Temporal validation of metabolic nodal response of esophageal cancer to neoadjuvant chemotherapy as an independent predictor of unresectable disease, survival, and recurrence

We recently reported the new concepts of metabolic nodal stage (mN) and response (mNR) of esophageal and gastro-esophageal junction (GEJ) cancer to neoadjuvant chemotherapy (NAC) [1, 2]. We found that patients with FDG-avid nodes within a standard lymphadenectomy field on ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) that persisted despite NAC (i.e. lacking a complete metabolic nodal response, CMR) were more likely to suffer disease progression during NAC which prevented resection (i.e., distant metastases, or locally unresectable disease). Furthermore, if resection was performed successfully, these patients were more likely to suffer disease recurrence. This was independent of pathological stage, and both pathological and metabolic regression of the primary tumor [1, 2], suggesting mNR to be a surrogate of regression of nodal metastases to NAC. Indeed, in some patients notable disparity was seen between primary and nodal response, suggesting mNR might represent a surrogate of the chemosensitivity of different clones, and perhaps by extrapolation occult distant metastatic clones.

mNR therefore represents a potentially novel and actionable biomarker of the success both of NAC and radical lymphadenectomy, for which there is an urgent need [3‐6]. Such a marker might have the potential to monitor response to NAC and perhaps personalize therapy, while also better prognosticating before surgery, and stratifying the risk of recurrence thereafter. To our knowledge, no studies have subsequently assessed mNR as a marker of disease progression and recurrence. We aimed to perform the first validation study of mNR as a marker of disease progression and recurrence, using a temporal cohort of patients immediately consecutive to our discovery cohort.

We previously reported lack of complete metabolic nodal response of esophageal cancer to NAC to be a new and independent predictor of disease progression to unresectable disease [1], death, and recurrence [2]. In this validation study of an immediately consecutive cohort of 200 patients, we confirmed these associations and were able to risk stratify recurrence and death within 1 and 2 years. Compared with our development cohort, effect sizes were entirely consistent for prognosis. That for unresectable disease while significant and consistent, was less clear, reflective of a reduction in event rate overall with time.

These findings have a number of implications. Most immediately, mNR appears to a simple way to risk stratify patients before surgery, firstly identifying patients at higher risk of occult disease resulting in an abandoned resection. Guidelines presently recommend restaging with CT to exclude disease progression before surgery [16]. We previously reported PET-CT to be more sensitive [1]; however, this still failed to identify incurable disease in 5% of our patients. Identifying lack of complete mNR might allow these patients to undergo additional investigations (such as laparoscopy, thoracoscopy, or magnetic resonance imaging). These patients may also benefit from more personalized and realistic information about their immediate risk of an abandoned resection, and medium- and long-term prognosis if surgery is successful. While this may not routinely alter practice—other than for patients unclear as to whether to proceed with surgery—patients can receive more realistic information before consenting to surgery. While there is little evidence or consensus as to follow-up, mNR might be incorporated into decision support tools for targeted surveillance, and future editions of the TNM classification. Finally, the suggestion that patients with avid nodal disease, seemingly in the absence of pathological nodal disease, have a worse prognosis than those without either is notable. Such instances might be dismissed as false positives on PET-CT, but the converse might be true, with these instances identifying occult but viable nodal micrometastases.

Biologically, this statistical independence of pN and mNR is intriguing. As evidenced by the prognostic significance of a novel pNmN hybrid stage, avid nodal metastases confer a worse prognosis than non-avid metastases. This suggests persistent nodal avidity to be a surrogate of a worse cancer phenotype. While the reasons for nodal avidity are complex and incompletely understood (perhaps reflecting mutational burden disrupting glucose utilization, in conjunction with tumor micro-environment, perfusion, and hypoxia), at a simplistic level, it may be possible to infer chemo(in)sensitivity. We previously reported primary tumor response on PET-CT (mTR) to be an imperfect surrogate of pathological response (pTR) [17], in agreement with other groups [18], including its successful use within the MUNICON trial [19]. Esophageal cancer comprises a limited number of cancer clones, which vary genomically and probably phenotypically, including their chemosensitivity and propensity to metastasize [20]. Nodal metastases may therefore comprise just one or two selected oligoclones [21, 22]. We, and other groups, have previously reported dramatic clonal evolution within the primary tumor during the selection pressure of NAC [23, 24], with chemo-resistant clones tending to persist or emerge, while chemosensitive clones are lost. Lack of mNR may therefore be an indicator of chemo-resistant clones within resectable lymph nodes, and therefore by extrapolation, a surrogate for the occult distant nodal or hematogenous micrometastases that are responsible for recurrence. This hypothesis is supported by evidence that nodal downstaging, evidenced by imaging in conjunction with pN stage, represents an independent prognostic marker, likely a surrogate of pathological nodal regression [25, 26]. Whether this plausibly might be used to guide neoadjuvant and adjuvant therapy is unknown.

While this study provides temporal validation of mNR as a biomarker, we acknowledge a number of limitations. Firstly, this represents a single-center study with a degree of subjectivity inherent to all imaging studies (although one subject to a rigorous MDT process); whether these findings can be generalized to other centers and imaging platforms is not clear. However, similar results have been reported from Japan [27] following largely platinum-based NAC as a marker of overall survival (although recurrence was not assessed). While we previously found no differences across reconstruction platforms [2], these, and other variables (such as NAC regimen) inevitable of evolving practice, may exert subtle effects we were unable to identify. We were also unable to reliably adjust for adjuvant therapy, and there may be additional factors that we have failed to identify. Secondly, detection biases have been introduced by “on-demand” investigations for recurrence rather than surveillance imaging. Thirdly, while we found consistent direction and sizes of effect for prognosis compared with our development cohort, we saw fewer patients overall with occult unresectable disease resulting in an abandoned resection. This probably reflects improvements in care with time, and hence while the association persisted, its effect size is likely to be less accurate, and requires further validation.

In conclusion, in a cohort of 200 patients immediately consecutive to our discovery cohort, we found lack of a complete mNR (i.e., the development or persistence of avid nodes despite NAC) to again be an independent and seemingly consistent marker of disease progression, recurrence, and death after surgery. This temporal validation provides supportive evidence justifying the assessment of mNR as a new candidate biomarker for these endpoints in external validation sets. If supported, mNR might represent a new mechanism by which to both risk stratify patients and personalize therapy with esophageal and GEJ cancer.