Ann Thorac Surg 2006;81:1082
© 2006 The Society of Thoracic Surgeons
Original article: General thoracic
Invited commentary
Jeffrey M. Piehler, MD
Department of Cardiothoracic Surgery, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160
(Email: jpiehler{at}kumc.edu).
Positron emission tomography (PET) scanning with 18F-FDG has significantly contributed to the management of esophageal cancer. This modality has a widely accepted benefit: (1) in the initial clinical staging of the disease, particularly regarding the detection of distant metastatic foci, (2) in the delineation of targets for radiation therapy, (3) in the assessment of response to neoadjuvant therapy with associated prognostic implications, and (4) in the detection and restaging of recurrence. An additional benefit of PET scanning is proposed by this provocative article by Rizk and colleagues [1] in that 18F-FDG-PET derived maximal standard uptake values (SUVmax) of the untreated primary tumor at presentation are strongly predictive of stage, and independently of survival.
Similar observations have been made for other malignancies, including lung cancer, but data pertaining to esophageal cancer have been sparse, particularly because of the confounding effects of neoadjuvant or adjuvant therapy, or both, which are currently offered to the majority of patients with the disease. The authors have appropriately selected out those patients who underwent surgery alone, with no other therapy, for analysis. The obvious price paid for this selectivity is a relatively small patient cohort, which the authors acknowledge, and which does emphasize the need for further confirmatory study. Nevertheless, the strongest clinical relevance of this work relates to those patients with early clinical and pathologic stage disease (T0-2 N0) who are frequently treated by surgery alone, and who represent the majority of patients in the study. Within this group, the SUVmax identified a previously occult subset with statistically worse survival, and for whom consideration of a more aggressive treatment plan would seem indicated. An additional proposal is that patients with high SUVmax determinations of the primary tumor at presentation should undergo enhanced scrutiny for metastatic lymph node or systemic involvement because of the greater likelihood of having advanced disease.
Although 18F-FDG uptake is generally acknowledged to be a measure of metabolic activity of the tumor, with increased uptake reflecting the enhanced substrate requirements of more rapidly proliferating cells, such is clearly the summation of a variety of biochemical, histologic, and environmental influences. Spurious factors, such as increased 18F-FDG uptake, as a consequence of radiation-induced inflammatory responses are eliminated by focusing upon the pretreatment scan. Inaccuracies in SUVmax as a consequence of diminished PET resolution of small tumors must be acknowledged. Furthermore, the SUV is proportional to the density of viable tumor cells and is diluted by loose histologic tumor architecture or tumor necrosis. Nevertheless, this article suggests that for esophageal cancer these factors do not mitigate the direct relationship between 18F-FDG uptake and tumor aggressiveness. Other studies with a variety of tumors have demonstrated that increased 18F-FDG uptake is associated with overexpression of cell membrane glucose transport proteins (such as Glut 1) and increased proliferative potential (as measured by Ki-67, Mib-1, mitotic cell count, and tumor doubling time), with resultant increased tumor invasiveness, increased metastatic potential, decreased response to therapy, and compromised survival. This article suggests similar relationships for esophageal cancer with the high PET SUVmax group being more likely to show high tumor grade, neural invasion, vascular invasion, more advanced stage, and worse prognosis.
This article provides further justification for the widely accepted practice of PET scanning at the presentation of patients with esophageal cancer, and it also lays fertile ground for further investigation. First, patients with early clinical stage disease but high SUVmax determinations seem to have a poor prognosis with surgery alone and may benefit from enrollment in neoadjuvant protocols, although this would require confirmation in an additional randomized study. Second, PET-derived SUV determinations after neoadjuvant therapy of esophageal cancer have been shown to be predictive of histologic response and survival in several studies. Although PET scans obtained both before and after neoadjuvant therapy seem to be independently informative in some facets, additional studies would be needed to determine if the benefits of two scans justify the cost. Third, additional studies will also be needed to establish an accepted cutoff in the continuous variable SUVmax above which adverse consequences would be anticipated. Fourth, the addition to the analysis of other tumor-specific variables, such as tumor size derived from computed tomographic measurements, may provide even more powerful prognostic information. Finally, more esoteric future study should investigate the possibility that increased 18F-FDG uptake reflects the presence of molecular markers of both tumor response to neoadjuvant therapy and overall survival, which, if present, could be exploited by preoperative targeted therapy. Perhaps PET scanning with isotopes other than 18F-FDG will prove fruitful in specific characterization of these tumors that could also be utilized therapeutically.
Although tumor stage has been accepted as the prime determinant of overall survival in esophageal cancer, clinical experience has taught that this often provides an incomplete picture of the true biologic profile of the tumor, most frequently for patients with apparent early stage disease. This article supports the concept that 18F-FDG uptake of the untreated primary tumor measured by SUV provides significant prognostic value independent of stage. Confirmation and expansion of these concepts has the potential to enhance our efforts in combating this challenging disease.
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References
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- Rizk N, Downey RJ, Akhurst T, et al. Preoperative 18[F]-fluorodeoxyglucose positron emission tomography standardized uptake values predict survival after esophageal adenocarcinoma resection Ann Thorac Surg 2006;81:1076-1082.[Abstract/Free Full Text]
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