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Journal of Clinical Oncology, Vol 26, No 28 (October 1), 2008: pp. 4542-4543 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.18.2147
Does Computed Tomography or Positron Emission Tomography Response After Neoadjuvant Chemotherapy for Resectable Non–Small-Cell Lung Cancer Predict Survival?Department of Radiology; Department of Pharmacology and Cancer Biology, Duke University Health System, Durham, NC Over the last several decades, measuring tumors on sequential imaging studies has played an essential role in managing patients with lung cancer. Using standardized Response Evaluation Criteria in Solid Tumors (RECIST) at designated time points, patients are stratified into a response category based on the percent change in tumor size.1 The RECIST guidelines represent an objective assessment of disease, are used to determine duration and reinstitution of therapy, and are ultimately intended as a surrogate marker to predict outcome. Interestingly, this paradigm has been propagated for decades2,3 without clear data to support that change in tumor size on radiologic studies will accurately reflect survival. The limitations in stratification by imaging criteria can probably be attributed to the arbitrary selection of percent change used to determine response categories and, more importantly, to the paucity of biologic information in an anatomic abnormality described on a radiographic study. Lung tumors are heterogeneous, and the host response is variable; often a robust inflammatory response to the tumor itself may produce the majority of the radiographic abnormality.4,5 Thus, although many investigators have suggested that more accurate tumor measurements, including three-dimensional volumetrics and better resolution, are needed to improve patient stratification, these technical features do not address the fundamental issue of the tumor's biologic behavior. In the current issue, Tanvetyanon et al6 report an intriguing prospective trial that examined the ability of changes in computed tomography (CT) or [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) before and after neoadjuvant chemotherapy for resectable non–small-cell lung cancer (NSCLC) to predict survival. This analysis was performed to help define an appropriate imaging evaluation for these patients so that therapy, and hopefully outcome, could be optimized. After thorough analysis, they found that the CT response as measured by the RECIST criteria seems to predict outcomes only in resectable stage III patients. They did not find a statistically significant correlation between the CT response and survival in resectable stage I and II disease. More interestingly, the investigators studied whether FDG-PET was a better predictor of survival compared with conventional imaging. No matter how the data were analyzed, the investigators could not find changes in FDG uptake that predicted outcome. Serial PET studies did not provide the requisite information needed to guide patient management. Although the numbers of patients in this study are relatively small, the conclusions are clear—change in tumor size on CT after neoadjuvant therapy for early-stage resectable NSCLC patients and change in FDG uptake after neoadjuvant therapy for all resectable NSCLC patients did not predict survival. This is a complex conclusion that begs the questions of how to best approach these patients if treatment is to be optimized and why this traditional, seemingly logical measurement strategy is ineffective. The fundamental concept that a tumor cell response equals tumor size response needs to be reconsidered. In some cases, therapy may destroy only the most susceptible tumor cells, leaving the more virulent resistant tumor cells to proliferate.7 In addition, if there is an increase in the inflammatory reaction, the lesion size could remain stable or even increase. In other cases, the tumor size could potentially decrease, but this may be a result of a reduction in the host inflammatory response, and tumor cells would remain or even propagate. It has been reported that survival correlates with tumor cell viability after therapy and not necessarily with the radiographic response.8 Despite these limitations, there is currently no alternative approach to response evaluation, and patients are still observed with serial imaging. It would be much more advantageous to work toward a system that predicts, at the time of diagnosis, the most favorable therapeutic plan. Unfortunately, although this is a laudatory goal, attempts to develop personalized medicine and targeted therapy have not yet proved sufficient to enter standard clinical practice. Thus, there remains an unmet need to develop better diagnostic tools. When FDG-PET was introduced into the imaging armamentarium, it was a new direction for radiology that extended beyond traditional anatomic and morphologic information. PET has proved to be useful in some scenarios in the thorax, including differentiating benign from malignant nodules and staging patients with lung cancer.9 However, the exact mechanism of FDG uptake and distribution within the various cells in a tumor remains unclear. Studies have shown no significant correlation between FDG activity in lung tumors and glucose transporters.10 Only through a better understanding of the molecular mechanisms that are responsible for radiotracer uptake and through rigorous imaging trials will the true utility of imaging oncology patients with PET be established. The study by Tanvetyanon et al6 focused on tumor response and did not report other imaging findings, such as treatment-related complications that may help guide patient management. However, the study findings elucidate several important issues concerning the use of imaging as a surrogate marker for outcome. First, although CT provides exquisite anatomic information, serial CT imaging is not optimal in most resectable patients as a predictive tool. Second, although PET has been shown to affect patient care in several well-defined clinical areas, changes in FDG uptake should not be used to guide therapy or predict survival. Third and most importantly, these studies support ongoing efforts to find better ways to determine optimal therapy at the time of diagnosis and better tools to evaluate response. Conventional imaging modalities, even with precise measurements and improvements in resolution, are ultimately not going to provide the diagnostic information required. As we begin to integrate tumor biology into clinical practice with the hopes of a personalized approach to medicine, new diagnostic strategies will be required if survival is to be improved. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: Edward F. Patz Jr, LabCorp REFERENCES
1. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 2. Gurland J, Johnson RO: Case for using only maximum diameter in measuring tumors. Cancer Chemother Rep 50:119-124, 1966[Medline] 3. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline] 4. Petersen RP, Campa MJ, Sperlazza J, et al: Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer 107:2866-2872, 2006[CrossRef][Medline] 5. Oremek GM, Sauer-Eppel H, Bruzdziak TH: Value of tumour and inflammatory markers in lung cancer. Anticancer Res 27:1911-1915, 2007[Medline] 6. Tanvetyanon T, Eikman EA, Sommers E, et al: Computed tomography response, but not positron emission tomography scan response, predicts survival after neoadjuvant chemotherapy for resectable non–small-cell lung cancer. J Clin Oncol 26:4610-4616, 2008 7. Dewhirst MW, Cao Y, Moeller B: Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 8:425-437, 2008[CrossRef][Medline] 8. Liu-Jarin X, Stoopler MB, Raftopoulos H, et al: Histologic assessment of non-small cell lung carcinoma after neoadjuvant therapy. Mod Pathol 16:1102-1108, 2003[CrossRef][Medline] 9. Marom EM, McAdams HP, Erasmus JJ, et al: Staging non-small cell lung cancer with whole-body PET. Radiology 212:803-809, 1999 10. Marom EM, Aloia TA, Moore MB, et al: Correlation of FDG-PET imaging with Glut-1 and Glut-3 expression in early-stage non-small cell lung cancer. Lung Cancer 33:99-107, 2001[CrossRef][Medline] Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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