Esophageal carcinoma (EC) comprises two well-defined histotypes, such as squamous cell carcinoma (SCC) and adenocarcinoma (AC), which are different each other in terms of etiology, epidemiology, prognosis and response to therapy (1). Unfortunately most studies about EC and even gastric cancer (GC) included indifferently SCC and AC, therefore making difficult to correlate the outcome to the specific histotype (2-6).
As reported in the American Joint Committee on Cancer (AJCC) 7th edition, the pathologic stage of EC comprises T1b (which invades submucosa), T2 (muscularis propria), T3 (adventitia) and T4 (adjacent structures). The N0 is correlated with stages up to the IIA and N+ regards stage IIB onwards. The T3–4 anyN and anyT N+ (IIA to IIIC stages) are defined as locally advanced and the T1–2 N0 (IA and IB stages) as localized.
The global prognosis of patients with EC remains poor, with 18% all-stages 5-year survival rate, 41% for localized and 23% for locally advanced (7). Prognosis is poorer for locally advanced SCC compared with AC (8).
While preoperative chemoradiation (CRT) (5) and perioperative chemotherapy (CHT) (6,9) compared with surgery alone have been demonstrated effective in locally advanced EC it is unclear if CHT or CRT are superior to surgery alone in localized EC. If on one hand respective surgery was always considered the first choice for the localized clinical stages on the other hand it should be taken in mind that the clinical stage could not correspond with the same pathologic stage after upfront surgery. This is particularly true for the cT2N0M0 (10). Of course the risk of clinical under-staging is directly correlated with the type of the staging work-up. For patients’ candidate to esophagectomy it is now recommended that the staging should include a neck-Chest-Abdomen CT-scan, an endoscopic ultrasound (EUS) and an FDG-PET/CT (11). However, it has been described that even with a staging including EUS and FDG-PET/CT, cN0 became pN+ after an upfront esophagectomy in 39% to 55% of cT2N0 patients (10,12,13).
On this basis localized EC were enrolled in the chemoradiotherapy for oesophageal cancer followed by surgery study (CROSS) trial (5), which demonstrated that induction CRT following by esophagectomy was superior to upfront esophagectomy. However the vast majority of tumors included in the CROSS trial were clinically locally advanced (around 80% cT3 and around 65% cN1). Furthermore despite a detailed clinical and pathological nodal assessment (cN0 31% and pN+ 75% in the upfront surgery arm) no data about the up-staging related to the cT2N0M0 were reported. The tumor population of CROSS trial was quite heterogeneous with about 60% low-third and about 15% middle third EC as the main sub-groups; moreover 75% of the whole population were AC. The Authors concluded that preoperative CRT improved survival among patients with potentially curable EC or esophagogastric-junction cancer, therefore including the cT2N0M0 as well.
The precise hypothesis that the neo-adjuvant treatment could be effective in clinically localized EC was the basis of the phase III trial FFCD 9901, comparing pre-operative CRT with upfront surgery in 195 patients with stage I–II EC, based on the AJCC TNM 5th edition (14). All tumors were thoracic EC, 90% below carina; 70% were SCC. Patients were enrolled on the basis of the 5th edition of the AJCC TNM Classification (15). Staging was based on Chest-Abdomen CT and EUS; 53% of patients had a stage IIA (cT2N0M0). No stage-migration data were reported.
This study showed no survival benefit in the CRT arm, although the tri-modal approach produced a significant advantage in locoregional recurrence and recurrent disease rate. A well scheduled pathological staging was reported for patients undergoing resection, with almost 40% of pathological stage III in the surgery arm, and about 12% in the CRT arm. Despite the Authors stated that upfront esophagectomy should be the first choice for localized EC, no definitive conclusions can be drawn for cT2N0M0, since a related sub-group analysis was not conducted.
Two previous trials had attempted to investigate neo-adjuvant CRT compared with surgery alone in early-stage EC (16,17). However the power of both were limited by suboptimal staging procedures, a non-standardized surgical approach and outdated neo-adjuvant treatment regimens. In the study by Le Prise et al., clinical staging using CT scan was not performed routinely, whereas EUS and FDG-PET/CT were not performed at all; the histologic analysis of patients treated solely with surgery revealed that more than half of patients had a locally advanced rather than an early-stage disease. In the study by Bosset et al., no survival benefit was shown, with significantly more post-operative deaths after neo-adjuvant CRT.
A major solid answer should derive from a randomized prospective trial in the specific setting of cT2N0M0 that has never been conducted so far. Currently we have only data from retrospective studies showing contrasting results.
In this journal, Markar et al. reported findings from a retrospective multi-center European study, the FREGAT, about 355 patients with cT2N0M0 EC, extrapolated by a website referring to 30 French-speaking European centres (18). All patients had been staged with CT scan and upper digestive US. Their findings were in line with FFCD 9901 trial and failed to demonstrate a benefit of induction therapy in terms of survival compared to upfront surgery, regardless of pathological TNM. The only advantage was described for the pathological T and N down staging. Additionally, despite retrospectively analyzed, the FREGAT study showed that the benefit of surgery was preserved independently from histotype (SCC or AC) and type of neo-adjuvant treatment (CRT or CHT). However some weaknesses of this study should be highlighted. Firstly, almost 18% of patients received an adjuvant therapy, which could have partially affected the outcome; secondly, the type of adjuvant treatment administered was not specified, if RT or CHT or both.
The aforementioned data (prospective and retrospective) seem to indicate that induction therapy of cT2N0M0 EC is not effective, even though the answer to the question if an upfront surgery or induction therapy should be preferred in cT2N0M0 EC is still pending. Probably the right question should be which cT2N0M0 patients deserve an induction therapy and which not? A recently published retrospective study addressed this issue, reporting a large retrospective series of cT2N0M0 EC, with 1,785 selected patients; 52% underwent upfront esophagectomy and 48% induction therapy followed by esophagectomy. This series represents 9% of all esophagectomies in M0 patients from 2006 to 2012 in the national cancer database (NCDB). Among the up-staged patients, which were 46% of the total, those receiving induction therapies had a significantly better OS (10). Importantly, the cT2N0 patients receiving upfront esophagectomy were significantly more likely to be pathologically up-staged versus induction therapy patients. Additional findings revealed that cT2N0 patients receiving upfront esophagectomy were significantly more likely to have a higher tumor grade and a higher rate of lymphovascular invasion, hence identifying a subgroup of patients at increased risk of pathological up-staging. Interestingly, up-staged patients from upfront surgery (who were almost 50%) who did not receive adjuvant therapy had a detrimental survival, although non-statistically significant, compared with those who did not receive an adjuvant therapy. Therefore, extrapolating the results of this study an induction therapy (CHT or CRT) could be effective in a subset of patients at increased risk for pathologic stage-migration, such as those with high tumor grade and lymphovascular invasion.
Therefore more in general in cT2N0M0 EC a CRT should be proposed according to the phase III CROSS trial, whereas no induction therapy should be considered according to the phase III FFCD 9901 trial. Unfortunately, neither CROSS nor FFCD 9901 were specifically focused on cT2N0M0. The only studies precisely addressing the cT2N0M0 EC, such as the FREGAT and Samson’s, were retrospective and they reported controversial conclusions. The FREGAT study and main randomized trials is shown in Tables 1,2.
Therefore the debate about cT2N0M0 EC still remains freezed into the watershed, since on one hand an upfront esophagectomy could be a putative undertreatment in this clinically under staged tumor population and on the other hand CRT could be an overtreatment for those around 50% of real cT2N0.
Moreover, as we do not have any evidence about adjuvant CRT in EC, choosing upfront esophagectomy as first choice could deprive those 50% of pN+ patients of receiving a proved effective CRT treatment in the preoperative setting.
Not least post-operative morbidity and mortality should represent a further factor for choosing between upfront surgery and induction therapy. In the FREGAT study, no significant difference in terms of in-hospital mortality and morbidity between surgery and CRT groups was observed, in line with the CROSS trial and FFCD 9901 trial, with the only exception of in-hospital mortality, slightly higher in the CRT subgroup, in this latter study.
In conclusion, given that stage-migration remains an issue even with the best staging procedures it is plausible thinking about a role of a neo-/adjuvant therapy in cT2N0M0 EC (21). Furthermore we think that on the basis of the current evidence it is probable that neo-adjuvant therapy is effective in some cases. Keeping in mind this hypothesis, clinicians should perform the best staging, with neck-Chest-Abdomen CT-scan + EUS + FDG-PET-CT, and they should try to obtain pathologic information about histotype, tumor grade and lymph-vascular invasion. Each case should be discussed within a multidisciplinary team, including surgeon, medical oncologist, endoscopist and radiotherapist, also considering the site of the tumor, the surgery invasiveness and clinical conditions of the patient. For patients clinically fit a neo-adjuvant CRT, CROSS trial-like, could be considered. Although it is not clear if cN+ has the same prognostic impact than cN0/pN+ and if a neoadjuvant CHT or CRT might improve prognosis in this setting, we think that this is better than discussing an adjuvant CHT or CRT after an upfront esophagectomy of upstaged EC.
It was not demonstrated if SCC and AC should be managed at the same way. At least for locally advanced low third esophageal AC recent evidence in favor of perioperative CHT (9) should be considered; similarly for locally advanced upper and mid third esophagus SCC even definitive CRT should be considered (19).
Further investigation about identification of predictive factors of high-risk upstaging tumors will be strongly encouraged. The answer to this dilemma is more likely to be found in a hypothetical study, which would compare the long term outcome of pathological T2N0 retrospectively assessed for upfront surgery versus preoperative approach, and separately analyzed according to histotype, baseline homogeneous clinical staging, type of induction therapy and adjuvant treatment.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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