Abstract
Background and scope
The management of GOJ cancers remains controversial and may vary between countries. Evidence-based attitudes and guidelines are not easy to elaborate since most of the trials and studies reported mixed cases of oesophageal (both adenocarcinoma and squamous cell tumours), GOJ and gastric cancers. The aim of this expert discussion and position paper is to elaborate practical recommendations that integrate evidence-reported literature and experience-based attitude covering all clinical aspects of GOJ cancer across different specialities and countries in Europe.
Methodology
Opinion leaders, selected on scientific merit were asked to answer to a prepared set of questions covering the approach of GOJ tumours from definition to therapeutic strategies. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine.
Results
Definition, classification, diagnosis and staging of GOJ tumours were updated and debated. Therapeutic aspects including endoscopic therapy, surgical management, both multimodal curative and palliative management were also reviewed for proposing practical and consensual positions and recommendations whenever possible.
Conclusion
GOJ tumours deserve specific attention,not only for uniformising clinical management across countries but also for performing specific clinical and translational research,mainly in the curative perioperative setting.
Keywords
1. Introduction, scope and methodology
The incidence of oesophageal and gastro-oesophageal junction (GOJ) adenocarcinoma is rising in Western countries with the highest incidence in the 65–74 year old age group [
[1]
].Temporal variations in incidence rates of gastric cancer differed according to subsite and histology, suggesting different etiological factors [
[2]
].The management of GOJ cancers remains controversial mainly due, on one side, to histological definition and classification and, on the other side, to accurate tumoural localization and staging. Moreover, management differences between countries can explain differences in long-term survival [
[3]
]. Evidence-based attitudes and guidelines are not easy to elaborate since most of the trials and studies reported mixed cases of oesophageal adenocarcinoma and squamous cell tumours, oesophageal and GOJ cancers and gastric cancers [4
, 5
, 6
].Furthermore, therapeutic management from endoscopic to surgical, including perioperative chemotherapy or chemoradiation may vary from one country to another [
[7]
].This article focuses on the multimodal management of GOJ tumours according to histological and clinical classification and staging and summarizes the expert discussion, which was organized by the ESDO during the 16th World Congress on Gastrointestinal Cancer (WCGIC) in June 2014 in Barcelona, Spain.
An expert panel was composed from different specialities and nationalities involved in all aspects of GOJ cancer management; opinion leaders, selected on scientific merit were asked to answer to a prepared set of questions covering the approach of GOJ tumours from definition to therapeutic strategies. All answers were then discussed during a plenary session and led to a position statement for each addressed topic.
In this paper, we report the main conclusions of the discussions, providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine.
The panel proposes minimal guidelines and when possible consensual opinion in managing such tumours and making treatment choices across different European countries.
2. Definition and classification of GOJ tumours
Most cancers that arise at the GOJ are adenocarcinomas. Histologically, several types are recognized: papillary, tubular, mucinous, signet ring cell and other poorly cohesive non-signet ring cell carcinomas, and mixed carcinomas. The relative proportion of well-differentiated, gland-forming carcinomas is significantly lower for tumours that arise in the GOJ compared with pure oesophageal carcinomas. Signet ring carcinomas are far less common in the proximal than in the distal stomach, and are not usually accompanied by atrophic gastritis. Well-differentiated “tubular” adenocarcinomas may present considerable difficulty for diagnosis since the neoplastic glands may reveal a deceptively bland and regular appearance, and are thus easily mistaken for benign hyperplasia or dysplasia, mainly in biopsies. Other rare histotypes are pylorocardiac carcinoma, adenosquamous carcinoma and small cell carcinoma.
2.1 WHO Classification
The WHO classification (2010) for GOJ tumours is the following: adenocarcinomas that straddle the junction of the oesophagus and stomach are designated as tumours of the GO Junction (GOJ). This definition includes many tumours formerly called cancers of the gastric “cardia” [
[8]
].Squamous cell carcinomas that occur at the GOJ are considered to be carcinomas of the distal oesophagus, even if they cross the GOJ.
The following guidelines are recommended by the WHO (2010):
- a)Adenocarcinomas that cross the GOJ are considered adenocarcinomas of the GOJ, regardless of where the bulk of the tumour lies;
- b)Adenocarcinomas located entirely above the GOJ, as defined above, are considered to represent oesophageal carcinomas;
- c)Adenocarcinomas located entirely below the GOJ are considered to be gastric in origin. For the latter group, use of the ambiguous and often misleading term “carcinoma of the gastric cardia” is discouraged in favour of the term “carcinoma of the proximal stomach”.
2.2 TNM staging
Staging of GOJ tumours is an important issue for clinicians and is currently based on the following TNM 7: a tumour whose centre is located within 5 cm of the GOJ and which also extends into the oesophagus is staged according to the scheme for oesophageal carcinoma. Tumours with an epicentre in the stomach >5 cm from the GOJ, or those within 5 cm of the GOJ without extension in the oesophagus, are staged according to the scheme for gastric carcinoma [
[9]
].The main clinical differences between staging for the oesophagus vs. the stomach are the following:
- 1)Oesophageal cancer incorporates tumour grade as a prognostic variable;
- 2)Metastasis in 7 or more regional lymph nodes (N3) is divided into N3a (7–15 nodes) and N3b (16 or more nodes) for gastric carcinomas.
Adenocarcinomas located at the GOJ have a proclivity for proximal spread mainly via lymphatics in the submucosa of the oesophagus. For this reason, intra-operative frozen-section examination of the proximal oesophageal resection margin is recommended for these cases.
2.3 Siewert types
Beside WHO classification and TNM staging system, and especially for planning surgical approaches, the Siewert classification is frequently used: type I: distal oesophagus; type II: cardia; type III subcardial gastric [
[10]
]. However, it may be difficult to distinguish the type in large locally advanced tumours that obliterate the GOJ and cross boundaries. In this case, the location of the bulk of the tumour should be indicated.In addition, the panel agreed that in case of well recognized Barrett’s oesophagus, such tumours should be classified as oesophageal cancers.
2.4 Molecular characteristics
At the molecular level, search for HER2 amplification and overexpression is currently supported by several studies [
[11]
]. HER2 (encoded by ERBB2 gene) is one of the four members of the human epidermal growth factor receptor family (EGFR or HER1, HER2, HER3 and HER4) in the receptor tyrosine kinase (RTK) superfamily. In gastric cancer, ERBB2 amplification or HER2 overexpression has been reported in 7–34% of the tumours, particularly in the GOJ carcinomas (proximal) and in intestinal type adenocarcinomas [12
, 13
]. The prognostic value of HER2 positivity in advanced gastric cancer is a controversial issue. There are reports indicating that ERBB2 amplification is associated with poor prognosis and aggressive disease whereas other reports show no difference in prognosis when compared with HER2- negative tumours [14
, 15
]. A recent study showed that HER2 status is not an independent prognostic biomarker in early GOJ adenocarcinoma [[16]
].Due to the frequent occurrence of HER2 staining variability and the slight difference in HER2-positivity rates between biopsy and surgical specimens, it is recommended that a number of representative biopsies (ideally 6–8) be collected for HER2 testing, as one or two samples may not give an accurate HER2 result. German guidelines recommend a minimum of eight samples for this reason [
[17]
]. Currently, HER2 analysis does not yet have therapeutic implications in locally advanced disease management, but this may change in the future considering the ongoing studies in this specific setting. Additionally, the biopsies/paraffin blocks should be stored for potential future analysis.3. Diagnosis and staging
3.1 Biopsies
Sampling and quality of biopsies are at least as important as number (full thickness mucosa preferably) and the experts encourage the setup of quality criteria, including time for inspection for upper GI endoscopy to make sure that lesions are appropriately detected. Novel endoscopic techniques such as chromoendoscopy or virtual chromoendoscopy are under investigation and may be helpful [
18
, 19
, 20
, 21
].In Barrett’s oesophagus which is found associated or adjacent to the tumour (mainly Siewert I), the panel recommended to biopsy all visible lesions and to perform random biopsies every 1–2 cm. In case of bigger lesions at least 6–8 biopsies should be taken. In case of small lesions, fewer biopsies are possible to allow subsequent complete endoscopic resection.
3.2 Procedure in case of low grade/high grade intraepithelial neoplasia/dysplasia in the biopsies
If dysplasia is noted, we recommend that it will be verified by consultation/opinion with a second pathologist with particular expertise in oesophageal histopathology. Current guidelines recommend surveillance or endoscopic eradication for patients with verified low-grade dysplasia. In this case, radiofrequency ablation (RFA) appears to decrease the risk of progression to high-grade dysplasia or adenocarcinoma. Therefore, the risks and benefits of RFA in patients who have verified low-grade dysplasia should be discussed [
19
, 20
, 21
, 22
].In case of high-grade dysplasia, endoscopic resection should be proposed in case of visible lesion (Endoscopic Mucosal Resection (EMR) or Endoscopic Submucosal Dissection (ESD)), combined to RFA for Barrett’s eradication [
19
, 20
, 23
, 24
]. In case of no visible or multifocal high grade dysplastic lesions, RFA is the treatment of choice [19
, 20
, 25
]. Surgery can be an option since it clearly removes all of the neoplastic epithelium, but it also has the highest rates of procedure-related mortality and long-term morbidity. Decision should be based on patient’s preference and skill of practitioners. For very old or infirm patients for whom invasive endoscopic procedures pose a substantial risk, intensive endoscopic surveillance is reasonable.The experts agreed that the situation may be considered more difficult at the GOJ as compared to the oesophagus. Anyway, therapeutic decisions should be made by a multidisciplinary team (MTD) of experts after review of all pathological specimens available (see treatment section).
3.3 Staging
Accurate staging relies on endoscopy, including accurate localization and mapping of the tumour and adjacent oesophagus/stomach, endoscopic ultrasound (EUS) ± fine needle aspiration (FNA) biopsies for distant lymph nodes and chest-abdomen CT scan for distant lesions.
There is no consensus on the impact of Positron Emission Tomography–Computed Tomography (PET–CT) which can be dependent on availability and expertise at certain places; PET–CT can especially add information on distant metastases and could avoid futile surgical resections in 10–15%; it can be more appropriate in case of advanced stage, i.e. from T2N+ although it does not add accurate findings to T and N staging.
Regarding the use of staging laparoscopy, the experts believe that it is not to be routinely recommended; it can be specifically considered in case of type III Siewert tumours (more than T2), bulky type II Siewert, suspicion of peritoneal carcinomatosis or diffuse type histology after multidisciplinary discussion (MDT).
Complementary to the staging, the general condition of the patient should be assessed as well as his/her nutritional status and weight loss percentage. For elderly patients with co-morbidities (Balducci 2 and 3), a specific oncogeriatric evaluation using appropriate comprehensive geriatric scales is recommended before any decision.
4. Treatment options for curative intent
4.1 Endoscopy
The panel agreed that the goal of endoscopic resection should be “en-bloc R0 resection “, allowing the pathologists to perform total embedding of the lesion and accurate pathological staging and evaluation [
[19]
].According the existing guidelines endoscopic treatment should be restricted to elevated lesions <2 cm, flat lesions <1 cm, histological grade I/II, absence of macroscopic ulceration, and tumoural infiltration limited to the mucosa or the submucosa up to 500 μm [
19
, 20
].At the current state of knowledge, EMR and ESD may both be appropriate for lesions <15 mm in the oesophagus [
23
, 24
]. ESD is preferred in the stomach [[21]
]. The experts insisted on the qualification of the endoscopists performing ESD; a minimun of 30 procedures per year is recommended [26
, 27
].Each resected pathological specimen (pT) should be reviewed by a multidisciplinary team for decision making and follow up; in case of positive deep margins, surgery should be considered while endoscopic retreatment or reassessment should be performed for positive lateral margins.
For follow up, endoscopy is recommanded every 3 months during the first year, then every 6 months in the second year, then once per year for 5 years in total [
[19]
].In case of local recurrence: for mucosal recurrence only (rT1a,N0M0), a second endoscopic resection may be considered (experienced endoscopist); otherwise, surgery is indicated in operable patients [
19
, 20
, 21
].4.2 Surgery
The goal of surgery is an R0 resection; transthoracic oesophago-gastrectomy (for Siewert type I) or transhiatal oesophago-gastrectomy or extended total gastrectomy (preferentially for Siewert type II/III) may be recommended based on surgeon experience; there is no major difference between both procedure; there may be some variations in surgical approach across Europe [
28
, 29
, 30
].The minimally invasive approach is still investigational while long-term oncological benefit remains unknown. However studies from France and the Netherlands suggest reduced respiratory morbidity [
31
, 32
].An adequate lymphadenectomy (2 field lymphadenectomy—up to paratracheal/hilar lymph nodes) should be recommended, aiming at resecting at least 15 lymph nodes. Therefore transhiatal oesophago-gastrectomy should be preferably limited to Siewert II(III) tumours. For Siewert III tumours which require a total gastrectomy, the consensus view is that a D2 lymphadenectomy should be performed for fit patients, as proposed in the Western literature [
[6]
]. A perioperative mortality rate <5% should be targeted; for this, expert panel recommends that treatment should be conducted in high volume centres with skillful surgeons (at least 30 resections/year) and multidisciplinary teams [4
, 6
, 28
, 29
].Schematically, surgical resection is:
Siewert I
transthoracic oesophago-gastrectomy
Siewert IIextended gastrectomy or transhiatal esophago-gastrectomy
Siewert IIItotal gastrectomy with D2 lymph node dissection preferable for fit patients
In case of R1 resection, and no possibility to salvage this situation by more extended surgery, the panel proposes to consider postoperative chemoradiation although robust data on the true benefit of that do not exist.
There is no defined role for surgery in the palliative management of GOJ tumours where endoscopic palliation, possibly combined with chemotherapy and/or radiation (obstruction or bleeding) should be considered.
The role of surgical resection in case of peritoneal metastases (peritonectomy ± hyperthermic intraperitoneal chemotherapy [HIPEC]) is investigational and should be performed in the setting of well conducted trials with highly selected patients.
Similarly, the role of surgery in resecting local recurrence or isolated liver metastases is yet unclear and should be restricted to rare selected cases after multidisciplinary evaluation.
4.3 Nutritional support
Nutritional assessment should be done routinely in all cases diagnosed with an upper GI tumour and patients should be supported accordingly.
Malnutrition is always detected in such patients and may deteriorate the tolerance and the completion of both surgical and perioperative chemotherapy or chemoradiation.
Nasogastric/duodenal tubes may be placed before initiation of neoadjuvant therapy. Jejunostomy may be preferable to preserve the gastric tube before (oeso)-gastrectomy; enteral nutrition should be preferred to parenteral nutrition.
4.4 Exclusive chemoradiation
Most of the data on definitive chemoradiotherapy for esophageal cancer have been obtained in patients with squamous cell cancer; there are less data for adenocarcinoma, and pathologic complete response rates after chemoradiotherapy are lower for adenocarcinoma as compared to those obtained for squamous cell carcinoma [
33
, 34
]. Thus, for patients with adenocarcinoma of the GOJ, the panel proposes to reserve definitive chemoradiotherapy for those patients who refuse surgery, or are no surgical candidates for anatomic or medical reasons.- Lutz M.P.
- Zalcberg J.R.
- Ducreux M.
- et al.
Highlights of the EORTC St. Gallen International Expert Consensus on the primary therapy of gastric, gastroesophageal and oesophageal cancer—differential treatment strategies for subtypes of early gastroesophageal cancer.
European Journal of Cancer. 2012; 48: 2941-2953
4.5 Multimodal treatment
There is no strict consensus on what exactly should be done as multimodal therapy in GOJ tumours. But it has become evident that some form of neoadjuvant treatment is beneficial in clinical stages 2 and 3 of GOJ tumours. Preoperative chemotherapy, perioperative chemotherapy, preoperative chemoradiation and postoperative chemoradiation are different options that have been evaluated in phase III trials that included patients with upper GI tract cancers, mixing GOJ tumors with either oesophageal cancers or gastric cancers. The preference of these different modalities may vary from one country to another or even within one country between centres [
[34]
].- Lutz M.P.
- Zalcberg J.R.
- Ducreux M.
- et al.
Highlights of the EORTC St. Gallen International Expert Consensus on the primary therapy of gastric, gastroesophageal and oesophageal cancer—differential treatment strategies for subtypes of early gastroesophageal cancer.
European Journal of Cancer. 2012; 48: 2941-2953
There is no robust proof that preoperative chemoradiation is superior to pre- or perioperative chemotherapy in oesophageal and GOJ adenocarcinoma [
33
, 34
, - Lutz M.P.
- Zalcberg J.R.
- Ducreux M.
- et al.
Highlights of the EORTC St. Gallen International Expert Consensus on the primary therapy of gastric, gastroesophageal and oesophageal cancer—differential treatment strategies for subtypes of early gastroesophageal cancer.
European Journal of Cancer. 2012; 48: 2941-2953
35
, 36
, 37
]. Therefore, the panel concluded that multimodal therapy that starts in the preoperative phase can be recommended for T3/T4 tumors with any node positive for both squamous and adenocarcinoma. T2/N+ tumors can also be considered for preoperative therapy. Based on long term results from both the CROSS and FFCD studies which had included 75% of oesophageal and GOJ adenocarcinoma [36
, 38
, 39
], the panel proposes that neoadjuvant chemoradiation or chemotherapy are equally valuable options that should be discussed within the setting of a multidisciplinary board. Prospective randomised comparison between both modalities are under way in GOJ and gastric cancer (see section “research and perspectives agenda”).4.6 Open questions in perioperative strategies
4.6.1 Chemotherapy regimen and duration of treatment
Platinum and fluoropyrimidines are the backbone of preoperative chemotherapy [
35
, 36
]. Triplet regimen using epirubicin (ECF) or docetaxel (DCF) as in the metastating setting, are optional while one recent negative study for epirubicine given in addition to cisplatin and capecitabine was reported [[40]
]; moreover, in the same study, intensification of chemotherapy (4 cycles vs. 2) did not translate into a clear survival benefit [[40]
]; of note, there is no phase III data reporting the benefit of adding docetaxel in the preoperative approach of GOJ/gastric cancer; regarding biologics, anti HER2 therapy is investigational in the perioperative setting while studies are ongoing and antiangiogenic therapy added to chemotherapy does not add benefit [[41]
].Carboplatin/paclitaxel or platinum/5FU infusional are the usual partners for chemoradiation therapy [
[38]
].4.6.2 Early response evaluation of preoperative therapy by PET–CT and restaging of tumour before surgery
Response evaluation using PET–CT remains investigational and is not recommended routinely by the panel although it is more and more used within the setting of protocols [
42
, 43
, 44
].There is no consensus by the panel on the tumour restaging during neoadjuvant therapy; the situation may vary from one country to another; there is agreement that tumour progression and the occurrence of distant metastases should be detected during this period and especially before surgery. Regarding evaluation of response to preoperative chemotherapy and adaptation of chemotherapy regimen in case of no response, different attitudes are observed in Europe. However, surgery remains the standard and chemotherapy change is investigational. Neither novel imaging techniques nor any molecular markers are able to reliably predict response by today.
4.6.3 Adjuvant chemotherapy as a part of perioperative therapy
Based on the MAGIC and French phase III trials, this should be given after surgery within 8 weeks; however in the MAGIC trial, only 42% received the planned postoperative chemotherapy; there is no consensus on early restaging before starting adjuvant therapy [
[35]
].4.6.4 Adjuvant chemoradiation
This modality remains optional in case of R1 resection, suboptimal D2 lymph nodes dissection in Siewert II/III tumours or – as an individual and non-evidence-based consideration – in case of no clinical and pathological response to preoperative chemotherapy or extensive lymph nodes involvement on the resected specimen.
4.6.5 Adjuvant chemotherapy
This can be considered in all Siewert tumours with N+ disease as it is proposed in gastric cancer [
[45]
]; preferable regimen is based on platinum and fluoropyrimidines; there is no restriction based on age while geriatric assessment is recommended for patients >70.4.6.6 Elderly patients
For older patients with operable/resectable disease, the panel recommended to perform and to rely on geriatric assessment while age is not a contraindication for multimodal or surgical management per se [
[46]
].5. Palliative treatment
The panel agreed that the aim of palliative therapy is to control tumour progression and related symptoms, to prolong survival and to maintain and improve the quality of life.
Palliative therapy should start once the diagnosis of metastatic disease is done and maintained as long as it is effective without progression of the disease and apparition of intolerable toxicity.
HER2 status should be determined prior starting treatment; no other molecular markers are routinely used until now.
5.1 Chemotherapy and biologics
In first line therapy, the most widely recommended regimens are the combinations of cisplatin and fluoropyrimidines with the addition of epirubicine (ECF regimen) or docetaxel (DCF regimen) [
47
, 48
, 49
, 50
]; in HER2+ (IHC 3+ or 2+/FISH+) tumours, trastuzumab is recommended in combination with cisplatin and fluoropyrimidines (5-FU or capecitabine) [[51]
]. In doublet and triplet regimens,like epirubicin-oxaliplatin-capecitabine (EOX) or fluorouracil/leucovorin–oxaliplatin–docetaxel (FLOT), oxaliplatin can replace cisplatin [[47]
] FOLFIRI (folinic acid, 5-FU and irinotecan) can also be used in first line therapy [[52]
].In second line therapy, irinotecan (+/− 5-FU/folinic acid), taxanes (docetaxel or paclitaxel) and recently antiangiogenic therapy with ramucirumab (alone or in combination with paclitaxel) are recommended options that have proven benefit as compared to best supportive care (BSC) [
53
, 54
].- Wilke H.
- Muro K.
- Van Cutsem E.
- et al.
RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial.
Lancet Oncology. 2014; 15: 1224-1235
In third line, antiangiogenic therapy using apatinib, a TKI targeting VEGFR-2 has shown modest but significant benefit as compared to placebo in Asian patients [
[55]
].Ongoing genomic landscape studies are beginning to define a new molecular classification of GOJ tumours, aiming to identify new targets and to direct treatment to molecularly defined subgroups [
[56]
].5.2 Supportive therapy in GOJ tumors
The panel agreed that stenting of severe dysphagia should only be performed in case of symptoms refractory to chemotherapy ± radiation therapy, in case of abstention of any systemic therapy or in case of oesophageal fistula; partially metallic covered stents are recommended.
External radiotherapy or endo-brachytherapy in case of massive tumour bulk in the oesophagus can also be proposed in selected indications.
6. Specific trials in GOJ tumors
The panel strongly pointed out the need for designing and performing specific trials and research in GOJ tumours, especially in the curative setting.
7. Executive summary of recommended positions by the panel
7.1 Scope
Elaborate practical recommendations that integrate evidence-reported literature and experience-based attitude covering all clinical aspects of GOJ cancer.
7.2 GOJ cancer characteristics
WHO classification is used for pathological definition and classification; TNM, integrating oesophageal and gastric schemes is used for staging; Siewert classification is considered for directing endoscopic and mostly surgical management; molecular characterisation is underway, HER2 status being the only molecular marker routinely used by today in the metastatic setting.
7.3 Diagnosis and staging
Biopsies sampling of the lesions should be of adequate number and quality to adequately guide evaluation of dysplasia, future molecular characterisation, therapeutic decision and follow up; staging should integrate accurate localisation and mapping of the tumour, local and distant extension, nutritional status and oncogeriatric evaluation for older patients.
7.4 Endoscopic treatment
It is recommended for well-defined superficial tumours (Tis/T1a), able to be “en-bloc R0 “ resected, using EMR or ESD performed by high qualified endoscopists (30 procedures/year) and allowing accurate pathological staging.
7.5 Surgical and multimodal treatment
Transthoracic (Siewert I), transthoracic or transhiatal oesophago-gastrectomy (Siewert II), extended gastrectomy or oesophago-gastrectomy (Siewert II) and total gastrectomy with D2 lymph node dissection for fit patients (Siewert III) are recommended and should be conducted in high volume centers integrating skilful surgeons (30 resections/year) and multidisciplinary management, only for curative intent. Nutritional support should be routinely and early considered in all cases. In stage II and III GOJ tumours (T3-T4/N0-N+), pre-or peri-operative chemotherapy or preoperative chemoradiation can be equally recommended today pending the results of ongoing trials. The evaluation of tumour response during the preoperative phase remains investigational; the postoperative adjuvant therapy should be discussed on an individual basis.
7.6 Medical and palliative treatment
Chemotherapy remain the backbone therapy based on platinum and fluoropyrimidines combination; taxanes, anthracyclines and trastuzumab (targeting HER2 overexpressing tumours) can be added with potential survival benefit in the palliative setting (first line therapy) as well as irinotecan and 5FU combination; recently, antiangiogenic therapy (ramucirumab, apatinib) were also reported as modestly active drugs in GOJ cancers in second and third line therapy. Chemotherapy should be proposed upfront before considering radiotherapy (both external or endobrachy) or endoscopic stenting.
8. Research and perspectives agenda
8.1 Molecular classification and taxonomy in gastro-oesophageal cancers
Recent data from The Cancer Genome Atlas studies may provide important insights regarding the molecular characterisation of gastro-oesophageal tumours, beyond histological subtypes and localization [
[57]
]. This may allow to better delineate the GOJ tumours at the genomic level and to conduct specific targeted and immunotherapies in specific enriched populations.8.2 Surgical perspectives
The optimal approach for surgery of GOJ tumours should rely on specific evaluation and trials in the future, performed in high volume centers and by expert surgeons. One important step is to determine if laparoscopic or hybrid approaches are of real benefit for the patients in terms of limiting complications (notably after neoadjuvant therapy) and assuring good oncological outcome. Emerging data from randomised trials (the MIRO French trial) or meta-analysis are promising in terms of decreasing postoperative complications [,
59
].8.3 Radiation therapy perspectives
Recent data from the CRITICS trial (83% of gastric cancer vs. 17% of GOJ tumours included) do not longer support adjuvant chemoradiation after D1/D2 gastrectomy in gastric cancer [
[60]
]. By contrast, efforts should be focused on the adequately designed evaluation of neoadjuvant use of chemoradiation and the identification of the best benefiters where a major or complete pathological response can be achieved by this modality, specifically in GOJ tumours. Newer imaging modalities (i.e. PET–CT, PET–MRI) aiming at optimalizing radiation therapy delivery should also be considered.8.4 Multimodal management options
Neoadjuvant therapy is nowadays emerging as one more and more recommended approach; many trials in gastro-oesophageal cancers have enrolled or will enroll a high proportion of GOJ tumours but specific trials should be preferentially designed for this localization; currently, ongoing trials (TOPGEAR-ACTRN12609000035224- and CRITICS 2-NCT01726452-) are evaluating which modalities (preop ± postop chemotherapy vs. preop chemoradiation) are the most efficacious in GOJ/gastric adenocarcinoma. Moreover, a randomised phase II trial (-NCT02359968-) is comparing the two standards of chemotherapy delivered with a common regimen of preoperative radiation (paclitaxel–carboplatin vs. FOLFOX concurrent with 41.4 Gy).
8.5 Innovative drugs
Targeting HER2 and beyond remains an important approach in advanced gastro-oesophageal cancers; combination of trastuzumab with or without pertuzumab is under investigation and is notably integrated into perioperative chemotherapy of HER2-positive GOJ/gastric adenocarcinomas in a randomised phase II trial (INNOVATION/EORTC 1203 -NCT02205047-). Beside ramucirumab, optimizing antiangiogenic therapy is also evaluated, using TKI targeting VEGFR-2 like afatinib or regorafenib but the most important field of research deals with immunotherapy; preliminary and emerging data using checkpoint inhibitors like pembrolizumab are promising [
[61]
] and along with ongoing phase III trials in second or third line, the current challenge is now to identify the best benefiters of such drugs (is there a predictive role of PD1/PD2 tumoural expression?), and develop strategies to increase the efficacy of PD-1/PD-L1 blockade in gastro-oesophageal cancers, such as combination with chemotherapy, radiation therapy or other immunotherapies. In this setting, the recent characterisation into 4 molecular subgroups of GOJ/gastric cancers will probably help us to identify tumours with high mutation rates or immunogenic antigen expression (i.e. Epstein-barr virus positive and MSI-high cancer) susceptible to benefit from immunotherapy [[57]
].8.6 Conclusions
The management of GOJ tumours should benefit from specific research and trials aiming at defining specific strategies for curative treatment and characterise molecular profile for precision medicine and integration of new drugs; the preoperative phase offers a good window of opportunity for the sequential evaluation by dynamic imaging and molecular histopathology of tumour changes after therapeutic intervention.
Conflict of interest disclosures
None of the authors disclosed any conflict of interest.
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Article info
Publication history
Published online: August 30, 2016
Accepted:
August 5,
2016
Received in revised form:
August 3,
2016
Received:
April 29,
2016
Identification
Copyright
© 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
