An estimated 180,000 new cases of bronchogenic carcinoma will be diagnosed in the United States this year. Most patients present with advanced disease, as evidenced by an overall 5-year survival rate of 14%.1
In an effort to improve survival, a numerous prognostic factors, including stage at presentation, performance status, weight loss, and molecular markers, are used to stratify patients for optimal treatment regimens.2-11 Other features, such as tumor growth rates, reflected by the tumor doubling time, have also been shown to be closely related to prognosis.12-15 Most of these series, however, require sequential imaging and, realistically, have had limited clinical application. In a more recent study, a correlation between tumor doubling time and fluorine-18 fluorodeoxyglucose (FDG), a d-glucose analog, was demonstrated as measured by positron emission tomography (PET).16 To determine whether the amount of FDG uptake, a measure of glucose metabolism, has prognostic significance, we retrospectively reviewed all patients with a new diagnosis of lung carcinoma and an FDG-PET study and correlated this with survival.
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- MATERIALS AND METHODS
Bronchogenic carcinoma continues to represent a major health problem in the United States and is the leading cause of cancer death for both men and women. Screening trials have failed to demonstrate clearly a survival advantage, although recent reexamination of these studies suggests that there may be some benefit in high risk patients.19 A number of clinical, radiologic, and pathologic features are used typically in determining treatment options and prognosis, although stage at presentation appears to be the most influential predictor of outcome. Tumor markers, including blood group antigens, DNA content, ras, p53, and c-erB-2, have become interesting targets for analysis, with the hope of understanding some of the molecular changes in tumor cells, and in determining which markers carry prognostic significance.2, 2-10, 20-28 Surface antigens or receptor overexpression may also help stratify patients into the most appropriate treatment protocols and, thus, improve survival rates.
Tumor growth rates and doubling times, as documented by sequential imaging studies, have also been shown to be related prognosis, although following lesions with repeat films is of limited practical value.12-15, 29-31 More recently, the amount of FDG-PET uptake in primary lung lesions has been shown to have a direct relation to tumor growth,16 and immunohistochemical analysis of cell membrane glucose transporter (Glut1 and Glut3) protein overexpression was correlated with a poor outcome.32 These data suggest that, presumably, tumors with increased glucose uptake are more metabolically active and more biologically aggressive.
Although the utility of FDG-PET imaging for diagnosing and staging lung carcinoma is well established,33-39 its potential as a prognostic marker has yet to be determined. FDG-PET takes advantage of one of the basic properties of tumor cells, increased glucose metabolism, and, theoretically, uses this feature in differentiating benign from malignant abnormalities. Although the sensitivity for detecting malignant lung lesions is high, the specificity is less than optimal. A spectrum of benign abnormalities has shown increased FDG uptake.33-36 It has become clear that FDG not only accumulates in tumor cells, but there is a component from the surrounding inflammatory immune response. A recent study demonstrated FDG uptake in a breast carcinoma animal tumor model and indicated that cancer cells were the main site of uptake, with only 20% uptake in nonneoplastic components.40 Other studies, however, have shown that FDG uptake is in predominately nonneoplastic cells. Kubota et al.41 indicated in their studies that the highest concentration of FDG uptake in FMA3A tumors in mice was found in newly formed granulation tissue around the tumor and in macrophages. In addition, Yamada et al.42 showed FDG accumulation in experimental turpentine-induced inflammatory tissue in rats, with highest concentration in areas with fibroblasts, endothelial cells from blood vessels, macrophages, and neutrophils. Although the specific cells of FDG accumulation within tumors remains a complex issue, our initial experience suggested that the more metabolically active the tumor, the worse the outcome.
This study addressed the role of FDG-PET in providing prognostic information and its potential to serve as a guide for therapeutic options. Univariate analyses showed that patients with tumors having an SUR >10 had a significant decrease in survival by approximately 13 months compared with those with an SUR < 10. Multivariate analyses revealed that an SUR > 10 provided prognostic information in addition to the clinical stage and lesion size. Thus, patients with tumors that are more active metabolically, as demonstrated by FDG-PET studies, should be considered to be at high risk for relapse regardless of clinical stage at presentation.
In addition (and more statistically significant), multivariate analysis demonstrated that the combination of increased SUR and large lesion size identified a subgroup of patients with the worst prognosis and a median survival of less than 6 months. These data may prove useful in several clinical scenarios. Patients with early Stage I or II disease and a large hypermetabolic lesion may benefit from chemotherapy and/or radiotherapy following surgery. There are currently no clear data that support the possibility that additional treatment in this setting improves survival. If a high risk group of these patients who realistically have microscopic metastasis at presentation could be identified, then improved outcomes may be possible. Those patients with more advanced Stage III or IV disease and a large hypermetabolic lesion may require a different treatment regimen than those with smaller, less metabolically active lesions. At this time, however, it is not clear whether a more aggressive treatment will improve survival, because the biology of these tumors may preclude successful tumor reduction or irradication with current therapeutic options.
Although, in some series, cell type and degree of differentiation may have prognostic value, there was no correlation with FDG uptake. This confirms a basic property of tumors, increased glucose metabolism, but it does not suggest that specific cell types or anaplastic tumors have more glucose utilization as demonstrated by FDG-PET.
In conclusion, these data indicate that FDG uptake in the primary lesion on PET studies in patients with lung carcinoma can provide prognostic information. We suggest that this may be important information when determining treatment options, particularly in patients with larger lesions, and further studies assessing patient survival following various therapeutic protocols are recommended.