Gastric Cancer DOI 10.1007/s10120-014-0347-1

MEETING REPORT

Third international conference of the European Union Network of Excellence on gastric and esophagogastric junction cancer, Cologne, Germany, June 2012 Stefan Paul Moenig • Hans-Joachim Meyer • William H. Allum • Giovanni De Manzoni • Alfredo Garofalo • Christoph Tobias H. Baltin Ulrich Klaus Fetzner • Arnulf Heinrich Hoelscher



Received: 20 August 2013 / Accepted: 13 January 2014 Ó The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2014

Abstract In 2012 the European Union Network of Excellence on gastric and esophagogastric junction cancer (EUNE) held its third conference in Cologne, Germany. The main themes discussed included translational research, standard and audit, early diagnosis, development of surgical treatment, adequate surgery for EGJ cancer, adjuvant and neoadjuvant treatment, prevention of peritoneal carcinomatosis and finally education and training. The meeting was attended by 150 experts from 18 different countries. Keywords Esophagogastric junction cancer  Gastric cancer  Conference  Treatment strategies  Guidelines  Multimodality treatment

S. P. Moenig (&)  C. T. H. Baltin  U. K. Fetzner  A. H. Hoelscher Department of General-, Visceral- and Cancer Surgery, University Hospital of Cologne, 50973 Cologne, Germany e-mail: [email protected] H.-J. Meyer German Society of Surgery, Luisenstr. 58/59, 10117 Berlin, Germany W. H. Allum Department of Surgery, The Royal Marsden NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK G. De Manzoni Department of Surgery, University of Verona, Verona, Italy A. Garofalo Department GI Surgery and Peritoneum, National Cancer Institute ‘‘Regina Elena’’, Via Elio Chianesi 53, 00144 Rome, Italy

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 costeffectiveness. The learning curve for ER can only be completed with a large case load available in a large

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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 thoracoabdominal 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

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molecular classification with clinically relevant features (Carboni). Adjuvant therapy still has a role but even after 5 metaanalyses 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].

Report of the third meeting of the EUNE

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 perioperative 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

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Speaker (country)

M. Moehler (Germany)

W. H. Allum (UK)

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2

Clinical management guidelines

Improving outcome guidance for commissioners

Scottish intercollegiate guidelines network

124 experts from 25 medical societies (including patient organizations) developed S3 guideline for the diagnosis and treatment of esophagogastric cancer

Basis for existing practice/existing guidelines

Table 1 Guidelines across Europe

Review of research evidence and review of implications for service configuration

SIGN guidelines (multidisciplinary, nationally representative groups, systematic review)

Decision in the best interdisciplinary consensus (GCP consensus)

Adaption of other international guidelines

Systematic de-novoliterature research

Approach for development/ improvement of guidelines

Symptoms of advanced disease–– no mention of ‘‘dyspepsia’’

Routine use of new endoscopic techniques (NBI, chromoendoscopy, confocal laser microscopy) beyond the video endoscopy is not considered to be necessary

Early endoscopy for pts. w/: dysphagia, recurrent vomiting, anorexia, weight loss, gastrointestinal bleeding

Standard includes a complete endoscopic examination

Primary diagnosis

EUS is obligatory, ultrasound of liver

A peritoneal lavage with cytology can be carried out to complete the staging (without influence on further therapy)

A staging laparoscopy can be performed to improve staging accuracy

For a curative therapy approach EUS is obligatory and CT of thorax and abdomen should be performed

Staging

n.a.

ER (or ESD) of early gastric cancer must be done as a complete en bloc resection to allow a complete histological evaluation of lateral and basal margins

Endoscopic resection

T1a (EMR-ve) and T1b-? requires D2

The proximal safety distance should be 5 cm (Laure´n intestinal type) or 8 cm (diffuse type) in situ

The extent of resection depends on tumor location, TNM classification and histological type

There is no standard for reconstruction after (distal) gastrectomy

The aim is R0

Standard therapy in potentially resectable tumors is surgery

Curative surgery

n.a.

The duration of the palliative medical tumour therapy should be decided depending on tumour response, treatmentassociated toxicity and patient’s request

Palliative medical tumor therapy should be initiated at the earliest possible time after diagnosis of inoperable, locally advanced or metastatic disease

Palliative chemotherapy

n.a.

HER-2 status should be determined as a positive predictive factor for treatment with trastuzumab

In cases of tumorrelated bleeding, palliative resection or angiographic embolization should be considered, palliative radiotherapy may be useful in chronic bleeding

Endoluminal or percutaneous radiotherapy beneficial in the long term

In case of stenosis of EGJ: stent for rapid symptom relief

Palliative (partial) gastric resection should be performed only in exceptional cases

Varia: therapy for tumor stenosis and tumor-related bleeding, nutrition, genetics

S. P. Moenig et al.

Speaker (country)

G. Manzoni (Italy)

M. Barczynski (Poland)

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Table 1 continued

PGCSG (Polish Gastric Cancer Study Group) is a network of 9 university departments of surgery to improve early detection of GC and outcome

GIRCG guidelines for diagnosis and treatment of gastric cancer

Basis for existing practice/existing guidelines

n.a.

n.a

Approach for development/ improvement of guidelines

In tertiary referral centers also: CT of chest and abdomen, EUS, diagnostic laparoscopy

Basic imaging: clinical examination, upper GI endoscopy, endoscopic biopsy, X-ray of the chest, US of the abdomen

Use of new endoscopic techniques to achieve higher accuracy in detection of EGC and definition of tumors margins (chromoendoscopy, ME-NBI, confocal laser microscopy)

Primary diagnosis

n.a.

Laparoscopy is necessary in staging gastric cancer (to assess serosal involvement, peritoneal lesions, distant metastasis, peritoneal cytology)

PET/CT is not standard in gastric cancer staging

EUS is not routinely used in gastric cancer staging

Staging

In tertiary referral centers: endoscopic mucosal resection, endoscopic submucosal dissection, laparoscopic resection with SLN biopsy

n.a.

Endoscopic resection

Proximal and distal margin: Lauren I: 5 cm, Lauren II: 7 cm

Advanced gastric cancer: T4, M0: multivisceral resection

General recommendation for (A) early gastric cancer: open surgery, upper 1/3 gastrectomy D2. (B) Other cases: subtotal gastric resection D2

In case of R1 resection line involvement reoperation should be considered for T2–T3 /N0–N1 patients

So far no consensus on proximal margin of resection (2 cm in EGC, 3 cm in AGC if expansive grow pattern, 5 cm in AGC if infiltrative grow pattern)

Curative surgery

Disease stage IV: palliative CHT or supportive care

Endoscopic stenting for cardia obstruction

Palliative gastrectomy only for risk of bleeding or obstruction

n.a.

Palliative chemotherapy

n.a.

In GIRCG experience in high volume centers surgical morbidity 23 vs. 17 % (p \0.032) but no difference in mortality.

Varia: therapy for tumor stenosis and tumor-related bleeding, nutrition, genetics

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Diagnostic laparoscopy is mandatory in patients with cT3, cT4, uT3, uT4 and all patients receiving neoadjuvant treatment

EUS in special situations only or if CT staging is not accurate

Instead of postoperative tube feeding consumption of fluid diet on postOP day 1 is prefered (studies: Lewis et al. [9], Lassen et al. [10])

n.a. n.a. Histological results after EMR/ESD should be presented at the local interdisciplinary tumour board (quality control) No laparoscopic biopsy retrieval from the primary tumor in potentially curable disease because of cell seeding (EUS guided biopsy is prefered) Hydro-CT: water (negative contrast medium) only: better contrast to contrast-enhanced gastric wall

Her2 validation not only regarding the IHC, ISH

Palliative chemotherapy Curative surgery Endoscopic resection Staging

Recommendations of the ASSO (Austrian Society of Surgical Oncology) J. Zacherl (Austria) 5

n.a.

Basis for existing practice/existing guidelines Speaker (country)

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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, perioperative 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

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Table 1 continued

Approach for development/ improvement of guidelines

Primary diagnosis

Varia: therapy for tumor stenosis and tumor-related bleeding, nutrition, genetics

S. P. Moenig et al.

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.

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starts with deep mucosal infiltration. Ann Surg. 2009;250(5):791–7. Probst A, Pommer B, Golger D, Anthuber M, Arnholdt H, Messmann H. Endoscopic submucosal dissection in gastric neoplasia––experience from a European center. Endoscopy. 2010;42(12):1037–44. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer. 2011;14:113–23. Moehler M, Al-Batran SE, Andus T, Anthuber M, Arends J, Arnold D, et al. German S3-guideline ‘‘Diagnosis and treatment of esophagogastric cancer’’. Z Gastroenterol. 2011;49(4):461531. Wittekind C, Compton C, Quirke P, Nagtegaal I, Merkel S, Hermanek P, et al. A uniform residual tumor (R) classification: integration of the R classification and the circumferential margin status. Cancer. 2009;115(15):3483–8. Schroeder W, Moenig SP, Baldus SE, Gutschow C, Schneider PM, Hoelscher AH. Frequency of nodal metastases to the upper

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mediastinum in Barrett’s cancer. Ann Surg Oncol. 2002;9(8):807–11. Hartgrink HH, Putter H, Klein Kranenbarg E, Bonenkamp JJ, van de Velde CJ. Value of palliative resection in gastric cancer. Br J Surg. 2002;89(11):1438–43. Kim KH, Lee KW, Baek SK, Chang JH, Kim YJ, Park do J, et al. Survival benefit of gastrectomy ? metastasectomy in patients with metastatic gastric cancer receiving chemotherapy. Gastric Cancer. 2011;14(2):130–8. Lewis SJ, Egger M, Sylvester PA, Thomas S. Early enteral feeding versus ‘‘nil by mouth’’ after gastrointestinal surgery: systematic review and meta-analysis of controlled trials. BMJ. 2001;323(7316):773–6. Lassen K, Kjaeve J, Fetveit T, Tranø G, Sigurdsson HK, Horn A, Revhaug A. Allowing normal food at will after major upper gastrointestinal surgery does not increase morbidity: a randomized multicenter trial. Ann Surg. 2008;247(5):721–9.

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Third international conference of the European Union Network of Excellence on gastric and esophagogastric junction cancer, Cologne, Germany, June 2012.

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