In this study, higher baseline SUVmax of esophageal cancer was significantly related to a middle-third tumor location and a cT3/4 stage, whereas higher TLG was related to cT3/4 and cN + stage. Baseline SUVmax >8.25 g/mL, TLG > 41.7 and MTV > 10.7 cm3 were associated with cT/4 stage, whereas SUVmax ≥12.7 g/mL predicted early recurrence and poor disease-free survival.
Currently, 18F- FDG PET/CT is mostly used for the detection of distant metastases as it can identify suspicious lesions as small as 1 cm [2, 14, 15]. Walker et al reported 18F- FDG PET/CT -detected distant lesions precluding curative treatment in 21% of patients [15], even though the specificity of an FDG ‘hot spot’ remains low [16]. Until recently, limited spatial resolution of PET for esophageal wall layers and adjacent structures had restrained this modality as a detector of distant metastases [15]. Recent data, however, reinforce the role of 18F- FDG PET/CT in better defining cTNM stage and the tumor’s biology, the latter being FDG-avid in 84–92% of cases especially if it infiltrates the submucosa [7, 15, 17].
It is generally admitted that all 18F- FDG PET/CT-derived parameters are higher in advanced and aggressive tumors, however no universally accepted cutoffs exist to this day, limiting their cTNM staging value in the individual patient. Malik et al suggested SUVmax > 4.1 (sensitivity 85%, and specificity 48%) and MTV > 23.4 cm3 (sensitivity 64%, specificity 67%) as optimal thresholds to distinguish cT1/2 from cT3/4 lesions [7]. In our study, SUVmax and TLG presented a higher predictive value than MTV in preoperative staging; ROC curve analysis yielded as significant cutoff values to predict preoperative cT3/4 status with high accuracy a SUVmax >8.25 g/mL, TLG > 41.7 and MTV > 10.70 cm3. This discrepancy may be explained by the predominance of adenocarcinoma in the Malik study (75% of patients, versus 53% in the present study); adenocarcinoma has being described as less FDG-avid with lower SUVmax values compared to squamous cell cancer, probably in relation to increased expression of the HK-II biomarker [3, 13]. However, as in our study tumor histology was not independently associated with SUVmax (Table 2), no separate cutoffs of SUVmax were justified for each type.
One might argue that EUS is sufficient to identify locally advanced lesions (cT3/4 or N+) and thus to direct the patient to neoadjuvant treatment before surgery. However, previous data from our institution suggest a rather low rate of accurate usT (51%) and usN (72%) staging, with the highest rates of understaging among active smokers [18]. Indeed, a three-modality workup strategy (18F- FDG PET/CT, CT and EUS) offers the highest probability (84%) to correctly select patients for surgery, a fortiori when 18F- FDG PET/CT is the first exam performed [3]. Complementary use of these exams could improve staging accuracy, directing patients with locally advanced lesions to neoadjuvant treatment and avoiding its unnecessary toxicity for early-stage tumors.
Although several studies have reported poor long-term prognosis associated with high baseline SUVmax its prognostic value for the individual patient remains limited, as great variability is seen in the suggested cutoffs (ranging from 3 to 9 g/mL) [16, 19–22]. This variability might be linked to patient-related factors (e.g. cardiac output, tumor histology) but also to the PET/CT configuration and interobserver variability. To overcome these limitations, tumor-to-blood Standard Uptake Ratio (SUR) has been recently published as a promising predictor of survival [23, 24]. Hofheinz et al [23] suggest the superiority of baseline SUR over SUVmax to predict overall survival in squamous cell cancer patients treated with definitive chemoradiation, whereas Bütof et al [24] propose the restaging SUR value along with baseline MTV as a reliable survival predictor. In a recent meta-analysis, Han et al reinforce the prognostic value of MTV and TLG for overall survival, although no specific cutoff value is suggested and both histological types are jointly taken into account [8]. In the present study none of the 18F- FDG PET/CT derived parameters demonstrated significant association with overall survival.
The added value of our study lies in the identification of SUVmax >12.7 g/mL as an independent predictor of early tumor recurrence, within the 1st postoperative year. This result is of major clinical importance, as it might help early identification of patients with resectable esophageal cancer, who may not benefit from surgical resection as their risk of short-term recurrence is significantly increased. Indeed, we observed a significantly shorter DFS for squamous cell tumors with a baseline SUVmax >12.7 g/mL; as definitive chemoradiation is a valid treatment option for this histological type, the above threshold may provide valuable prognostic information for the individual patient and guide accordingly therapeutic management. Schreurs et al. previously reported worse DFS for patients with baseline SUVmax >3.67 g/mL, although no correlation with overall survival was found in that study either [3]. Markers of aggressive biology (GLUT-1, p53, Ki-67, HK-II) were studied in relation to SUVmax, although no clear immunohistochemical profile was found for high-FDG uptake tumors compared to the others [3]. Thus, even though it is generally admitted that high baseline SUVmax may herald tumor aggressiveness and early recurrence, the underlying mechanism remains poorly understood. Our team previously reported active smoking as an independent predictor of early recurrence after esophagectomy [25], which is being confirmed in the present analysis along with a baseline SUVmax >12.7 g/mL, and may express pathologic DNA-methylation patterns and tumor proliferation genes [26].
This study has some limitations that need to be addressed. Retrospective analysis has an inherent drawback in data completeness, even though our institutional database is maintained prospectively, with a stringent follow-up of all patients. The use of two different PET/CT scanners over the years might have introduce some bias in SUVmax measurements especially in the smaller-volume lesions, because of a better resolution recovery in the newer PET/CT scanner (from September 2011 and thereafter). However, both scanners measured similar SUV for lesions above 1.2 cm diameter (about 4 cm3). Since the mean MTV in our series was well above this threshold (48 cm3 ± 83 cm3), it can be estimated that this scanner change had little effect on the results. Moreover, we compared the SUVmax across both scanners in lesions with a MTV ≥ 30 cm3 (where SUVmax would be similar with both scanners) vs. lesions < 30 cm3, where the new scanner could measure SUVmax better. No differences were observed across scanners in the large lesions (MTV ≥ 30 cm3: SUVmax 20.6 ± 7.8 g/mL for the new scanner vs. 17.3 ± 12.0 g/mL for the previous one, p = 0.36). This was also the case for the smaller lesions (MTV < 30 cm3: SUVmax 9.9 ± 4.9 g/mL for the new scanner vs. 11.9 ± 4.4 g/mL for the previous one, p = 0.17). Results of this comparative analysis between the two CT scans are provided as supplementary material, and enhance our belief that the scanner change could not influence significantly our results.
Although there was practically no heterogeneity in 18F- FDG PET/CT results over the years, inaccuracies in the preoperative workup may have occurred for both T and N staging especially with EUS, confounding associations with 18F- FDG PET/CT parameters. As mentioned above, histological type and patient-related factors may influence 18F- FDG PET/CT-derived parameters and limit the use of universally accepted cutoffs. In the present study, due to the small number of patients per histological type our subgroup analyses can be considered as exploratory, needing validation in larger cohorts. Prospective validation of the suggested cutoffs should take into account the specificities of histological types studied.