Professional Documents
Culture Documents
doi:10.1093/annonc/mdw329
for men and the UK for women [1]. Variation between coun- of the American College of Gastroenterology [5].
guidelines
tries is high and may reflect different prevalence of risk factors, All patients with new dysphagia, gastrointestinal bleeding,
use of screening and diagnostic methods. recurrent aspiration or emesis, weight loss and/or loss of appe-
Between 2000–04 and 2005–09, oesophageal cancer mortality tite should undergo an upper intestinal endoscopy [III, A].
declined by 7% (from 5.34 to 4.99/100 000) in EU men, and by Approximately three-quarters of all ACs are found in the distal
3% (from 1.12 to 1.09/100 000) in EU women. Predictions to oesophagus, whereas SCCs occur more frequently in the
2015 show persistent declines in mortality rates for men in the proximal to middle oesophagus [3]. Biopsies should be taken
EU overall and stable rates for EU women, with rates for 2015 of from all suspect areas. The minimal recommended number of
4.5/100 000 men (∼22 300 deaths) and 1.1/100 000 women biopsies is not defined. The diagnosis should be made from an
(∼7400 deaths). endoscopic biopsy with the histology classified according to
Oesophageal cancer has two main subtypes—oesophageal the World Health Organization (WHO) criteria [6]. The differ-
squamous cell carcinoma (SCC) and oesophageal adenocarcin- entiation between SCC and AC is of prognostic and clinical
oma (AC). Although SCC accounts for ∼90% of cases of oe- relevance.
sophageal cancer worldwide, mortality rates associated with AC Immunohistochemical stainings are recommended in poorly
are rising and have surpassed those of SCC in several regions in and undifferentiated cancers (G 3/4) according to WHO to
the EU [2]. differentiate between SCC and AC [V, B]. Additionally, small
Oesophageal carcinoma is rare in young people and increases in cell carcinoma and other rare histologies (endocrine tumours,
incidence with age, peaking in the seventh and eighth decades of lymphoma, mesenchymal tumours, secondary tumours and
life. AC is three to four times as common in men as it is in women, melanoma) must be identified separately from SCC and AC and
whereas the sex distribution is more equal for SCC [3]. should be treated accordingly.
The main risk factors for SCC in Western countries are
smoking and alcohol consumption, whereas AC predominantly
occurs in patients with chronic gastro-oesophageal reflux staging and risk assessment
disease and their risk is correlated with the patient’s body mass Decisions on the initial treatment approach of oesophageal
index with a higher risk for obese persons [3, 4]. cancer are taken on the basis of clinical staging, which should be
done with the highest degree of accuracy possible. Staging
should include a complete clinical examination and a computed
*Correspondence to: ESMO Guidelines Committee, ESMO Head Office, Via L. Taddei 4,
6962 Viganello-Lugano, Switzerland. tomography (CT) scan of the neck, chest and abdomen [III, A].
E-mail: clinicalguidelines@esmo.org Ultrasound of the abdomen can be carried out initially as a
†
simple and inexpensive test to exclude stage 4 liver metastases.
Approved by the ESMO Guidelines Committee: August 2003, last update August 2016.
This publication supersedes the previously published version—Ann Oncol 2013; 24 In candidates for surgical resection, endoscopic ultrasound
(Suppl. 6): vi51–vi56. (EUS) should be carried out to evaluate the T and N tumour
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.
Annals of Oncology clinical practice guidelines
categories [III, B]. The sensitivity and specificity of EUS for the Table 1. TNM staging for oesophageal cancer (UICC/AJCC, 7th
correct evaluation of the T category are 81%–92% and 94%– edition) [8, with permission]
97%, respectively. It is lower for the N category [7]. 18F-fluoro- Definition of TNM (2009)
deoxyglucose-positron emission tomography (FDG-PET; today Primary tumour (T)
mostly done as PET-CT) is particularly helpful to identify other-
wise undetected distant metastases. 18F-FDG-PET should, TX Primary tumour cannot be assessed
therefore, be carried out in patients who are candidates for oeso- T0 No evidence of primary tumour
phagectomy [III, B], as the finding of otherwise unknown Tis Carcinoma in situ/high-grade dysplasia
distant metastases may prevent patients from futile surgery. T1 Tumour invades lamina propria or submucosa
T1a Tumour invades mucosa or lamina propria or muscularis
However, the availability of PET-CT differs among countries
mucosae
and centres.
The regional lymph nodes, irrespective of the site of the primary tumour,
management of local/locoregional are those in the oesophageal drainage area including coeliac axis nodes and
disease (M0) paraoesophageal nodes in the neck but not supraclavicular nodes.
Edge et al. [8]. Used with the permission of the American Joint Committee
Upfront interdisciplinary planning of the treatment is manda-
on Cancer (AJCC), Chicago, IL, USA. The original source for this material
tory [III, A]. The main factors for selecting primary therapy are
is the AJCC Cancer Staging Handbook, 7th edition (2010) published by
tumour stage and location, histological type, and the patient’s
Springer Science and Business Media LLC, www.springer.com.
performance status (PS) and comorbidities. Nutritional status
matters and should be corrected. Endoscopic stenting should
not be used in locoregional disease in operable patients and al-
ternative routes of feeding (e.g. with needle catheter jejunost- limited disease (cT1–T2 cN0 M0)
omy) should be preferred [II, A] [11]. Patient preferences Surgery is the treatment of choice in limited disease. In patients
should also be assessed and be taken into account. A summary with T1a AC, endoscopic therapy is the preferred therapeutic
of treatment recommendations is shown in Figure 1. approach, being both effective and well tolerated [II, A].
Endoscopic mucosal resection (EMR) and endoscopic sub- bloc resections were shown to be higher with ESD [II, B]. In
mucosal dissection (ESD) are both regarded as effective endo- addition, relapses occurred less often [13].
scopic resection techniques. Similar cure rates compared with Radical and transthoracic oesophagectomy (Ivor-Lewis pro-
surgical resection have been reported in specialised centres [12]. cedure) is the surgical technique of choice [I, B] in localised oe-
Furthermore, in patients with superficial submucosal infiltration sophageal cancer beyond very early stages (T1a N0). A
of an AC, but without further risk criteria ( pT1sm1; <500 μm prospective randomised study showed a strong trend towards
invasion, L0, V0, G1/2, <20 mm diameter, no ulceration), endo- better survival outcomes for this approach in resectable stage I–
scopic resection can be considered as an alternative to oesopha- IV AC and OGJ AC, compared with less radical transhiatal re-
gectomy, but outcomes are still more limited than in mucosal section in AC of the oesophagus [14]. Details concerning endo-
AC [IV, B]. In the case of a high-grade intraepithelial neoplasia scopic and surgical resection techniques are not in the scope of
or a mucosal carcinoma (L0, V0, no ulceration, grading G1/G2, this article but can be found elsewhere [15, 16]. The role of a min-
infiltration grade m1/m2) in the squamous epithelium, an endo- imally invasive approach to the thoracic and/or abdominal cavities
scopic en bloc resection should be carried out [III, A]. ESD is increasing in clinical practice. Recent randomised studies suggest
should be preferred over EMR, especially in lesions >15 mm, as that either thoracoscopic oesophagectomy or Ivor-Lewis procedure
in Japanese studies en bloc resection rate and the rate of R0 en with laparoscopic gastric mobilisation and open right thoracotomy
Table 2. Personalised medicine synopsis table for lower oesophageal and gastric cancer
Biomarker Method Use LOE,
GOR
HER2 Immunohistochemistry for HER2 protein expression or ISH Used to select patients with metastatic disease for treatment II, B
for HER2 gene amplification with a trastuzumab-containing regimen
HER2, human epidermal growth factor receptor 2; ISH, in situ hybridisation; LOE, level of evidence; GOR, grade of recommendation
All patients with new dysphagia, gastrointestinal bleeding, recurrent aspiration or emesis, weight loss and/or loss of appetite should undergo an upper
intestinal endoscopy [III, A].
Immunohistochemical stainings are recommended in poorly and undifferentiated cancers (G 3/4) according to WHO to differentiate between SCC and
AC of the oesophagus [V, B].
Staging and risk assessment
Decisions on the initial treatment approach of oesophageal cancer are taken on the basis of clinical staging, which should be carried out with the highest
degree of accuracy possible. Staging should include a complete clinical examination and a CT scan of the neck, chest and abdomen [III, A].
In candidates for surgical resection, EUS should be carried out to evaluate the T and N tumour categories [III, B].
18
F-FDG-PET should be carried out in patients who are candidates for oesophagectomy [III, B].
In the case of oesophageal SCC due to chronic tobacco and alcohol consumption, meticulous investigation of the oral cavity, oropharynx and
hypopharynx by an ear, nose and throat specialist, as well as trachea-bronchoscopy to exclude synchronous second cancers in the aerodigestive tract,
should be carried out [IV, B].
Continued
In locally advanced (T3/T4) ACs of the OGJ infiltrating the anatomic cardia, laparoscopy can be done [IV, C].
The nutritional status and history of weight loss should be assessed according to the ESPEN guidelines [III, A].
Nutritional support according to the ESPEN guidelines is an integral part of the medical care for patients with oesophageal cancer in the curative and in
the palliative setting [II, A].
Management of local/locoregional disease
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 external RT, since it provides better long-term relief of dysphagia with fewer complications than
metal stent placement [I, B].
Chemotherapy is indicated for palliative treatment in selected patients, particularly for patients with AC who have a good PS [III, B].
In squamous cell oesophageal cancer, the value of palliative combination chemotherapy is less proved. Therefore, BSC or palliative monotherapy should
also be considered [II, B].
Personalised medicine
Follow-up visits should be concentrated on symptoms, nutrition and psychosocial support [V, D].
In the case of complete response to CRT and no operation, a 3-month follow-up based on endoscopy, biopsies and CT scan may be recommended to
detect early recurrence leading to a discussion about salvage surgery [IV, B].
WHO, World Health Organization; SCC, squamous cell carcinoma; AC, adenocarcinoma; CT, computed tomography; EUS, endoscopic ultrasound; FDG-
PET, 18F-fluorodeoxyglucose positron emission tomography; OGJ, oesophago-gastric junction; ESPEN, European Society for Clinical Nutrition and
Metabolism; ESD, endoscopic submucosal dissection; CRT, chemoradiotherapy; 5-FU, 5-fluorouracil; FOLFOX, oxaliplatin/5-FU/folinic acid; RT,
radiotherapy; PS, performance status; BSC, best supportive care
Table 4. Levels of evidence and grades of recommendation (adapted from the Infectious Diseases Society of America–United States Public Health
Service Grading Systema)
Levels of evidence
I Evidence 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
II Small 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
III Prospective cohort studies
IV Retrospective cohort studies or case–control studies
V Studies without control group, case reports, experts opinions
A Strong evidence for efficacy with a substantial clinical benefit, strongly recommended
B Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended
C Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, ...), optional
D Moderate evidence against efficacy or for adverse outcome, generally not recommended
E Strong evidence against efficacy or for adverse outcome, never recommended
a
By permission of the Infectious Diseases Society of America [41].
(failing) endoscopic resection or definitive CRT, there is no evi- Amgen, Biontech, Bristol-Myers Squibb, Eli Lilly, Ganymed,
dence that regular follow-up after initial therapy has an impact Merck-Serono, MSD, Nordic and Roche; travel support from
on survival outcomes. Amgen, Bayer, Roche and Taiho. CM has reported research
Therefore, follow-up visits should concentrate on symptoms, grants from Nestlé; lecture honoraria from Merck-Serono,
nutrition and psychosocial support [V, D]. Often, during the Nestlé, Roche and Sanofi; travel grants from Ethicon, Bard and
follow-up phase, a multidisciplinary care team is required, coor- Roche. RO has received lecture and advisory honoraria from
dinated by the physician who is seeing the patient on a regular Amgen, Roche, Eli Lilly and Nordic and has received travel
basis. Every patient will develop a variety of needs and problems, support from Merck, Bayer and Roche. DA has reported hon-
which are related to the new condition of life without an oe- oraria/consultancy for Roche, Merck-Serono, Bayer, Lilly and
sophagus or to other treatment sequelae or to psychosocial Servier; research support from Roche. KH has reported no po-
needs. The expertise of a dietician, a radiologist, a gastroenter- tential conflicts of interest.
ologist, a psychologist and a social worker is often needed
during follow-up.
In the case of complete response to CRT and no operation, a references
3-month follow-up based on endoscopy, biopsies and CT scan 1. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J et al. Cancer incidence and
may be recommended to detect early recurrence leading to a mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer
discussion about salvage surgery [IV, B] [28]. 2013; 49: 1374–1403.
2. Castro C, Bosetti C, Malvezzi M et al. Patterns and trends in esophageal cancer
mortality and incidence in Europe (1980–2011) and predictions to 2015. Ann
methodology Oncol 2014; 25: 283–290.
These clinical practice guidelines were developed in accordance 3. Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med 2014; 371:
2499–2509.
with the ESMO standard operating procedures for clinical prac-
4. El-Serag HB, Hashmi A, Garcia J et al. Visceral abdominal obesity measured by CT
tice guidelines development, http://www.esmo.org/Guidelines/
scan is associated with an increased risk of Barrett’s oesophagus: a case-control
ESMO-Guidelines-Methodology. The relevant literature has study. Gut 2014; 63: 220–229.
been selected by the expert authors. A summary of recommen- 5. Shaheen NJ, Falk GW, Iyer PG, Gerson LB. ACG clinical guideline: diagnosis and
dations is shown in Table 3, and an overview of these recom- management of Barrett’s esophagus. Am J Gastroenterol 2016; 111: 30–50.
mendations related to therapy is shown in Figure 1. Levels of 6. Hamilton SR, Aaltonen LA (eds). World Health Organization Classification of
evidence and grades of recommendation have been applied Tumours. Pathology and Genetics of Tumours of the Digestive System. Lyon,
using the system shown in Table 4 [41]. Statements without France: IARC Press 2000.
grading were considered justified standard clinical practice by 7. Puli SR, Reddy JB, Bechtold ML et al. Staging accuracy of esophageal cancer by
endoscopic ultrasound: a meta-analysis and systematic review. World J
the experts and the ESMO faculty. This manuscript has been
Gastroenterol 2008; 14: 1479–1490.
subjected to an anonymous peer review process.
8. Edge SB, Byrd DR, Compton CC et al. (eds). AJCC Cancer Staging Manual, 7th
edition. New York, NY: Springer 2010.
conflict of interest 9. Kondrup J, Allison SP, Elia M et al. ESPEN guidelines for nutrition screening 2002.
Clin Nutr 2003; 22: 415–421.
FL has received research support from GlaxoSmithKline and 10. Weimann A, Braga M, Harsanyi L et al. ESPEN guidelines on enteral nutrition:
Fresenius Biotech; lecture and advisory honoraria from surgery including organ transplantation. Clin Nutr 2006; 25: 224–244.