine use of CSRAs. However, he is troubled that the Working Group recommended against use of these agents outside the clinical trial setting.

ASCO’s role is to provide guidance to its members, not by any means to dictate individual practice. Guidelines and technology assessments are not intended to supplant physician judgment. Working Group members wholeheartedly agree with Dr Castro that clinical autonomy is important. They also agree that it is critical to rigorously and prospectively evaluate technologies before they are adopted. Patients routinely approach oncologists with a desire to pursue individually customized approaches to their cancer treatment. In these circumstances, it is critical that oncologists have current knowledge regarding the state of the science. It is certainly each practitioner’s prerogative to order CSRAs or any other medical test. However, it is important to specify to the patient what the treatment would be in the absence of the assay and to be clear about if and how the information will be used to inform treatment decision making. The alternative is to risk our credibility with our patients and the public whose trust is critical to our mission. The Working Group’s challenge to the dedicated scientists who have developed CSRAs and the dedicated practitioners like Dr Castro who use them is to develop collaborations to systematically evaluate and thereby determine the appropriate uses of this technology.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Institute of Medicine: Assessing Medical Technologies: Report of a study by a committee of the Institute of Medicine, Council on Health Care Technology and Divisions of Health Science Policy and Health Promotion and Disease Prevention. Washington, DC, National Academy Press, 1985

2. Fryback DG, Thornbury JR: The efficacy of diagnostic imaging. Med Decis Making 11 : 88 -94, 1991

3. Blue Cross and Blue Shield Association Technology Evaluation Center: Chemotherapy Sensitivity and Resistance Assays. TEC Assessments 17 : 1 -39, 2002 . http://www.bcbs.com/tec/vol17/17_12.pdf

4. Winick NJ, Carroll WL, Hunger SP: Childhood leukemia: New advances and challenges. N Engl J Med 351 : 601 -603, 2004[Free Full Text]

5. Stadtmauer EA, O'Neill A, Goldstein LJ, et al: Conventional-dosechemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer: Philadelphia Bone Marrow Transplant Group. N Engl J Med 342 : 1069 -1076, 2000[Abstract/Free Full Text]

6. Lippman ME. High-dose chemotherapy plus autologous bone marrowtransplantation for metastatic breast cancer. N Engl J Med 342 : 1119 -1120, 2000[Free Full Text]

7. Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 288 : 321 -333, 2002[Abstract/Free Full Text]

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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 Schrag, D. Articles by Somerfield, M. R. Search for Related Content PubMed Articles by Schrag, D. Articles by Somerfield, M. R. Related Articles Related Correspondence Social Bookmarking                            What's this?