Introduction

On June 8th and 9th 2012 the European Union Network of Excellence on gastric and esophagogastric junction cancer (EUNE) held its third conference in Cologne, Germany.

The meeting was attended by 150 experts from 18 different countries. The congress was supported by the International Gastric Cancer Association (IGCA), the German Society of Surgery (DGCH), the German Society for General and Visceral Surgery (DGAV), and the Working Group for Internal Oncology (AIO). The main focus was the further development of European Guidelines for gastric cancer and cancer of the esophagogastric junction. This report describes the proceedings of the congress highlighting the specific topics and those areas for further work.

Early gastric cancer (T1 disease)––endoscopic therapy

The subclassification of T1 carcinoma should form the basis for deciding to proceed with curative endoscopic resection (ER). ER is associated with excellent prognosis in m1 or m2 infiltration (“m1–3” refers to depth of mucosal infiltration) and grade I disease and <2 cm diameter. A curative ESD-en-bloc-resection is preferred with careful examination by the pathologist (Neuhaus). Surgical series confirms that lymph node metastasis starts with deep mucosal infiltration (m3) [1]. The rate of recurrence is high using the “piece meal technique” in gastric cancer as incomplete resections are essentially “big biopsies” [2]. ER should be only undertaken in high volume centers to concentrate expertise with an added advantage of cost-effectiveness. The learning curve for ER can only be completed with a large case load available in a large referral center (Haringsma) and it has to be recognised that this is exacerbated by the low incidence of early cancers in Europe.

Adenocarcinoma of the esophago-gastric junction (AEGJ)

In western countries we observe a shift of gastric cancer from aboral to oral and a rapid increase of distal esophageal cancer. By contrast in Japan 80 % of gastric carcinomas develop in the distal third, therefore distal gastrectomy is still the major procedure in Japan with special attention to the proximal resection margin [3]. There needs to be an international unification of the D-classification of lymphadenectomy, depending on the type of gastric resection (Sano).

The classification of carcinoma of the esophagogastric junction remains controversial and there needs to be careful evaluation of outcomes based on documentation of surgical approaches and pathology (D’Ugo).

Surgery for AEGJ cancer includes a number of approaches and methods of reconstruction. In the UK a thoraco-abdominal approach is preferred for type II tumours because of the involvement of mediastinal nodes which are resected en bloc (Griffin). In other European centers extended total gastrectomy is undertaken with a transhiatal dissection (Kolodziejczak). In the Far East there is increasing experience with minimally invasive techniques. Yang advocated that type II and III should be considered as one entity as their biological behaviour is the same.

Following resection gastrointestinal continuity is achieved usually using transposed jejunum or with stomach after oesophago-gastric resection. The Merendino procedure has not kept its promises because quality of life is worse than in more radical procedures yet morbidity is equivalent. However, it can only be oncologically sufficient in early cancer, because the number of harvested lymph nodes is much less than in esophagectomy (Lorenz). When stomach is not available, colon interposition is to be considered and there are fewer anastomotic strictures than after reconstruction with gastric pull-up (Kumar).

Locally advanced cancer: multimodality treatment

Perioperative chemotherapy is indicated in cT2N1, cT3 and cT4 [4]. There remains controversy for cT1N1 and cT2N0. Adjuvant chemoradiotherapy should be considered after R1 resection (Allum, Wilke and Wijnhoven).

Subtypes of gastric cancer are now being recognised not only in terms of epidemiologic and histologic differences but are also distinguished by gene expression profiles. Different miRNA profiles are likely to lead to a new molecular classification with clinically relevant features (Carboni).

Adjuvant therapy still has a role but even after 5 meta-analyses over the last 20 years it is still not known who benefits (Lordick). In the UK it is advocated with or without radiotherapy in high-risk pathology if neoadjuvant therapy has not been used. Linitis Plastica remains a difficult condition to treat as it is diagnosed at a late stage. Despite attempted R0 resection the curative resection rate is only 30 % and the rate of recurrence is very high. Because of the rates of peritoneal recurrence there is a case for considering hyperthermic intraperitoneal chemotherapy (HIPEC) (Roviello).

Neoadjuvant therapy––response

The changes in the 7th edition of TNM for esophageal and gastric cancer have been criticized especially for the T- and N category, stage grouping and the stage IV category. In T1b it is unclear whether to include invasion of the muscularis propria. A differentiation of T2 into T2a and T2b could differentiate between infiltration of the inner and outer layer of the muscularis propria. In N-category extracapsular lymph node spread or the ratio of affected and not affected lymph nodes could play a future role. In future the R classification may be extended to R1dir when the tumour reaches the resection margin and to R2 a-c with local (a), distant (b) or both (c) macroscopic residual tumour [5].

Assessment of the response to neoadjuvant treatment remains a challenge. Systematic reviews confirm that gastroscopy with or without re-biopsy, endoscopic ultrasound (EUS) and FDG-PET have no influence on therapeutic decisions (Barr). Although there are examples of grading systems showing correlation between response and prognosis (Drebber) there are no nationally or internationally accepted grading system. Therefore, a standardized regression grading system for gastric cancer should be developed for international histopathological evaluation of response to neoadjuvant therapy [6].

Investigational studies suggest there may be a role for molecular markers. GNAS and 4-gene-expression seems to play an important role in esophageal cancer, HER2 in gastric cancer (Metzger). Results with PET–CT scanning suggest a positive correlation between metabolic and pathological response (Van Heijl), but the results are controversial.

Metastatic gastric cancer

Palliative surgery for gastric cancer seems to be beneficial in patients under 70 years with at least one symptom such as obstruction or bleeding [7].

In selected cases liver resection for synchronous or metachronous liver metastases may improve disease free survival and may be curative but the decision to operate should always to be made in an interdisciplinary team (Lang).

Peritoneal carcinomatosis can be difficult to evaluate radiologically [8]. However it is recommended to use the Sugarbaker peritoneal cancer index (PCI) which describes 4 levels (Cotte). HIPEC is now considered to be a safe technique with a survival benefit but should only be used in carefully selected applying strict inclusion and exclusion criteria (Garofalo).

New trials

There are wide variations in the application of neoadjuvant and adjuvant treatments in gastric cancer. Trials should be designed to take into account prognostic factors so that appropriate issues are addressed (van Cutsem).

In the UK the STO 3 study is a randomized phase II/III trial of perioperative chemotherapy with or without Bevacizumab in operable adenocarcinoma of the stomach and gastro-esophageal junction. The aim is to recruit 1100 patients. In the initial phase II study which is a safety evaluation in 200 patients there was no difference in toxicity between the two groups.

Current trials in advanced disease include the COUGAR-2 study and REAL 3. ROMIO is a randomized trial of minimally invasive or open esophagectomy (Allum).

From France the latest results were presented from a phase III trial of immunonutrition to improve the quality of life of upper gastrointestinal cancer patients undergoing neoadjuvant treatment prior to surgery. A new trial is being developed to test if primary surgery is superior to standard perioperative chemotherapy in signet ring cell gastric adenocarcinomas (PRODIGE 19) (Mariette).

In Italy where the incidence of gastric cancer in Italy is higher than in other European countries there are the NEOX-RT and the ITACAS-2 trials underway (Pozzo).

The NEOX-RT study includes patients with locally advanced uT3-4 (“u” refers to ultrasound), N0 or any uT, N + M0 (laparoscopy and peritoneal staging) potentially resectable, locally advanced gastric cancer. The aim of the ITACAS-2 study was to compare the efficacy of a peri-operative versus a post-operative chemotherapy regimen in patients with operable gastric cancer and to assess the benefit of a post-operative chemo-radiotherapy. There are two main objectives (overall survival and local-relapse free survival) and three secondary objectives (disease free survival, overall survival for RT, tolerability).

There are a number of trials underway in Germany. The QUADRIGA trial is planned to assess the quality of life adjusted survival after palliative gastric resection and chemotherapy versus chemotherapy alone in stage IV gastric cancer (Lehnert).

The FLOT4 study comprises n = 590 patients (FLOT4 vs. ECF3) with primary endpoint of DFS. In the FLOT 3 study newly diagnosed operable or metastatic adenocarcinoma of the stomach or GEJ with no prior treatment were included. From February 2009 until January 2010 a total of 252 (OL/LM/DM 52/67/133) patients were recruited for FLOT3 in 47 German centers (Al-Batran).

The SurgAEGII study is a planned randomized controlled multicenter trial that aims to identify the optimal surgical treatment for AEGJ II carcinoma. The trial compares transhiatal extended gastrectomy with distal esophagectomy (TEG) including D2-lymphadenectomy and lymphadenectomy of the lower mediastinum with a thoracoabdominal esophagectomy (TAE) plus proximal gastrectomy including 2-field lymphadenectomy (Moenig).

Data recording and quality criteria

Although EUROCARE-4 shows a 5 year survival of 25 % for gastric cancer, there are differences between individual countries reflecting incomplete or old data. Centralisation of surgery has been shown in many studies to reduce operative mortality. In Denmark the centralization of gastric cancer surgery from 37 to 5 hospitals resulted in a decrease in operative mortality from 8.2 to 2.4 %.

Centers need to ensure careful data collection to allow accurate audit. Clinical auditing involves a concise collection of detailed information on the patient, tumour, treatment, and outcomes. In a study comparing data recorded by national cancer registries there is considerable variation in hospital volumes and 30-day mortality between the participating countries. However, there was a significant correlation between volume and 30-day mortality. Limitations of the study are the differences between datasets (comorbidity, TNM stage, multimodality therapy). Therefore, there is a strong case to establish a uniform European upper GI cancer registry. This would facilitate a comparison of outcomes after surgery, resection rates, patterns of care, as well as long term outcomes across European countries (Dikken).

Good data collection requires a strong infrastructure to support both clinical and related biological data. The Italian Group for Research on Gastric Cancer (G.I.R.C.G.) established in 1990 comprises several Italian cancer centers. The database management is in Siena and holds information on about 1.700 patients with a supplementary database on family history information and biological material. The biological material bank includes more than 600 samples with information about normal and paired tumoural mucosa, whole blood and serum samples and genomic DNA/RNA (Roviello). Within the context of this database is the need for careful lymph node dissection and retrieval to increase the number of examined lymph nodes, allowing a correct staging of the disease. This would be important in light of the role of the number of positive lymph nodes in current TNM classification. There is also a case for including lymphatic tumour invasion in N0 and N-ratio in N+ (Marelli).

Hospital and surgeon volume influence the quality of treatment outcome in gastric cancer. This reflects both the number of operations and the structural processes and characteristics of a high volume hospital. Comparison of data from the prospective German multicenter observational study (QCGC 2007–2009) with the EGGCS 2002 has shown an improvement in survival from 40 to 48.5 % (Meyer).

Enhanced recovery after surgery (ERAS) has been introduced in many countries as a multi-modal, peri-operative standardized clinical pathway designed to reduce surgical stress and support basic bodily functions. It aims to accelerate patient recovery, shorten hospital stay, and reduce complication rates following surgery. Studies have shown that ERAS principles are applicable to both esophageal and gastric cancer surgery and result in an improved outcome by a reduction in length of stay, complication rates, and cost. They may also obviate many of the benefits seen from laparoscopic surgery (Preston).

A review of the literature showed that there are few papers on gender specific evaluation of esophagogastric cancer surgery. Most of them show completely heterogenous results. However, there is an increased overall survival irrespective of treatment for females in Europe. However, gender specific risk factors cannot explain the difference in the gender specific incidence. More research with larger series is required for a better evaluation of this topic (Ott).

European guidelines––towards a consensus

A consensus discussion highlighted the varying use of guidelines across Europe (Table 1). Many countries have their own but some use those in the published literature. There was discussion about producing a unified European guideline. Although there are many common issues there is variability reflecting the differences between countries with respect to disease incidence and epidemiology and provision of services.

Table 1 Guidelines across Europe
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