Routinely staging gastric cancer with ¹⁸F-FDG PET-CT detects additional metastases and predicts early recurrence and death after surgery

The contemporary utility of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET-CT) in gastric cancer is unclear. While in esophageal and gastro-esophageal junctional (GOJ) cancer it has clear utility in identifying metastases [1, 2], experience in gastric cancer is limited to two small studies of locally advanced disease from Korea and America. This lack of experience is perhaps due to initial reports that gastric cancer (particularly the diffuse subtype) is frequently not avid [3]. PET-CT is therefore not recommended routinely in Europe [3, 4].

We recently reported a novel aspect of PET-CT’s utility in esophageal and GOJ cancer: metabolic nodal stage (mN). We found that patients with FDG-avid nodes within a standard lymphadenectomy field had a higher risk of disease progression before surgery and recurrence and death afterwards [5‐7]. However, whether this is true in gastric cancer is unclear, previously assessed by just two studies of Korean and Chinese populations [8, 9].

Radical treatment risks death and complications, and despite ostensibly curative surgery, recurrence remains common [10]. There is therefore an urgent need to improve staging to prevent futile treatment and develop prognostic markers. We have routinely staged patients with esophageal and gastric cancer with PET-CT for 10 years in the absence of unequivocal metastases on CT and conducted the largest retrospective study to date to determine its utility in a Western population.

Two hundred seventy-nine consecutive patients were identified (Table 1). EUS was performed in 61 (21.9%), laparoscopy in 220 (79.9%).

We found that routinely staging all patients with gastric cancer with ¹⁸F-FDG PET-CT was useful, both identifying unsuspected metastases and risk-stratifying patients. In 4.7% of patients, PET-CT identified unsuspected metastases which would not have been detected by conventional staging. One quarter of patients had FDG-avid nodes, which conferred a worse prognosis: a significantly higher risk of coincident incurable disease at staging and worse disease-free survival following surgery if curable (independent of clinical and pathological nodal stage). Utility was not influenced by the Lauren classification and was supported by decision theory and cost-effective in a limited economic model.

These findings build on a small number of retrospective studies. In a 2005 Korean study of 68 patients, Chen et al reported PET to improve staging by conferring greater sensitivity for identifying resectable metastases [22]; however, this study excluded patients with diabetes mellitus and performed PET without hybrid CT images and did not demonstrate greater sensitivity for distant metastases. Subsequently, Smyth et al reported selective PET-CT to identify occult metastases in 10% of non-consecutive patients with advanced (T3–4) gastric cancer in the USA, with a similarly favorable cost profile, although did not assess its utility in patients with less advanced disease and did not assess nodal avidity [23]. Some smaller studies have reported the presence of FDG-avid nodes to confer a worse prognosis, although in less defined cohorts. In 151 patients undergoing gastrectomy in Korea, Song et al found those with resectable FDG-avid nodes (SUVmax > 2.8) to have worse OS and DFS [8], although did not quantify mN stage. Moreover, this study assessed only patients with nodal involvement pathologically following surgery, by definition not assessing the utility of PET-CT in detecting metastases, and also excluding patients receiving NAC (the majority in clinical practice). In 2016, Wang et al assessed the latter in 50 patients in China, finding those with mN stage 2 had worse OS, but notably included patients undergoing non-curative surgery [9]. Coupe et al previously reported FDG-avid nodes to confer a worse prognosis in 68 patients with GOJ or gastric cancer, although did not assess the staging utility of PET-CT and also included patients undergoing non-curative treatment [24]. However, we believe ours to be the largest study to date, the first in a primarily Caucasian population of non-junctional cancer and also the first to demonstrate associations between avid nodes and metastatic disease. The latter suggests a mechanism by which FDG-avid nodes confer a worse prognosis, as a surrogate for a more aggressive and metastatic cancer phenotype. This is illustrated by the relative insensitivity but absolute specificity of PET-CT as regards nodal disease, suggesting the merit of PET-CT to be the identification of a subset of patients with nodal metastases with worse disease.

If validated, these novel findings have a number of implications. Firstly, they suggest that a sizable minority of patients when not staged by PET-CT have detectable metastatic disease and undergo futile radical therapy. Routine use of PET-CT might allow these patients to commence palliative therapies sooner and obviate the risks, complications, trauma, and costs of well-intentioned but ultimately futile treatment. Secondly, routine PET-CT may identify metastatic disease rendering laparoscopy and EUS unnecessary, similarly obviating their risks and costs (although both retain invaluable roles in patients without metastases evident on PET-CT). Thirdly, patients with FDG-avid nodes at staging may have a more aggressive phenotype.

This is independent of the mere presence of nodal metastases, suggesting FDG avidity is a useful surrogate biomarker. Such high-risk patients might be targeted for more intensive staging and restaging investigations. Finally, these patients (particularly those with a definitive mN stage before surgery) can be counseled more fully as to their prognosis, allowing them to make more informed decisions and undergo tailored surveillance.

These findings also highlight priorities for research. Our cohort was insufficient to determine whether restaging patients with PET-CT rather than CT is preferable, but intuitively the greater sensitivity of PET-CT should translate to restaging (as we previously reported in esophageal cancer) [13]. It is also unclear whether PET-CT may have similar utility in monitoring response of nodal metastases to NAC [6]. While we did not find mN stage to be an independent marker of prognosis once adjusting for pathological stage, this might be due to the limited number of patients with a definitive pre-operative mN stage.

We acknowledge our study to have a number of limitations and sources of bias; these include its retrospective nature—although by performing PET-CT routinely, we believe the potential for selection bias is minimal, and the results generalizable, although we acknowledge potential bias in the use of PET-CT to corroborate suspicious but equivocal metastases on prior CT; a study period spanning evolution in technology and clinical practice potentially introducing performance bias, as well as the need to consider cT2 and cT3 diseases as a single variable and its single-center nature. Consequently, prospective and external validation will be required. Our economic modeling was by necessity limited and conservative. We chose the UK NHS tariffs as a consistent and pragmatic estimate of costs; in reality, once additive costs are included, and most importantly those financial, physical and psychological costs incurred by patients and those supporting them, it is likely that the net savings of will be far greater. Beyond this, as our primary aim was to assess staging utility, we have included a number of patients with limited follow-up, with resultant detection bias and performance bias for prognostication. Also, by performing on-demand investigations for recurrence tailored to symptoms, it is again likely that some instances of recurrence in these patients are yet to be detected.

In summary, we found routine staging PET-CT to identify metastases in 7% of patient with non-junctional cancer, most of which would not be identified by conventional staging. This prevented patients receiving futile radical therapy, and its routine use was supported both by decision theory and limited economic modeling. Furthermore, PET-CT identifies patients with avid nodes who are at substantially higher risk of metastatic disease and a worse prognosis following radical treatment. mN stage therefore appears to be a novel and useful biomarker when staging non-junctional gastric cancer.