Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

The crude incidence of oesophageal cancer in the European Union (EU) is about 4.5 cases/100 000/year (43 700 cases) with considerable geographical differences within the EU ranging from 3/100 000 in Greece up to 10/100 000 in France [1.Bosetti C. Bertuccio P. Levi F. et al.Cancer mortality in the European Union, 1970–2003, with a joinpoint analysis.Ann Oncol. 2008; 19: 631-640doi:10.1093/annonc/mdm597Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar]. The age adjusted mortality is about 5.4/100 000/year (20 750 deaths) in men and 1.1/100 000/year (6 950 deaths) in women, respectively. The main risk factors for squamous cell carcinomas (SCCs) in Western countries are smoking and alcohol consumption, whereas adenocarcinomas (ACs) predominantly occur in patients with gastro-oesophageal reflux disease and their risk is correlated with the patient's body-mass index. While the incidence of SCC remains stable, the incidence of AC, particularly in the lower oesophagus, is rapidly rising in Western countries [2.Dikken J.L. Lemmens V.E. Wouters M.W. et al.Increased incidence and survival for oesophageal cancer but not for gastric cardia cancer in the Netherlands.Eur J Cancer. 2012; 48: 1624-1632doi:10.1016/j.ejca.2012.01.009Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar] and it now constitutes more than half of all oesophageal cancer cases. The diagnosis should be made from an endoscopic biopsy with the histology to be classified according to the World Health Organization criteria. Small cell carcinomas, which are very uncommon, must be identified and separated from SCCs and ACs and be treated accordingly. Since therapeutic strategy is based on clinical staging, all efforts should be made to assess the optimal pre-therapeutic tumour stage. Staging should include clinical examination, blood count, liver-, pulmonary- and renal function tests, endoscopy (including upper-aerodigestive tract endoscopy in case of tumours at or above the tracheal bifurcation), and a computed tomography (CT) scan of chest and abdomen. In candidates for surgical resection endoscopic ultrasound and positron emission tomography (PET)-CT should be added in order to evaluate the T- and N-category of the tumour. Nevertheless, the accuracy of clinical N-staging does not exceed 80%. Moreover, PET (or PET-CT) may be helpful in identifying otherwise undetected distant metastases [II, B]. In locally advanced (T3/T4) ACs of the oesophago-gastric junction (OGJ) infiltrating the anatomic cardia, laparoscopy can be added to rule out peritoneal metastases which are found in about 15% of patients [III, B]. With this procedure, the sensitivity for detecting peritoneal metastases was 70% compared with about 15% with ultrasound or CT scan. For selection of local treatments, tumours should be ascribed to the cervical or intrathoracic oesophagus or to the OGJ [IV, C]. The stage is to be given according to the American Joint Cancer Committee (AJCC)/Union for International Cancer Control (UICC) TNM system with corresponding stage grouping (7th edition) (Table 1) [3.Edge S.B. Byrd D.R. Compton C.C. AJCC Cancer Staging Handbook.7th ed. Springer, New York, NY2010Google Scholar]. Of note, lymph node metastases in the region of the coeliac trunk and in para-oesophageal nodes in the neck are now defined as regional metastases.Table 1TNM staging for esophageal cancer (AJCC/UICC 7th Edition) [3.Edge S.B. Byrd D.R. Compton C.C. AJCC Cancer Staging Handbook.7th ed. Springer, New York, NY2010Google Scholar]Definition of TNM (2009) Primary tumor (T)TXPrimary tumor cannot be assessedT0No evidence of primary tumorTisCarcinoma in situ/High-grade dysplasiaT1Tumor invades lamina propria, or sub-mucosaT1aTumor invades mucosa or lamina propria or muscularis mucosaeT1bTumor invades sub-mucosaT2Tumor invades muscularis propriaT3Tumor invades adventitiaT4Tumor invades adjacent structuresT4aTumor invades pleura, pericardium, diaphragm or adjacent peritoneumT4bTumor invades other adjacent structures such as aorta, vertebral body or treachea Regional lymph nodes (N)NXRegional lymph nodes cannot be assessedN0No regional lymph node metastasisN1Metastasis in 1–2 regional lymph nodesN2Metastasis in 3–6 regional lymph nodesN3Metastasis in 7 or more regional lymph nodes Distant metastasisMXDistant metastasis cannot be assessedM0No distant metastasisM1Distant metastasisStage grouping Carcinomas of the esophagus and gastro-esophageal junctionStage 0TisN0M0Stage IAT1N0M0Stage IBT2N0M0Stage IIAT3N0M0Stage IIBT1, T2N1M0Stage IIIAT4aN0M0T3N1M0T1, T2N2M0Stage IIIBT3N2M0Stage IIICT4aN1, N2M0T4bAny NM0Any TN3M0Stage IVAny TAny NM1The regional lymph nodes, irrespective of the site of the primary tumor, are those in the esophageal drainage area including coeliac axis nodes and paraesophageal nodes in the neck but not supraclavicular nodes.Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Handbook, 7th ed. New York, NY.: Springer, 2010. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Handbook, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springer.com. Open table in a new tab The regional lymph nodes, irrespective of the site of the primary tumor, are those in the esophageal drainage area including coeliac axis nodes and paraesophageal nodes in the neck but not supraclavicular nodes. Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Handbook, 7th ed. New York, NY.: Springer, 2010. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Handbook, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springer.com. Upfront interdisciplinary planning of the treatment is mandatory. The main factors for selecting primary therapy are tumour stage and location, histological type and the medical condition, as well as considerations from patients. Independent prognostic factors for long-term survival comprise N/T category and grading for AC as well as N/T category and localisation for SCC [4.Rice T.W. Rusch V.W. Ishwaran H. et al.Cancer of the esophagus and esophagogastric junction: data-driven staging for the seventh edition of the American Joint Committee on Cancer/Union Against Cancer cancer staging manuals.Cancer. 2010; 116: 3763-3773doi:10.1002/cncr.25146Crossref PubMed Scopus (370) Google Scholar]. Surgery alone is regarded as standard treatment only in carefully selected operable patients with localised SCC (T1-2 N0-3 M0) [II, B]. Transthoracic oesophagectomy with two-field lymph node dissection and a gastric tube anastomosed in the left neck (supra-bifurcal tumours) or in the upper thorax is recommended [5.Boone J. Livestro D.P. Elias S.G. et al.International survey on esophageal cancer: part I surgical techniques.Dis Esophagus. 2009; 22: 195-202doi:10.1111/j.1442-2050.2008.00929.xCrossref PubMed Scopus (69) Google Scholar] for intrathoracic SCC [III, B]. Minimally invasive techniques have been introduced to reduce post-operative complication rates and recovery times. Debates continue as to whether these challenging techniques decrease morbidity and whether the oncological outcome is compromised. Part of this answer is given in a recent randomised trial [6.Biere S.S. van Berge Henegouwen M.I. Maas K.W. et al.Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial.Lancet. 2012; 379: 1887-1892doi:10.1016/S0140-6736(12)60516-9Abstract Full Text Full Text PDF PubMed Scopus (1078) Google Scholar], showing a threefold decrease in post-operative pulmonary infection rate after totally mini-invasive oesophagectomy compared with open transthoracic surgery. Open surgery remains the standard of care. No standard surgical treatment can be identified for carcinomas of the cervical oesophagus. The extent of surgery in ACs is still a matter of debate. One randomised study showed a non-significant improvement in long-term survival for extended transthoracic compared with transhiatal resection [7.Omloo J.M. Lagarde S.M. Hulscher J.B. et al.Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/distal esophagus. Five-year survival of a randomized clinical trial.Ann Surg. 2007; 246: 992-1001doi:10.1097/SLA.0b013e31815c4037Crossref PubMed Scopus (10) Google Scholar], but this benefit appears to be restricted to patients with AC of the lower oesophagus (type I according to Siewert classification) [8.Hulscher J.B. van Sandick J.W. de Boer A.G. et al.Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus.N Engl J Med. 2002; 347: 1662-1669doi:10.1056/NEJMoa022343Crossref PubMed Scopus (1329) Google Scholar]. Preoperative or post-operative radiation alone (without chemotherapy) does not add any survival benefit to surgery alone [9.Arnott S.J. Duncan W. Gignoux M. et al.Preoperative radiotherapy for esophageal carcinoma.Cochrane Database Syst Rev. 2005; : CD001799PubMed Google Scholar]. This treatment is not recommended for curative intent in localised tumours [I, A]. Evidence for clinical benefit from preoperative chemotherapy exists for all types of oesophageal cancer, though it is stronger for AC. Patients with AC of the lower oesophagus/OGJ should be managed with pre- and post-operative chemotherapy (or chemoradiation)[10.Cunningham D. Allum W.H. Stenning S.P. et al.Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.N Engl J Med. 2006; 355: 11-20doi:10.1056/NEJMoa055531Crossref PubMed Scopus (4486) Google Scholar, 11.Ychou M. Boige V. Pignon J.P. et al.Peroperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial.J Clin Oncol. 2011; 29: 1715-1721doi:10.1200/JCO.2010.33.0597Crossref PubMed Scopus (1337) Google Scholar, 12.Sjoquist K.M. Burmeister B.H. Smithers B.M. et al.Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis.Lancet Oncol. 2011; 12: 681-692doi:10.1016/S1470-2045(11)70142-5Abstract Full Text Full Text PDF PubMed Scopus (1255) Google Scholar] [I, B]. A couple of meta-analyses and two recent phase III trials [13.Kranzfelder M. Schuster T. Geinitz H. et al.Meta-analysis of neoadjuvant treatment modalities and definitive non-surgical therapy for oesophageal squamous cell cancer.Br J Surg. 2011; 98: 768-783doi:10.1002/bjs.7455Crossref PubMed Scopus (146) Google Scholar, 14.Tepper J. Krasna M.J. Niedzwiecki D. et al.Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781.J Clin Oncol. 2008; 26: 1086-1092doi:10.1200/JCO.2007.12.9593Crossref PubMed Scopus (1070) Google Scholar, 15.Van Hagen P. Hulshof M.C. van Lanschot J.J. et al.Preoperative chemoradiotherapy for esophageal or junctional cancer.N Engl J Med. 2012; 366: 2074-2084doi:10.1056/NEJMoa1112088Crossref PubMed Scopus (3320) Google Scholar, 16.Stahl M. Stuschke M. Lehmann N. et al.Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus.J Clin Oncol. 2005; 23: 2310-2317doi:10.1200/JCO.2005.00.034Crossref PubMed Scopus (1042) Google Scholar] suggested that preoperative chemoradiation confers a survival benefit [I, B], and it appears that patients benefit with increased tumour down-staging from preoperative chemoradiation [III, B]. Of note, post-operative mortality may be increased. Data on adjuvant chemo(radio)therapy is limited, except for lower oesophageal/OGJ AC after limited surgery (lymph node dissection D1 and less). Therefore, adjuvant therapy is not recommended. Selected unfit patients with localised tumours not considered for surgery can be treated with (also) curative intent with combined chemoradiation [16.Stahl M. Stuschke M. Lehmann N. et al.Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus.J Clin Oncol. 2005; 23: 2310-2317doi:10.1200/JCO.2005.00.034Crossref PubMed Scopus (1042) Google Scholar, 17.Bedenne L. Michel P. Bouché O. et al.Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102.J Clin Oncol. 2007; 25: 1160-1168doi:10.1200/JCO.2005.04.7118Crossref PubMed Scopus (948) Google Scholar, 18.Crehange G. Maingon P. Peignaux K. et al.Phase III trial of protracted compared with split-course chemoradiation for esophageal carcinoma: Federation Francophone de Cancerologies Digestive 9102.J Clin Oncol. 2007; 25: 4895-4901doi:10.1200/JCO.2007.12.3471Crossref PubMed Scopus (54) Google Scholar]. Otherwise, principles of palliative therapy are recommended for these patients (see treatment of metastatic disease). Surgery is the treatment of choice in early cancer (Tis-T1a N0). Endoscopic resection is a treatment option for selected patients as similar cure rates in specialised centres have been reported [19.Pech O. Bollschweiler E. Manner H. et al.Comparison between endoscopic and surgical resection of mucosal esophageal adenocarcinoma in Barretts esophagus at two high-volume centers.Ann Surg. 2011; 254: 67-72doi:10.1097/SLA.0b013e31821d4bf6Crossref PubMed Scopus (231) Google Scholar] [II, B]. For localised disease without suspected lymph node involvement (T1-2 N0M0), surgery is regarded as a standard treatment [II, B]. However, long-term survival does not exceed 25% if regional lymph nodes are involved (pN1-3). Therefore, preoperative treatment can also be justified. For localised disease with suspected lymph node involvement (T1-2N1-3M0), preoperative therapy is recommended in patients with AC. Meta-analyses showed a small but significant benefit for preoperative chemotherapy [12.Sjoquist K.M. Burmeister B.H. Smithers B.M. et al.Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis.Lancet Oncol. 2011; 12: 681-692doi:10.1016/S1470-2045(11)70142-5Abstract Full Text Full Text PDF PubMed Scopus (1255) Google Scholar, 13.Kranzfelder M. Schuster T. Geinitz H. et al.Meta-analysis of neoadjuvant treatment modalities and definitive non-surgical therapy for oesophageal squamous cell cancer.Br J Surg. 2011; 98: 768-783doi:10.1002/bjs.7455Crossref PubMed Scopus (146) Google Scholar], but they included very limited numbers of patients with localised tumours (e.g. tumour category T1-2). A couple of meta-analyses in unselected patient groups revealed a significant benefit for preoperative chemoradiation. The extent of this benefit was smaller for patients with T2 tumours [20.Gebski V. Burmeister B. Smithers B.M. et al.Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis.Lancet Oncol. 2007; 8: 226-234doi:10.1016/S1470-2045(07)70039-6Abstract Full Text Full Text PDF PubMed Scopus (1039) Google Scholar]. A French phase III trial (FFCD 9901) predominantly in localised SCC did not show increased survival with preoperative chemoradiation. Studies with post-operative chemotherapy in oesophageal SCC have been carried out in Asian patients only. In a randomised Japanese trial, adjuvant chemotherapy was inferior to the identical neoadjuvant therapy. This treatment is not recommended. Data with adjuvant chemotherapy in oesophageal AC may be extrapolated from studies and meta-analyses in gastric cancer. Therefore, the recommendations of the gastric cancer guideline may be followed. For patients unable or unwilling to undergo surgery, combined chemoradiation is superior to radiotherapy alone [21.Minsky B.D. Pajak T.F. Ginsberg R.J. et al.INT 0123 (Radiation Therapy Oncology Group 94–05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy.J Clin Oncol. 2002; 20: 1167-1174doi:10.1200/JCO.20.5.1167Crossref PubMed Scopus (1242) Google Scholar] [I, A]. Four courses of cisplatin/5-fluorouracil (5-FU) combined with radiation doses of 50.4 Gy in fractions of 1.8 Gy are regarded as standard treatment of definitive radiotherapy in the United States. Increased radiation doses up to 60 Gy in fractions of 1.8–2.0 Gy are recommended in parts of Europe and Japan for definitive chemoradiotherapy. This is due to an obvious dose–response correlation of radiotherapy in oesophageal cancer and the positive experience with these radiation doses in prospective multi-centre trials [16.Stahl M. Stuschke M. Lehmann N. et al.Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus.J Clin Oncol. 2005; 23: 2310-2317doi:10.1200/JCO.2005.00.034Crossref PubMed Scopus (1042) Google Scholar, 17.Bedenne L. Michel P. Bouché O. et al.Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102.J Clin Oncol. 2007; 25: 1160-1168doi:10.1200/JCO.2005.04.7118Crossref PubMed Scopus (948) Google Scholar] (Figure 1). Surgery alone is not a standard treatment in these stages since a complete (R0) tumour resection is not possible in about 30% (pT3) to 50% (pT4). Furthermore, even after complete tumour resection, long-term survival rarely exceeds 20%. Therefore, preoperative treatment is clearly indicated in operable patients. A couple of meta-analyses and two recent phase III trials [12.Sjoquist K.M. Burmeister B.H. Smithers B.M. et al.Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis.Lancet Oncol. 2011; 12: 681-692doi:10.1016/S1470-2045(11)70142-5Abstract Full Text Full Text PDF PubMed Scopus (1255) Google Scholar, 13.Kranzfelder M. Schuster T. Geinitz H. et al.Meta-analysis of neoadjuvant treatment modalities and definitive non-surgical therapy for oesophageal squamous cell cancer.Br J Surg. 2011; 98: 768-783doi:10.1002/bjs.7455Crossref PubMed Scopus (146) Google Scholar, 14.Tepper J. Krasna M.J. Niedzwiecki D. et al.Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781.J Clin Oncol. 2008; 26: 1086-1092doi:10.1200/JCO.2007.12.9593Crossref PubMed Scopus (1070) Google Scholar, 15.Van Hagen P. Hulshof M.C. van Lanschot J.J. et al.Preoperative chemoradiotherapy for esophageal or junctional cancer.N Engl J Med. 2012; 366: 2074-2084doi:10.1056/NEJMoa1112088Crossref PubMed Scopus (3320) Google Scholar] demonstrate that patients with locally advanced disease benefit from preoperative chemotherapy or, most likely to a greater extent, from preoperative chemoradiation, with higher rates of complete tumour resection and better local tumour control and survival [I, A]. It is suggested, however, that preoperative chemoradiation will also increase post-operative mortality rates. In cases of response to neoadjuvant chemo(radio)therapy (40–50 Gy), further continuation of chemoradiation resulted in equivalent overall survival compared with surgery, albeit that the non-operative strategy was associated with higher local tumour recurrence [16.Stahl M. Stuschke M. Lehmann N. et al.Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus.J Clin Oncol. 2005; 23: 2310-2317doi:10.1200/JCO.2005.00.034Crossref PubMed Scopus (1042) Google Scholar, 17.Bedenne L. Michel P. Bouché O. et al.Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102.J Clin Oncol. 2007; 25: 1160-1168doi:10.1200/JCO.2005.04.7118Crossref PubMed Scopus (948) Google Scholar]. Therefore, chemoradiotherapy with planned surgery or definitive chemoradiotherapy with close surveillance, and salvage surgery for local tumour persistence or local tumour progression, may be considered as a definitive treatment of selected patients with locally advanced disease [22.Ariga H. Nemoto K. Miyazaki S. et al.Prospective comparison of surgery alone and chemoradiotherapy with selective surgery in resectable squamous cell carcinoma of the esophagus.Int J Radiat Oncol Biol Phys. 2009; 75: 348-356doi:10.1016/j.ijrobp.2009.02.086Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar] [I, B]. Experienced multidisciplinary teamwork is warranted for this treatment approach and post-operative mortality will increase with the dose of radiotherapy applied. Definitive chemoradiotherapy is recommended for cervically localised tumours [III, B]. For patients unable or unwilling to undergo surgery, treatment recommendations from the ‘limited disease’ section may be adapted. Perioperative chemotherapy with cisplatin and 5-FU should be considered standard in locally advanced AC of OGJ [10.Cunningham D. Allum W.H. Stenning S.P. et al.Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.N Engl J Med. 2006; 355: 11-20doi:10.1056/NEJMoa055531Crossref PubMed Scopus (4486) Google Scholar, 11.Ychou M. Boige V. Pignon J.P. et al.Peroperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial.J Clin Oncol. 2011; 29: 1715-1721doi:10.1200/JCO.2010.33.0597Crossref PubMed Scopus (1337) Google Scholar, 12.Sjoquist K.M. Burmeister B.H. Smithers B.M. et al.Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis.Lancet Oncol. 2011; 12: 681-692doi:10.1016/S1470-2045(11)70142-5Abstract Full Text Full Text PDF PubMed Scopus (1255) Google Scholar] [I, A]. Preoperative chemoradiotherapy is preferred in oesophageal AC for selected patients, since meta-analyses and a recent phase III trial [12.Sjoquist K.M. Burmeister B.H. Smithers B.M. et al.Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis.Lancet Oncol. 2011; 12: 681-692doi:10.1016/S1470-2045(11)70142-5Abstract Full Text Full Text PDF PubMed Scopus (1255) Google Scholar, 15.Van Hagen P. Hulshof M.C. van Lanschot J.J. et al.Preoperative chemoradiotherapy for esophageal or junctional cancer.N Engl J Med. 2012; 366: 2074-2084doi:10.1056/NEJMoa1112088Crossref PubMed Scopus (3320) Google Scholar] revealed a significant survival benefit for AC. This benefit was particularly seen in high-risk patients, e.g. those with locally more advanced stages. The preference for chemoradiotherapy is also supported by the results of a phase III study which compared chemoradiotherapy to chemotherapy before surgery [23.Stahl M. Walz M.K. Stuschke M. et al.Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction.J Clin Oncol. 2009; 27: 851-856doi:10.1200/JCO.2008.17.0506Crossref PubMed Scopus (732) Google Scholar]. Chemotherapy with cisplatin/5-FU combined with 41.4–50.4 Gy in fractions of 1.8–2.0 Gy has long been standard treatment, but two recent randomised trials showed a favourable toxicity profile for (bi)weekly combinations of oxaliplatin/5-FU or carboplatin/paclitaxel with radiotherapy [15.Van Hagen P. Hulshof M.C. van Lanschot J.J. et al.Preoperative chemoradiotherapy for esophageal or junctional cancer.N Engl J Med. 2012; 366: 2074-2084doi:10.1056/NEJMoa1112088Crossref PubMed Scopus (3320) Google Scholar, 24.Conroy T. Galais M.P. Raoul J.L. et al.Phase III randomized trial of definitive chemoradiotherapy (CRT) with FOLFOX or cisplatin and fluorouracil in esophageal cancer (EC): final results of PRODIGE 5/ACCORD17 trial.J Clin Oncol. 2012; 30 (suppl); 239s (abstr LBA4003)Crossref Google Scholar]. Even after complete tumour response to preoperative chemo(radio)therapy operable patients with AC should proceed to surgery [IV, C] (Figure 2). Patients with metastatic oesophageal cancer can be considered for different options of palliative treatment depending on the clinical situation. Single-dose brachytherapy may be a preferred option even after percutaneous radio(chemo)therapy, since it provides better long-term relief of dysphagia with fewer complications than metal stent placement [25.Homs M.Y. Steyerberg E.W. Eijkenboom W.M. et al.Single-dose brachytherapy versus metal stent placement for the palliation of dysphagia from oesophageal cancer: multicentre randomised trial.Lancet. 2004; 364: 1497-1504doi:10.1016/S0140-6736(04)17272-3Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar] [I, B]. Chemotherapy is indicated for palliative treatment in selected patients [III, B], particularly for patients with AC who have a good performance status. Newer regimens based on oxaliplatin/fluoropyrimidine combinations are an alternative to the ‘classical’ cisplatin/5-FU schedule [26.Cunningham D. Starling N. Rao S. et al.Capecitabine and oxaliplatin for advanced esophagogastric cancer.N Engl J Med. 2008; 358: 36-46doi:10.1056/NEJMoa073149Crossref PubMed Scopus (1786) Google Scholar]. Infusional 5-FU may be replaced by capecitabine if swallowing of tablets is not compromised. As in gastric cancer, taxanes are recommended in first-line combinations or as monotherapy in second-line therapy also in AC of OGJ. In SCC, the value of palliative chemotherapy is less proven. Cisplatin-based combinations showed increased response rates but no survival gain compared with monotherapy. Overall, results with palliative chemotherapy are inferior to those in AC. Therefore, best supportive care or palliative monotherapy has also to be considered. Randomised data with biologically targeted medical therapies are limited in oesophageal carcinoma. For treating patients with HER2-positive tumours, the recommendations of the gastric cancer guideline should be followed. Response is routinely evaluated by evaluation of tumour related symptoms, endoscopy, and CT scan. In case of local tumour progression of (still) locoregional manifestations, the potential benefit of a surgical intervention must be discussed by a multi-disciplinary board. If distant metastases may be detected, the recommendations for metastastic disease should be followed. Biopsies may be taken after neoadjuvant intended chemo-radiotherapy in case a patient has increased operative risks, and surgery may be omitted if a complete tumour remission will be documented. However, this is not a standard procedure. Additionally, tumour response to chemotherapy may be predicted early by fluor-18-fluorodeoxyglucose(FDG)-PET(-CT) in oesophago-gastric AC [27.Lordick F. Ott K. Krause B.J. New trends for staging and therapy for localized gestroesophageal cancer: the role of PET.Ann Oncol. 2010; 21: vii294-vii299doi:10.1093/annonc/mdq289Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar] [III, C]. However, at the present time, this will not change the therapeutic strategy. Except for those patients who may be potential candidates for an early ‘salvage surgery’ after (failing) endoscopic resection or definitive chemoradiation, there is no evidence that regular follow-up after initial therapy may have impact on the outcome. Follow-up visits should be concentrated on symptoms, nutrition and psycho-social support [IV, D]. An overview of recommendations related to therapy is given on Figure 1. Levels of evidence and grades of recommendation have been applied using the system shown in Table 2. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.Table 2Levels of evidence and grades of recommendation (adapted with permission from the Infectious Diseases Society of America-United States Public Health Service Grading SystemaDykewicz CA. Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Clin Infect Dis 2001; 33: 139–44. By permission of the Infectious Diseases Society of America.)Levels of evidence IEvidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomised trials without heterogeneity IISmall randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity IIIProspective cohort studies IVRetrospective cohort studies or case–control studies VStudies without control group, case reports, experts opinionsGrades of recommendation AStrong evidence for efficacy with a substantial clinical benefit, strongly recommended BStrong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended CInsufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, …), optional DModerate evidence against efficacy or for adverse outcome, generally not recommended EStrong evidence against efficacy or for adverse outcome, never recommendeda Dykewicz CA. Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Clin Infect Dis 2001; 33: 139–44. By permission of the Infectious Diseases Society of America. Open table in a new tab Prof. Arnold has reported research grants from Roche and Sanofi . The other authors have reported no potential conflicts of interest.