Prognostic significance of fluorodeoxyglucose uptake in non-small cell lung cancer. A blurry picture?

Noninvasive assessment of tumor grading and prediction of patient outcome were among the first applications of positron emission tomography (PET) in oncology (1). Since then, the relationship between tumor glycolytic activity, as measured by the metabolism of the glucose analogue fluorodeoxyglucose, and patient survival has been analyzed in a variety of malignant tumors. In non–small cell lung cancer (NSCLC), a series of studies has indicated that high tumor fluorodeoxyglucose uptake is associated with a poor prognosis, irrespective of tumor size or stage (2–6). Furthermore, studies have indicated that tumor fluorodeoxyglucose uptake is correlated with tumor cell proliferation and grading (7, 8), further supporting the concept that fluorodeoxyglucose-PET allows noninvasive assessment of the biological aggressiveness of the tumor tissue and provides prognostic information. In this issue of Clinical Cancer Research , Vesselle et al. (9) report the results of a prospective study evaluating the relationship between tumor fluorodeoxyglucose uptake and patient survival in 208 patients with potentially resectable NSCLC. In accordance with previous studies, the authors found that ‘‘high’’ tumor fluorodeoxyglucose uptake [defined in this study as a standardized uptake value (SUV) of >7] was significantly correlated with patient survival, although the association was weaker than reported in previous studies (hazard ratio, 2.01). However, tumor fluorodeoxyglucose uptake was not an independent prognostic factor in a multivariate analysis, including tumor size (measured by computed tomography) and stage. Tumor stage was determined by fluorodeoxyglucose-PET and computed tomography and confirmed by histopathology. Several statistical, methodologic, and biological factors need to be considered when trying to understand these unexpected results. The first question is whether the study was adequately powered to detect a significant correlation between tumor fluorodeoxyglucose uptake and survival. The article does not include a formal power analysis, but there is little doubt that the study had enough power to detect such a relationship in the whole group of patients because previous publications (3, 6) have unanimously reported that high tumor fluorodeoxyglucose uptake is a very strong prognostic factor (hazard ratio, >3). However, in patients within one stage group, the correlation between fluorodeoxyglucose uptake and patient survival was less strong or absent in some studies (2, 10, 11). Thus, the study by Vesselle may still have been underpowered to detect survival differences in the subgroup analyses. It is also important to emphasize that most of the previous studies evaluating the correlation between tumor fluorodeoxyglucose uptake and patient survival were retrospective and used post hoc, data-driven definitions of ‘‘high’’ fluorodeoxyglucose uptake. Thus, they might easily have overestimated the prognostic significance of tumor fluorodeoxyglucose uptake because definitions of ‘‘high’’ and ‘‘low’’ fluorodeoxyglucose uptake were selected to maximize differences in patient survival. Furthermore, threshold values for a ‘‘high’’ tumor SUV range from 5 to 20 (2, 3, 5, 6, 12), suggesting a considerable heterogeneity of patient populations and/or data analysis. Methodologic differences include the use of average or maximum tumor fluorodeoxyglucose uptake, differences in the start of data acquisition, etc. A further concern about retrospective studies is the accuracy of tumor staging, especially in nonsurgically treated patients. This may have made stratification of patient survival by tumor stage inaccurate. On the methodologic side, the study by Vesselle et al. (9) used partial volume-corrected SUVs in addition to raw SUVs, whereas most previous studies used only raw SUVs. Partial volume effects occur when lesions are smaller than the resolution of an imaging system. In PET, this causes the activity within a lesion to be blurred over an area larger than the actual lesion. This results in the activity within such a lesion being underestimated (13). For typical whole-body fluorodeoxyglucose-PET scans, partial volume effects become significant for lesions <2 to 3 cm, with the magnitude of the effect increasing with decreasing size of the lesion. For lesions with a diameter of <1.5 cm and a typical image resolution of 0.7 cm in clinical whole-body studies, partial volume effects become severe, resulting in a >50% underestimation of the true activity. Applied to NSCLC, this means that fluorodeoxyglucose uptake of T1 tumors (diameter, <3 cm) is systematically underestimated by PET imaging. Consequently, the SUV of a 1.5-cm T1 tumor will be significantly lower than that of a 5-cm T2 tumor, even if the true fluorodeoxyglucose uptake by these tumors is identical. Thus, partial volume effects can cause a spurious correlation between tumor fluorodeoxyglucose uptake and tumor size or stage. Because tumor size is a strong prognostic factor in NSCLC, partial volume effects would also lead to an apparent correlation between tumor fluorodeoxyglucose uptake and patient survival, even if the true fluorodeoxyglucose uptake of all studied tumors were identical. SUVs of small lesions can be corrected for partial volume effects, if their size and shape are known (13). Vesselle et al. (9) used computed tomography measures of lesion size to estimate Editorial