SEOM Clinical Guideline for the diagnosis and treatment of esophageal cancer (2016)

Preoperative chemoradiation followed by surgery is the most common approach for patients with resectable esophageal cancer. Different meta-analyses have suggested that preoperative chemoradiation based on Cisplatin and 5FU plus surgery significantly improved survival, compared with surgery alone [13]. The phase III CROSS study showed that preoperative chemoradiation (carboplatin plus paclitaxel) improved OS and DFS compared to surgery in patients with T2-3, N0-1, M0 neoplasias (median survival 49 vs. 24 months) [14]. However, this approach is not a standard therapy in stage I–II because the FFCD 9901 study did not improve OS with chemoradiation therapy with Cisplatin and fluorouracil compared with surgery (3-year OS 47.5 and 53%, p = 0.94). In this study the postoperative mortality rate was 11% for chemoradiation compared to 3.4% for surgery alone (p = 0.049) [15]. (E: moderate; R: strong).

Definitive Chemoradiotherapy: Two randomized trials [16, 17] did not confirm a survival benefit with surgery added to potentially curative chemoradiation (defined as a higher radiation dose of 60–66 Gy) in SCC, although there is a significant local control benefit. Although, both studies have important limitations (suboptimal design, high treatment-related mortality and poor accrual) definitive chemoradiotherapy can be considered an option in SCC (E: moderate; R: insufficient). The benefit/risk balance between surgery and close surveillance should be discussed in a committee, considering each case individually (E: moderate R: strong) [18].

Preoperative Chemotherapy: Preoperative chemotherapy adds a small but significant benefit over surgery alone for all types of esophageal cancer, though it is stronger for ADC [13] (E: moderate; R: weak). A small randomized phase II study [19] compared neoadjuvant chemotherapy with chemoradiotherapy. The corresponding median OS or DFS was not different; however, the pathological response rate and R1 response rate favored chemoradiation arm (E: low).

Postoperative chemoradiation: the efficacy of this approach has not been demonstrated in randomized trial in patients with EC (E: high; R: strong).

Preoperative chemoradiation (as described above) and perioperative chemotherapy are both accepted strategies in adenocarcinoma of esophageal cancer. Preoperative chemotherapy can be considered with the remarks described above (E: moderate; R: strong).

Perioperative Chemotherapy: perioperative chemotherapy approach may be offered to patients with resectable ADC of the lower esophagus. Two phase III studies showed OS and PFS benefit over surgery [20, 21]; these studies were mainly designed for gastric or EGJ cancer, but also included a small proportion of patients with adenocarcinoma of the lower esophagus (E: moderate; R: strong).

Even after complete tumor response to preoperative therapy, patients with ADC should proceed to surgery [21] (E: high; R: strong).

Despite differences in the biology [27], metastatic SCC and ADC EC are treated similarly. A first-line treatment with Cisplatin or Oxaliplatin combined with fluorouracil or Capecitabine can improve survival (E: high; R: strong) [28]. Best supportive care should be offered to all metastatic esophageal cancer patients since the first visit. In very good performance status patients addition of Epirrubicin and Taxanes could offer some additional benefit in GEJ adenocarcinomas [29, 30] (E: moderate; R: weak). Nonetheless, a less toxic two-drug regimen is usually preferred for patients with metastatic disease.

When progression occurs, the role of second-line chemotherapy in esophageal cancer is controversial since no randomized phase III trials have been done in this clinical setting, in either SCC or ADC, and there is only scarce data for its clinical effectiveness [31] (E: low; R: weak). The evidence of positive results, with improvement in overall survival, from second-line therapy in gastric cancer cannot be extrapolated to esophageal cancer in view of the clinical and biological differences between both tumor locations.

Recent insights into the molecular mechanism of esophageal cancer have led to the development of various targeted agents in this disease. Specifically, EGFR, HER2, VEGR and c-MET were shown in preclinical models as valuable targets for esophageal cancer. Despite signs of efficacy in early phase clinical trials, results with different anti-EGFR, anti-VEGFR and Anti-cMET/HGF agents have been unsuccessful so far [32‐35] and these agents cannot be recommended at this time. Only Trastuzumab, antiHER2 directed monoclonal antibody, has been shown to improve overall survival in the 10–15% of patients with HER2 positive advanced gastric or gastro esophageal adenocarcinomas [36] (E: high; R: strong). Unfortunately, these positive results were not replicated in recent trials with other antiHER2 agents (Lapatinib, T-DM1). Novel strategies with agents targeting FGFR or Hedgehog pathways, poly (adenosine diphosphate-ribose) polymerase inhibitors or next-generation immune checkpoint antibodies are undergoing investigation in early phase trials that include esophageal cancer patients, with preliminary data demonstrating for immune checkpoint inhibitors manageable toxicity and promising antitumor activity in heavily treated patient.

Evidence to date shows that molecularly unselected patient cohorts derive no benefit from targeted therapies [37]. This way future research should focus on preselected molecular subgroups of patients with this disease.

Patients with esophageal cancer refractory to the standard anticancer treatment or those who are medically unfit for any therapy (performance status >2) require focusing our efforts on the relief of symptoms and the improvement in quality of life [38]. An adequate caloric intake should be maintained in these patients primarily in the multimodality treatment scenario. Oral supplementation (preferred), feeding tubes for enteral nutrition or total parenteral nutrition are the main options (E: moderate; R: strong) Malignant dysphagia is one of the major issues in esophageal cancer. The insertion of endoluminal stents, the administration of palliative external beam radiation therapy and brachytherapy are the preferred options to alleviate dysphagia (E: high; R: strong); finally, pain, nausea and vomiting should be treated according to specific guidelines. (E: high; R: strong).