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Originally published as JCO Early Release 10.1200/JCO.2005.07.007 on September 26 2005 © 2005 American Society of Clinical Oncology.
Use of Positron Emission Tomography Scans in Ovarian Cancer: A Diagnostic Technique in Search of an IndicationThe University of Texas M.D. Anderson Cancer Center, Houston, TX Recent evidence that specific molecular abnormalities strongly influence the activity of gefitinib in lung cancer,1 and trial results demonstrating the effectiveness of trastuzumab employed as breast cancer adjuvant therapy in the presence of HER-2 overexpression,2 emphasize the relevance of diagnostic testing in influencing cancer patient management. Furthermore, based on existing data, it is reasonable to conclude that the development of novel biologic markers and innovative imaging strategies have the realistic potential to alter substantially the approach oncologists traditionally use to both initiate and modify anticancer treatment. However, as in other areas of oncology, the enthusiasm for promising new diagnostic tests must be accompanied by appropriate and critical analysis of what has been claimed.3 Thus, one might reasonably propose several questions to be asked of all investigators who suggest in their publications (or in public discussions) that any new strategy should leave the realm of investigative medicine and become an established component of the standard-of-care in a particular clinical setting (Table 1).
In this issue of the Journal of Clinical Oncology, Avril et al4 report the results of a prospective evaluation of the utility of sequential [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) in patients undergoing neoadjuvant chemotherapy for ovarian cancer. Although the investigators are to be commended for performing a prospective examination of this issue, and their article appropriately notes the limitations of the current analysis, it is important to answer the questions outlined in Table 1, particularly because the researchers conclude that "FDG-PET predicted patient outcome as early as after the first cycle of neoadjuvant chemotherapy and was more accurate than clinical or histopathologic response including changes in tumor marker CA-125," and that "FDG-PET appears to be a promising tool for early prediction of response to chemotherapy." QUESTION 1 The investigators draw their conclusion regarding superior "accuracy" based on a total sample size of only 33 individuals (four additional women initially included in the study were excluded from the analysis), receiving different treatment regimens, and who presented with varying stages, tumor grades, and evidence of lymph node involvement. Furthermore, the justification for use of the particular definitions of "CA-125 response" or "histopathologic response" in this analysis is unclear. However, of perhaps even greater concern is the fact the sample sizes comparing responders to nonresponders are extremely limited. For example, only four patients in this series had a CA-125 decrease of less than 75% (defined as nonresponders by CA-125 criteria), and only six patients achieved a histopathologic response. The criticism here is not for the legitimate attempt of the investigators to analyze their data rigorously, but rather for the appropriateness of the specific study design and the interpretation of the findings. QUESTION 2 Even if one accepts the statement that changes in PET scan results obtained after the first and third cycles of chemotherapy provide accurate prognostic information not available through other standard measures (such as known pretreatment extent of disease, clinical evidence of response, or changes in CA-125 antigen level), how does this information influence subsequent patient management? Is there any evidence that treatment should be altered if the anticipated median survival in advanced ovarian cancer is 39 months (metabolic response) versus 20 months (no metabolic response), as claimed in this report? Can one justify switching from an evidence-based standard treatment of a platinum and taxane chemotherapy regimen to an alternative strategy based on these data? If not, is the only current value associated with this information that one can inform a patient that her overall prognosis is somewhat better or worse than the median? QUESTION 3 The substantial costs associated with newer diagnostic imaging techniques, including PET scans, are well recognized, especially if more than a single scan were required, as in the Avril study. Based on an objective assessment of available data, is there reason to believe the prognostic information (discussed in Question 2) made available through this testing can justify the costs of even a single scan? QUESTION 4 Does the analysis permit the conclusion (or even the suggestion) that the performance of a PET scan in ovarian cancer patients receiving neoadjuvant chemotherapy will provide data of greater benefit to the patient compared with what is currently routine clinical evaluation (physical examination, status of cancer-related symptoms, CA-125 blood tests, and the judicious use of abdominal/pelvic computed tomography scans)? In this discussion of the potential clinical utility of PET scans in ovarian cancer, it is appropriate to reflect on the experience with the performance of a second-look laparotomy or laparoscopy in this patient population, outside the setting of an investigative trial. It is now well recognized that although surgical reassessment can define the presence or absence of macroscopic disease within the peritoneal cavity, it cannot document the disappearance of residual microscopic cancer.5,6 Of greater importance, there is no evidence currently that specific modifications of patient management based on the surgical findings influence an individual patient’s ultimate outcome.7,8 Therefore, although the results of this invasive diagnostic test may be of prognostic significance, just as favorable or unfavorable changes in PET scan findings may educate the clinician regarding the biology of the disease process in an individual patient, currently there is no evidence they can be used to predict a more beneficial management strategy. This experience should be remembered when considering the clinical utility of PET scans, or any other new diagnostic modality in patients with ovarian cancer. Finally, at a time of rapidly escalating health care costs (significantly influenced by the introduction of new medical technology),9,10 when the future existence of major companies has been linked to their ability to control medical expenditures,11 and when disquieting questions have been raised regarding the appropriateness of physician use of expensive imaging modalities,12 it becomes increasingly important that the entire oncology community actively participate in this critical assessment of the genuine benefits of these new diagnostic tests. Thus, if modification of disease management based on PET scan results can be shown, through the conduct of appropriately designed prospective clinical evaluations, to affect favorably a meaningful clinical outcome (such as overall survival or reduction in major treatment-related morbidity) in specific settings in women with ovarian cancer, and not merely inform an oncologist and the patient that the news is "relatively bad" or "relatively good," the modality should be routinely used in those settings. However, in the absence of such data, the test should remain in the realm of investigative oncology. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest.
REFERENCES
1. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004
2. Tuma RS: Trastuzumab trials steal show at ASCO meeting. J Natl Cancer Inst 97:870-871, 2005
3. Tatsioni A, Zarin DA, Aronson N, et al: Challenges in systemic review of diagnostic technologies. Ann Intern Med 142:1048-1055, 2005 4. Avril N, Sassen S, Naehrig J, et al: Prediction of Response to Neoadjuvant Chemotherapy by Sequential F-18-Fluorodeoxyglucose Positron Emission Tomography in Patients With Advanced-Stage Ovarian Cancer. J Clin Oncol 23:7445-7453
5. Copeland LJ, Gershenson DM: Ovarian cancer recurrences in patients with no macroscopic tumor at second-look laparotomy. Obstet Gynecol 68:873-874, 1986
6. Rubin SC, Randall TC, Armstrong KA, et al: Ten-year follow-up of ovarian cancer patients after second-look laparotomy with negative findings. Obstet Gynecol 93:21-24, 1999
7. Nicoletto MO, Tumolo S, Talamini R, et al: Surgical second look in ovarian cancer: A randomized study in patients with laparoscopic complete remission—A Northeastern Oncology Cooperative Group-Ovarian Cancer Cooperative Group Study. J Clin Oncol 15:994-999, 1997 8. Greer BE, Bundy BN, Ozols RF, et al: Implications of second-look laparotomy in the context of Gynecologic Oncology Group Protocol 158: A non-randomized comparison using an explanatory analysis. Gynecol Oncol 88:156, 2003[CrossRef]
9. Bodenheimer T: High and rising health care costs. Part I: Seeking an explanation. Ann Intern Med 142:847-854, 2005
10. Bodenheimer T: High and rising health care costs. Part II: Technologic innovation. Ann Intern Med 142:932-937, 2005 11. Welch D, Beucke D: Why GM's plan won't work. Business Week. May 9, 2005 12. Armstrong D: MRI and CT centers offer doctors way to profit on scans. Wall Street Journal. May 2, 2005 Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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