State of the Art Oncology in EuropeFont: aaa

Oesophageal Cancer – 2016

UPDATED NOVEMBER 2016

1. GENERAL INFORMATION

1.1 Epidemiological data

1.1.1 Incidence and mortality

Oesophageal cancer is the sixth most common cancer in the non-industrialized countries and it ranks as the 18th most frequent cancer in industrialized countries. Predictions to 2015 show 22,300 deaths in men and 7,400 deaths in women in the EU (Castro 2014).
In 2013, about 40,000 new cases of epithelial oesophageal cancer occurred in Europe (EU28), accounting for 1.5% of all cancers (RARECAREnet).
The four clinically relevant oesopageal cancer entities are rare cancers (RARECAREnet). The squamous cell carcinoma and the adenocarcinoma of oesophagus have similar incidence with an annual rate of slightly more then 3 per 100,000, with about 19,000 new diagnoses per year. The other more uncommon epithelial oesophageal cancers are salivary gland tumours and undifferentiated carcinoma with very low incidence rates (below 0.05 per 100,000) with less than 300 new diagnoses per year in the EU28.
There are differences in incidence between gender: the disease is four time more common in men than women, the age-adjusted rate (per 100,000/year) was 8.7 and 2.4 in male and female, respectively (RARECAREnet).
The disease is extremely rare under the age of 24 years; then incidence rates increase to 5 and 26 per 100,000/year in both sexes for the age groups of 25-64 and 65+ years, respectively (RARECAREnet).
Geographical differences are marked: in men the age-adjusted annual incidence rate was highest in the UK and Ireland (8 per 100,000), intermediate in Central Europe (5 per 100,000), and low in South and East of Europe (3 per 100,000) (RARECAREnet). Interestingly, the major incidence differences across European regions were for adenocarcinoma, while differences were minor for squamous cells carcinoma.
In Europe, during the period 1995-2007 incidence significantly increased from 5 to 5.8: referreing only to adenocarcinoma, it increases from 2.3 to 3.2.
According to Globocan, in 2015 in EU28 slightly more than 30,000 deaths have been estimated for oesophagel cancer: 66% were in people ≥65 years old. Seventy-five percent of deaths due to oesophageal cancer were found in the male population.

1.1.2 Survival

Based on slightly more than 100,000 cases, survival from epithelial tumours of oesophagus diagnosed in Europe during 2000 and 2007 was 41% at one year, 17% at three years, and 13% at five years. Five-year survival was slightly, but significantly, better for adenocarcinoma then for squamous cell carcinoma (12% vs. 14%). Survival was also bad in salivary gland-type tumours of oesophagus; the worst prognosis was observed for undifferentiated carcinoma (RARECAREnet).
There has been a moderate improvement in European survival figures since the end of the 1990s, especially for 1-year survival, which increased from 36% to 42%. Three- and 5-year survival improved from 13% to 17% and from 10% to 13%, respectively. Survival improved for both adenocarcinoma and squamous cell carcinoma, but no for undifferentiated cancers (RARECAREnet).
Interestingly, 5-year survival was statistically better in women (14%) than men (10%) for squamous cell carcinoma, but the contrary happened for adenocarcinoma (11% vs. 14%).
Patients older than 65 years had 5-year survival of 10% compared to 29% of the youngest age group (25-64 years of age).
In Europe (EU28), about 85,500 persons are living with a diagnosis of epithelial tumour of oesophagus (RARECAREnet).
Tumour stage is the strongest known prognostic factor of survival (Trivers 2005). Data from the Netherlands Cancer Registry has shown that short-term and long-term survival after surgery for oesophageal cancer have improved significantly, where the 5-year relative survival in patients with localized adenocarcinoma raised form 17.4% during 1999-2003 to 25.3% during 2004-2008. The reason of this improvement was attributed to the increased use of preoperative therapy and to the centralisation of the treatment for oesophageal cancer in the Netherland over the past years (Dikken 2012).

1.2 Aetiologic and risk factors

1.2.1 Tobacco use

Tobacco consumption is a strong risk factor for oesophageal cancer (both squamous cell carcinoma and adenocarcinoma). In cohort studies the risk of oesophageal cancer has been about five times higher among cigarette smokers than nonsmokers (Schottenfeld 2006). A cohort study has shown that ever-smoking have a population attributable risk of 77% (95%CI 0.55-0.89) for oesophageal squamous cell carcinoma, and 58% (95%CI 0.38-0.72) for oesophageal adenocarcinoma (Freedman 2007). It has been observed a dose-response relationship for tobacco consumption; moreover, current smokers have a higher risk of oesophageal squamous cell carcinoma than former smokers (Schottenfeld 2006; Freedman 2007; Ishiguro 2009; Fan 2008).

1.2.2 Diet

The World Cancer Research Fund and the American Institute for Cancer Research update (WCRF 2016), which renew a large review of the literature on diet, physical activity, and prevention of cancer, riaffirms that most cases of oesophageal cancer are preventable by appropriate diet and associated factors, together with not smoking. A panel of experts considered slightly more than 300 pubblications. They concluded that there is strong evidence of:

  • being overweight or obese increases the risk of adenocarcinoma of the oesophagus;
  • consuming alcohol increases the risk of oesophageal squamous cell carcinoma;
  • regularly consumption of maté, as drunk very hot in the traditional style in South America, increases the risk of oesophageal squamous cell carcinoma.

It is biologically plausible that body fatness is a cause of oesophageal cancer. High body fatness is associated with increased gastro-oesophageal reflux and Barrett’s oesophagus. It also directly affects levels of many circulating hormones, such as insulin, insulin-like growth factors, and oestrogens, creating an environment that encourages carcinogenesis and discourages apoptosis. Body fatness stimulates the body inflammatory response, which may contribute to the initiation and progression of several cancers (WCRF 2007).

1.2.3 Occupational factors

IARC classified dry cleaning and rubber industry production as carcinogenic for oesophagus (without distinguishing histology subtype) with “limited evidence” (IARC 2013), i.e., IARC recognise a positive association for which a causal interpretation is considered to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence (IARC 2006). For squamous cell carcinoma, associations with several agents have been suggested, including carbon black, sulfuricacid, asbestos, and polycyclic aromatic hydrocarbons (PAHs) (Gustavsson 1998; Parent 2000). On the other hand, adenocarcinoma has been linked to sulfur compounds and lead (Santibanez 2008).

1.2.4 Genetic susceptibility

Genetic predisposition to the malignancy is uncommon. 95% of patients with congenital palmar and plantar keratosis (tylosis) (Ellis 2015) develop an oesophageal cancer before the age of 65. Although familial aggregation of both types of oesophageal cancer is not usual, a Swedish study based on the Family-Cancer Database found that familial risks of oesophageal adenocarcinoma were increased when parents presented with oesophageal cancer (Ji 2006).

1.2.5 Other diseases

Barrett’s oesophagus can be seen as a precancerous condition. It is found in 8%-20% of patients undergoing endoscopy for gastrointestinal reflux disease. Cancer risk seems limited to patients with intestinal metaplasia (specialised columnar metaplastic epithelium), where there is a 5% chance of progression to cancer within 5 years and a 10%-12% prevalence of adenocarcinoma. Clinical reports suggest that patients with Barrett’s oesophagus or oesophageal adenocarcinoma often have a prior history of hiatal hernia or duodenal ulcer with gastroesophageal reflux (Lagergren 2011).

1.2.6 Infectious agents

Human papillomavirus (HPV) infection, notably HPV type 16 and 18, may play an important role in the pathogenesis of squamous cell carcinoma in high-incidence areas, including China and South Africa. HPV infection occurs infrequently in association with squamous cell carcinoma in patients from low risks areas (Italy, North America, North Europe). Like other infectious agents, it may be a necessary cause but is not a sufficient cause. It may also play a role in the divergent geographical distributions of this cancer (Syrjanen 2002, Bucchi 2016).

2. PATHOLOGY AND BIOLOGY

2.1 Biological data

2.1.1 Chromosomal abnormalities

Oesophageal carcinoma ranks among the 5 malignant diseases with the highest frequence of somatic gene mutations (Lawrence 2013). This is probably a result of an accumulation of mutations in multiple suppressor genes and proto-oncogenes. Oesophageal carcinoma has shown multiple chromosomal breaks and deletions, including at 13q, 5q, 18q, 3p, 9p, 17q, 16p. Significant aneuploidy is often detected. An increase in the prevalence of chromosomal losses (17p, 18q, 5q) in the Barrett mucosa-columnar dysplasia-adenocarcinoma sequence has been reported and losses of 18q and 17p occur earlier than 5q loss (Wu 1998).

2.1.2 p53 and oncosuppressor genes

The most extensive study with polymerase chain reaction (PCR), revealed extensive loss of heterozygosity for p53 (55% of cases) and loss of tumour suppressor genes (Rb 48%, APC 66% and DCC 24%). Some of them correlate with prognosis. p53 mutations have been shown to be an early event in the progression of oesophageal carcinomas ; p53 mutations or over-expression were detected in a wide spectrum of lesions from metaplasia or low grade dysplasia, Barrett’s oesophagus, in situ carcinoma, to invasive carcinoma (both adenocarcinoma and squamous). p53 aberrations, either mutations or over-expression or both, were observed in over 50% of oesophageal carcinomas. HPV DNA are not mutually exclusive events (Coggi 1997; Chang 1997; Lam 1997a). The vast majority of oesophageal adenocarcinomas and high-grade dysplasias present high level of telomerase RNA (Morales 1998).
However, a recent meta-analysis of somatic and germline DNA sequence biomarkers revealed that only a small number of variants appear reliable and should be evaluated in large prospective studies (Findlay 2015).

2.2 Histological types

2.2.1 Squamous cell carcinoma

The ICD-O (International Classification of Diseases for Oncology) codes are provided in brackets. Squamous cell carcinoma [M-8070/3] is the most common histotype (80%) among oesophageal malignancies. Macroscopically it can be classified into vegetating, infiltrating and ulcerated tumour. Most of them appear histologically as well differentiated neoplasms. Poorly differentiated cancers may be composed of polyhedral cells, sometimes simulating a glandular-like epithelium. In other cases, either “small cells” or giant cells may be present in poorly differentiated squamous cancers. In advanced cancers, histology frequently demonstrates areas of necrosis. Tumour grading does not seem to be a significant prognostic parameter. Verrucous carcinoma [M-8051/3] is a rare variant of well-differentiated squamous cancers. Spindle cell carcinoma [M-8074/3] is a variant of poorly differentiated squamous cancers; it may be mistaken for a sarcoma or carcinosarcoma. Basaloid squamous cell carcinoma [M-8123/3] is a recently recognized variant of poorly differentiated squamous cancers; after surgery the prognosis is similar to that of patients with typical squamous cell carcinoma.

2.2.2 Adenocarcinoma

The ICD-O codes are provided in brackets. Adenocarcinoma [M-8140/3] is now the most common histotype reaching up to 60% of oesophageal cancers in industrialized countries. It is formed by a glandular epithelium, with papillary and/or tubular structure. Most oesophageal adenocarcinomas originate from areas of Barrett’s epithelium, or glandular metaplasia of the oesophageal mucosa. Adenocarcinoma has a site predilection for the distal third of the oesophagus. Macroscopic characteristics of these tumours are similar to those of squamous cancers. Other sites of origin of adenocarcinomas are islands of heterotopic gastric mucosa or cardiac glands and oesophageal glands in the submucosa.

2.2.3 Precancerous lesions

Dysplasia is an epithelial precancerous lesion. Histologically it is characterized by nuclear enlargement and hyperchromaticity with increased mitotic activity. Dysplasia in the oesophagus can be either squamous or glandular. Squamous cell dysplasia is found preceding or combining with squamous carcinoma. Glandular dysplasia is associated with adenocarcinoma complicating Barrett’s oesophagus; dysplasia develops more frequently in the intestinal than in the gastric type of mucosa. Increasing grades of dysplasia, from mild to severe, appear to be associated with increasing risk of cancer. In China, when dysplasia was histologically evaluated, the cumulative incidence of squamous cell carcinoma is reported to be 30% for moderate dysplasia, 65% for severe dysplasia or carcinoma in situ in a 3.5 year observation period (Lightdale 1998). High-grade dysplasia is described as carcinoma in situ. Natural history of high-grade glandular dysplasia is not well defined, since high grade dysplasia can either remain stable without progressing, or it can even disappear (Levine 1996; Schnell 1996). High-grade dysplasia in Barrett’s oesophagus may be associated with invasive cancer in one third of patients (Spechler 1994).

2.3 Specific histotypes

The ICD-O (International Classification of Diseases for Oncology) codes are provided in brackets.

  • Other epithelial cancers are:
    • Adenosquamous Carcinoma [M-8560/3];
    • Basaloid squamous cell carcinoma [M-8083/3];
    • Verrucous carcinoma [M-8051/3];
    • Mucoepidermoid carcinoma [M-8430/3];
    • Adenoid cystic carcinoma [M-8200/3];
    • Small cell carcinoma [M-8041/3];
    • Undifferentiated carcinoma [M-8020/3];
    • Large cell neuroendocrine carcinoma [M-8013/3];
    • Mixed neuroendocrine adenocarcinoma [M-8244/3].
  • Non-epithelial cancers are:
    • Leiomyosarcoma [M-8890/3];
    • Kaposi sarcoma [M-9140/3].
  • Miscellaneous tumours are:
    • Carcinosarcoma [M-8980/3];
    • Malignant melanoma [M-8720/3];
    • Carcinoid [M-8240/3];
    • Malignant lymphoma [M-9590/3].

3. DIAGNOSIS

3.1 Diagnostic cues

3.1.1 Symptoms

Early stage cancer has no typical symptom. Symptoms of advanced cancers of the oesophagus are nonspecific and mostly correlate with the presence of a mass causing a difficult transit of the bolus through the oesophageal tube. Dysphagia is the most common symptom; usually progressive dysphagia is reported for solid foods at first, and then, lately, liquids. The presence of an ulcerating tumour can be responsible for odynophagia (painful swallowing). Regurgitation and sialorrhea are frequent when the mass causes oesophageal obstruction. Weight loss is due both to the interference with diet habits of the patient and subsequent malnutrition and to the presence of a malignant tumour. Bronchopneumopathy can be associated either with regurgitation and aspiration or can be indicative of a tracheo-oesophageal fistula. The appearance of dysphonia can be predictive of direct tumour infiltration of the recurrent laryngeal nerve or of its involvement by metastatic nodes.

3.1.2 Signs

A supraclavicular or cervical adenopathy can be discovered by palpation in advanced cancers. Metastatic involvement of the celiac nodes or of the liver can be suspected if a mass is palpated in the abdomen. Patients affected by tylosis, an autosomal dominant disorder, have a high risk of developing a cancer of the oesophagus. In patients with this rare condition, a hyperkeratosis of the palms and soles can be the only physical evident sign.

3.2 Diagnostic strategy

3.2.1 Clinical assessment

In patients with dysphagia, upper gastrointestinal bleeding or recurrent vomiting flexible endoscopy is the first step in the diagnosis of oesophageal diseases. In case of aspiration indicative of a tracheo-oesophageal fistula, a double contrast oesophagogram with watersoluble contrast medium is recommended additionally. High solution endoscopy is reflecting the standard of care. During endoscopy vital staining using Lugol’s iodine solution may be performed in patients at high risk for squamous cell cancer (history of squamous cell cancer of the upper aero-digestive tract, long-term smoking and severe alcohol abuse) (Hori 2011). Lugol’s solution stains normal epithelium dark brown, but not neoplastic areas. This procedure has a sensitivity of 90%-100% and a specificity of 60%-72% for squamous neoplasia; it is safe, cheap, simple and rapid to perform. It is helpful in detection of foci of squamous dysplasia or squamous oesophageal cancer unassociated with morphological or colour change of the mucosa and in delineation of both invasive and noninvasive neoplastic lesions. After vital staining it is possible to take multiple-aimed bioptic specimens and brush cytology samples in order to exclude multiple localisations or precisely define the borders of cancer. Iodine solution does not stain glandular mucosa. There is no evidence that iodine staining can detect foci of glandular dysplasia or adenocarcinoma within Barrett’s mucosa. When early squamous cancer is suspected, endoscopy with careful search of areas of discoloration, mucosal iodine staining and multiple cytologic and bioptic samples of modified mucosa is recommended on a type C basis (Lambert 1995). The addition of iodine staining to endoscopy improves the detection of high-grade intraepithelial lesions (sensitivity shifts from 62% to over 95%) and it improves the visualization of lesion extent (Dawsey 1998). When early adenocarcinoma is suspected in Barrett’s mucosa, large biopsy sampling (biopsies every 2 cm in every quadrant along the entire length of columnar epithelium and extensive biopsies of all suspicious lesions) is recommended on a type C basis (Qumseya 2013) to optimize the probability of finding dysplastic or malignant epithelium, which may occur in the absence of endoscopic abnormalities.

3.2.2 Pathologic assessment

Cytologic and histologic samples obtained during endoscopy usually allow the diagnosis of an oesophageal malignancy in virtually all patients. A biological staging (DNA analysis and oncogenes evaluation) of oesophageal malignancy has also been performed on bioptic samples in the attempt to evaluate the tumour aggressiveness and to predict response to neoadjuvant cytoreductive treatments. Although some authors have reported encouraging results, apart from Her-2 overexpression or amplification in adenocarcinoma of the oesophagogastric junction biological markers of oesophageal cancer are under investigation.

4. STAGING

4.1 Stage Classification

4.1.1 Formal stage classification

TNM classification, based on independent measures of primary tumour size, regional lymph node involvement, and distant metastases, forms the basis for stratifying oesophageal cancer patients into prognostic stage groups. International consensus for oesophageal cancer staging was reached in 1988 with worldwide approval from all national TNM committees of the fourth edition of the Union Internationale Contre le Cancer (UICC) classification and the third edition of the American Joint Committee on Cancer (AJCC) Manual for Staging of Cancer 1997, with the last revision of the staging systems in 2009 (7th edition) (Edge 2009), some modifications regarding lymph nodes metastasis were added and adenocarcinomas of the oesophagogastric junction (type I and II according to Siewert classification) are now classified as oesophageal cancer. The new system is based on anatomic location of primary tumour, depth of wall penetration, lymph node involvement and distant metastasis these four variables being most predictive of survival.

4.1.2 Site TNM classification

TNM classification is used only for carcinomas. The site of the tumour is classified according to the following:

  • Cervical oesophagus extends from the lower border of the cricoid cartilage to the thoracic inlet (lower level approximately 18 cm from the upper incisor teeth).
  • Intrathoracic oesophagus is divided into:
    • upper thoracic oesophagus: from the thoracic inlet to the tracheal bifurcation (lower level approximately 24 cm from the upper incisor teeth);
    • middle thoracic oesophagus: from the tracheal bifurcation and the distal oesophagus just above the oesophagogastric junction (lower level approximately 32 cm from the upper incisor teeth);
    • lower thoracic oesophagus: approximately 8 cm in length, it includes the intra-abdominal portion of the oesophagus and the oesophagogastric junction (lower level approximately 40 cm from the upper incisor teeth).
  • The oesophagogastric junction is including adenocarcinomas within 5 cm of the anatomic cardia with tumourgrowh extending the Z-line.
  • Regional nodes aredefined independently from the localization of the primay tumour. They comprise all lymph nodes within the drainige area of the oesophagus including the coeliac nodes and the paraoesophageal nodes of the neck, but not the supraclavicular nodes (Edge 2009).
4.1.3 TNM classification (UICC 2002)
Table 1. TNM classification.
Primary tumour (T)
T0 No evidence of primary tumour
Tis Carcinoma in situ / high-grade intraepithelial neoplasia
T1 Tumour invades lamina propria, muscularis mucosae or submucosa
T1a Tumour invades lamina propria or muscularis mucosae
T1b Tumour invades submucosa
T2 Tumour invades muscularis propria
T3 Tumour invades adventitia
T4 Tumour invades adjacent structures
T4a Tumour invades pleura, pericard, diaphragm
T4b Tumour invades other structures, like aorta, vertebral body or trachea
Regional nodes (N)
Nx Regional nodes cannot be assessed
N0 No regional node metastases
N1 1-2 regional node metastases
N2 3-6 regional node metastases
N3 7 or more regional node metastases
Distant metastasis (M)
M0 No distant metastases
M1 Distant metastases are present
4.1.4 Staging grouping
Table 2. Staging classification.
Stage Characteristics
0 Tis; N0; M0
IA T1; N0; M0
IB T2; N0; M0
IIA T3; N0; M0
IIB T1; N1; M0
T2; N1; M0
IIIA T4a; N0; M0
T3; N1; M0
T1; N2; M0
T2; N2; M0
IIIB T3; N2; M0
IIIC T4a; N1; M0
T4a; N2; M0
T4b; any N; M0
Any T; N3; M0
IV Any T; Any N; M1

4.2 Staging procedures of cancer of the cervical oesophagus

4.2.1 Site staging procedures (cervical oesophagus)

Recommended staging procedures for the evaluation of site and anatomical markers are: ear-nose-throat visit, endoscopy of oesophagus, stomach and duodenum, tracheobronchoscopy and, in special situations, upper gastrointestinal barium swallow. Primary cancers of the cervical oesophagus should be distinguished from other primaries involving this organ, such as primary cancer of the hypopharynx or locally advanced tumours of the larynx, even if in advanced malignancy the site of origin may be impossible to determine. Multiple synchronous primaries are reported in 6-28% of cases: most of them involve the upper aerodigestive tract. Ear-nose-throat visit and endoscopy, in addition to tracheobronchoscopy are also aimed at detecting the presence of synchronous cancers. Tumours of the cervical oesophagus can infiltrate surrounding structures: the thyroid cartilage, recurrent laryngeal nerves, thyroid gland, trachea, prevertebral fascia, and major vessels of the neck. CT scan of the neck is recommended routinely, being the most important examination to detect posterior and posterolateral cervical infiltration of the tumour, but it has only a 60% accuracy in predicting invasion of the adjacent structures.
During endoscopy vital staining with Lugol solution (see paragraph 3.2) may be done in order to precisely define the borders of cancer and to recognise multiple localisations. Ear-nose-throat visit also permits the evaluation of the vocal cord mobility: a vocal cord palsy can be the sign of a recurrent laryngeal nerve infiltration by oesophageal cancer. The exact site of the tumour with respect to the upper oesophageal sphincter must be precisely defined, in order to evaluate, in case of surgical resection, the need for a total laryngectomy associated to oesophagectomy. Rigid oesophagoscopy is the best method of accurately measuring the distance between the proximal margin of the tumour and the pharyngoesophageal sphincter, and represents the recommended diagnostic tool on a type R basis whenever difficulties arise in correctly defining the site of a tumour of the cervical oesophagus.

4.2.2 Tumour staging (cervical oesophagus)

CT scan of chest and abdomen is recommended to rule out distant metastases and to judge for local tumour extension (see paragaph 4.2.1). CT scan is unable to differentiate between different oesophageal layers, thus it cannot differentiate category T1 from T2 neoplasms. For this reason, endoscopic ultrasonography (EUS) is recommended routinely in low-sited accessible cancers of the cervical oesophagus. It proved to be the best examination to stage the T parameter, with a diagnostic accuracy of 80-90% for passable stenoses in superficial cancer (Thosani 2012). The major limit of endoscopic ultrasound is stenotic tumours, where thorough examination is impossible. However, non-passable stenoses prove, in most cases (88%), to be T3 or T4 tumours. Invasion on the tracheobronchial tree by an oesophageal cancer is suspected when CT shows displacement or indentation of the posterior wall of either the trachea or bronchus. The accuracy of CT in the diagnosis of infiltration of the tracheobronchial tree is about 75%. Tracheobronchoscopy is the most accurate examination to demonstrate a direct infiltration of the trachea by the tumour. In a study, the overall accuracy of bronchoscopy with multiple brush cytology and biopsies in proving or excluding airway invasion in 75 patients with operable oesophageal cancer (most located above the tracheal bifurcation) was over 95%; macroscopic findings alone are not reliable (positive predictive value of all abnormalities was 3.6%); 10% of patients with otherwise potentially operable tumours were considered unresectable because of airway invasion recognized only by bronchoscopy. The results of bronchoscopy and CT were discordant in 40% of the patients; specificity and positive predictive value are higher for bronchoscopy than for CT (Riedel 1998). Tracheobronchoscopy with multiple brush cytology and biopsies is therefore recommended routinely.

4.2.3 Nodal staging of cervical oesophageal cancer

Metastases to the regional lymph nodes are reported in 50%-70% of cases. Tumours of the pyriform sinus frequently give early metastases in the ipsilateral deep jugular lymph nodes. Retrocricoid tumours give metastases to deep jugular, recurrential and paratracheal lymph nodes. Tumours of the posterior wall of the hypopharynx give metastases bilaterally to deep jugular, recurrential, and paratracheal lymph nodes. Tumours of the cervical oesophagus give metastases bilaterally to deep jugular, recurrential, paratracheal, perioesophageal and supraclavicular lymph nodes. Of note, only perioesophageal lymph nodes belong to the regional nodes. Upper mediastinal lymph nodes may also be involved in the presence of cancers of the cervical oesophagus. Palpation and neck ultrasound with fine needle aspiration biopsy of enlarged nodes is the recommended option to stage cervical nodes. In the ultrasound evaluation of nodes, the most useful parameters are size of nodes, heterogeneity of internal echoes, morphology of the margins, and the deformation caused by compressive instrumental manipulation. These criteria, indicated by the Japanese Society for Oesophageal Diseases, yield a high sensitivity and diagnostic specificity (up to 90%) in staging unpalpable, but enlarged, cervical nodes. Approximately 10% of patients with oesophageal cancer has metastases to cervical nodes. A high incidence of lymph node metastases has been reported in patients with oesophageal cancer localized to the thoracic supracarinal tract and in patients with cervical and lower oesophageal cancer (Bonvalot 1996; Doldi 1998). CT scan for the detection of mediastinal nodes has a sensitivity of 20%-40%, specificity of 70%-100%% and accuracy of 50%-70%. More than 1 cm size nodes are considered neoplastic nodes, but CT is unable to differentiate metastatic from benign reactive hyperplastic nodes and moreover it is unable to recognise tumour in normal size nodes. Unlike CT, endoscopic ultrasonography (EUS) can assess the shape, margins and internal structure, as well as the size, of mediastinal and celiac nodes: size greater than 1 cm, hypoechoic, distinct margins, and round shape predict malignant invasion. EUS accuracy for nodal status is about 70%-80%; however, EUS tends to overestimate histological involvement (sensitivity 90%, specificity 60%). Both CT scan and EUS are recommended routinely for staging mediastinal lymph nodes. MRI has the same limitations as CT. Prospective studies evaluating the role of PET for staging cancer of the cervical oesophagus are lacking, and thus its use is at present investigational only.

4.2.4 Distant metastases

Chest X-ray, liver ultrasound, chest and abdomen CT are recommended in order to detect visceral metastases. Such investigations are recommended before accurate T and N staging with EUS on a type R basis. Total body scintiscan, brain CT or whole-body PET scan are performed only when there are specific indications.

4.3 Staging procedures of cancer of the thoracic oesophagus

4.3.1 Site staging procedures (thoracic oesophagus)

The site of the tumour with respect to anatomical markers is defined by means of barium swallow (full column and double contrast) and upper gastrointestinal endoscopy: the anatomical markers to be taken into consideration are the tracheal bifurcation, visible on X-ray, and endoscopic markers such as the upper and the lower oesophageal sphincters. During endoscopy vital staining is recommended. Barium swallow radiography is recommended (Siewert 1995), since it is helpful in defining site, longitudinal extension and topographic situation of the tumour with adjacent structures and gives a general vision of oesophagus, stomachs and duodenum. Ear-nose-throat visit can detect the presence of syncronous cancers as well as permits the evaluation of the vocal cord mobility: vocal cord palsy can be the sign of a recurrent laryngeal nerve infiltration by oesophageal cancer.

4.3.2 Tumor staging (thoracic oesophagus)

The definition of local tumour spread is the subsequent diagnostic step for staging thoracic oesophageal cancers: the level of parietal involvement and the presence/absence of infiltration to surrounding structures (tracheobronchial tree, vertebrae, major blood vessels). CT scan is unable to differentiate between different oesophageal layers, thus it cannot differentiate category T1 from T2 neoplasms; its accuracy of T category is only 50-60%. Endoscopic ultrasonography (EUS) is the most accurate technique for the definition of the T category with an accuracy of 80-90% for passable stenoses, and is the recommended examination. EUS is useful in differentiating T1-T2 from T3-T4 tumours with a more than 90% accuracy (Puli 2008). An error in extent estimation may be as high as 15%, mainly in T1-T2 groups (T2 may be overstaged or understaged) (Dittler 1993; Lambert 1995; Lightdale 1994). In the presence of T1 stage tumour, EUS accuracy for the distinction between mucosal and submucosal tumour is unsatisfactory (lower than 80%) (Fékété 1995). A frequency of 20 MHz is required to identify the muscolaris mucosae (Lambert 1995). The accuracy of EUS in the diagnosis of infiltration to adjacent anatomical structures is somewhat lower (80%). The inability to pass an oesophageal stenosis ranges from 16 to 36% of cases. Oesophageal dilation prior to EUS is not recommended for the risk of visceral perforation, lower accuracy (30%-70%) of EUS after dilation and because the majority of patients (above 90%) present with advanced disease (T3-T4 and N1) (Catalano 1995; Dittler 1993).
In a report, in 11 patients with complete luminal obstruction both T and N extension have been correctly predicted by limited endoscopic ultrasonography within the mediastinum (Vickers 1998). The use of high-frequency (20 MHz) ultrasound probes or newly designed miniprobes in high-grade malignant strictures is investigational. CT scan is useful to define the spread to surrounding structures and is the recommended diagnostic technique in these patients: CT accuracy in assessing tumour infiltration in the aorta is about 80%. CT detection of aortic invasion can be based on the degree of direct contact between the tumour and the aorta. If the contact is less than 45° (less than one-eighth the circumference of the aorta), the aorta is considered without evidence of invasion. When the oesophageal contact exceeds 90° (more than one fourth the circumference) invasion is likely. Contact between 45-90° is considered indeterminate. A new more accurate criterion to predict aortic invasion is based on the loss of the triangular fat space between the oesophagus, aorta and spine (Takashima 1991). Invasion of the pericardium is suspected when a fat plane separating the oesophageal mass from the pericardium is not visible on all CT sections. The accuracy of CT in the detection of pericardial invasion is about 85%. Invasion on the tracheobronchial tree by an oesophageal cancer is suspected when CT shows displacement or indentation of the posterior wall of either the trachea or bronchus. The accuracy of CT in the diagnosis of infiltration of the tracheobronchial tree is about 75%. Tracheobronchoscopy is the most accurate examination to demonstrate a direct infiltration of the trachea by the tumour. The results of bronchoscopy and CT were discordant in 40% of the patients; specificity and positive predictive value are higher for bronchoscopy than for CT (Riedel 1998). Tracheobronchoscopy can also detect the presence of synchronous cancers. In tumours of the supra- and juxtacarinal oesophagus, tracheobronchoscopy with multiple brush cytology and biopsies is therefore recommended routinely. Positron emission tomographic imaging (PET) identifies the primary oesophageal cancer in 96% of patients, but PET or PET-CT is not able, such as CT scan, to assess the extent of wall invasion (Kole 1998).

4.3.3 Nodal staging

Staging of the N category is more difficult. Palpation and neck ultrasound with fine needle aspiration biopsy is recommended option for staging of cervical nodes. In the ultrasound evaluation of nodes, the most useful parameters are size of nodes, heterogeneity of internal echoes, morphology of the margins, and the deformation caused by compressive instrumental manipulation. These criteria, indicated by the Japanese Society for Oesophageal Diseases, yield a high sensitivity and diagnostic specificity (up to 90%) in staging unpalpable, but enlarged, cervical nodes. A high incidence of lymph node metastases has been reported in patients with oesophageal cancer localized to the thoracic supracarinal tract and in patients with cervical and lower oesophageal cancer (Bonvalot 1996; Doldi 1998). The identification of metastases to mediastinal nodes is less accurate. The accuracy of CT in diagnosing the mediastinal lymph node status ranges around 60%-70% (sensibility 50%-60%, specificity 80%-90%) (Puli 2008; Tranchemontagne 2009). The current radiologic criterion for an abnormal node on CT is a transverse axis of 10 mm or greater. Unlike CT, EUS can assess the shape, margins and internal structure, as well as the size, of mediastinal and celiac nodes: size greater than 1 cm, hypoechoic, distinct margins, and round shape predict malignant invasion. EUS accuracy for mediastinal nodal status is about 60%-80%, depending on expertise of single center; however EUS tends to overestimate histological involvement (sensitivity 45%-70%, specificity 65%-90%). If T3 or T4 disease is found, the patient has node positive disease in at least 80% of cases and the identification of lymph node involvement is correlated with systemic spread and prognosis (Peyre 2008). Oesophageal dilation prior to EUS is not recommended for the risk of visceral perforation, lower accuracy (30%-70%) of EUS after dilation and because the majority of patients (90%) present with advanced disease (T3-T4 and N1) (Catalano 1995; Dittler 1993). In a report, in 11 patients with complete luminal obstruction both T and N extension have been correctly predicted by limited endoscopic ultrasonography within the mediastinum (Vickers 1998). The use of high-frequency (20 MHz) ultrasound probes or newly designed miniprobes in high-grade malignant strictures is investigational. Both CT scan and EUS are recommended routinely for staging mediastinal lymph nodes. Finally, ultrasound-guided fine-needle aspiration of mediastinal lymph nodes may improve accuracy of nodal staging, showing accuracy of 70% to 80% in meta-analysis (van Vliet 2008). At present the routine use of magnetic resonance imaging (MRI) for pre-treatment staging of oesophageal cancer cannot be recommended, as it is virtually identical to accurate CT scan. As reported by small recent studies, accuracy of positron emission tomography (PET) in detecting nodal metastases from lower oesophageal adenocarcinoma ranges from 48% to 90%, while PET scan seems more sensitive than CT scan for revealing regional metastases (45%-92% vs. 30%-40%) (Flanagan 1997; Luketich 1997a; Block 1997; Kole 1998). The impact of minimally invasive techniques, such as thoracoscopy and laparoscopy in the pretreatment staging of oesophageal cancers is under investigation (Krasna 1998). Accuracy of thoracoscopy procedure in detecting regional nodal extension is 93%. Thoracoscopy is also useful in biopsies of direct mediastinal invasion. Accuracy of laparoscopy in detecting metastatic celiac nodes is 94%. The detection of M1- lymph node metastases is facilitated by the use of laparoscopic ultrasound. Laparoscopy and thoracoscopy improve the accuracy of staging lymph node metastases.

4.3.4 Distant metastases

Routine chest X-ray, liver ultrasound and chest and abdomen CT are recommended in order to detect visceral metastases. CT is very accurate for the detection of distant metastasis in the chest or abdomen. Such investigations are recommended before accurate T and N staging with EUS on a type R basis. The association of CT and EUS yields a global accuracy of 85% (Botet 1991). Although it is not reimbursed in most of the European countries, staging with PET-CT has demonstrated to reveal unexpected distant metastases in 5% to 28% of the patients and moreover, may discover synchrone second malignancies in up to 4% (Marzola 2011). Brain CT or MRI is performed only when there are specific indications. The impact of minimally invasive techniques, such as thoracoscopy and laparoscopy or both in the pretreatment staging of oesophageal cancers is under investigation.

4.4 Staging procedures of cancer of the oesophago-gastric junction

4.4.1 Site staging procedures (oesophago-gastric junction)

It is important to distinguish adenocarcinomas of the lower oesophagus, those with their tumour center within 5 cm above the anatomic cardia infiltrating the stomach (Siewert type I) and those with their tumour centre within 5 cm below the anatomic cardia infiltrating the oesophagus (Siewert type II) (Figure 1) (Siewert 1998). This can best be performed with endoscopy, adding EUS in case of uncertain results and witha coronar CT scan.

Figure 1. Siewert type I and II carcinomas.
figura3_Oesophagus
4.4.2 Tumour staging (oesophago-gastric junction)

The limitations to accurately define the T category with CT and EUS is outlined in 4.3.2. This is particularly true for defining T3 in type II carcinomas due to anatomical reasons (missing adventitia in the gastric cardia).

4.4.3 Nodal staging

The difficulties in nodal staging are described in 4.3.3. CT and EUS are recommeded to recognize lymph node involvement. The accuracy of EUS in diagnosing lymph nodes at the coeliac trunc is even higher than in the mediastinum (80%-90%) (van Vliet 2008; Tranchemontagne 2009).

4.4.4 Distant metastases

Most of the statements given in the chapter of thoracic oesophagus are also true for carcinomas of the oesophago-gastric junction. Laparoscopy identified radiographically occult distant metastases (peritoneal carcinosis or liver metastases) in up to 20% of series with locally advanced carcinoma of the oesophagogastric junction, thus preventing unnecessary thoraco-abdominal exploration (O’Brien 1995; Nieveen 1997; Luketich 1997b; Bonavina 1997).

4.5 Resectability evaluation

4.5.1 Surgical evaluation

The aim of this evaluation is to predict a radical (R0) resection, which represents the most important prognostic factor. A uniform definition of what is “resectable” is lacking. The UICC R criteria which refer to the absence/presence of residual neoplastic tissue after surgery are:

  • RX: presence of residual tumour tissue cannot be assessed;
  • R0: no residual tumour tissue;
  • R1: microscopic residual tumour tissue;
  • R2: macroscopic residual tumour tissue.

Prediction of an R0 resection is determined by T category and by infiltration of surrounding structures. As reported by European studies, resectability rate varies from 20% for T4, to 50% for T3 and 80-90% for T1-T2 (Siewert 1994). T1 and T2 suprabifurcal carcinoma, T1 to T3 (and exceptionally T4) subcarinal carcinoma may be considered radically resectable (Dittler 1993). Preoperative staging is critical for the prediction of resectability, but non-invasive staging is not completely adequate in determining resectability. It may be impossible to predict resectability prior to intraoperative evaluation (Roth 1994). Prediction of resectability by EUS is 72-92%. Using surgical correlation as a proof, there is a significant difference in actual R0 resection rate depending on histology (80% for adenocarcinoma and 60% for squamous cell carcinoma). These differences are due to the submucosal diffusion of squamous cell carcinoma, which may reach the proximal or distal resection margin (R1 stage); this diffusion is not detected by EUS. R0 resection rate of non-transversable stenosis is only 25% (Dittler 1993). CT or MR accuracy for resectability (in terms of aortic, pericardium or tracheobronchial invasion) ranges from 65% to 85% (Takashima 1991; Botet 1991). Preliminary experience with the combination of endoscopic ultrasonography (EUS) and laparoscopic ultrasonography (LUS) for resectability assessment of upper gastrointestinal tract malignancies showed that this combination seems superior to that of CT+US, laparoscopy and EUS: EUS + LUS identified all non-resectable patients, whereas the sensitivity of CT + US, laparoscopy, and EUS were 14%, 36%, and 79%, respectively. Its use is still investigational (Mortensen 1996). In a small study, the reported diagnostic accuracy in determining resectability was 65% for CT, 88% for PET and 92% for CT and PET together (Kole 1998).

4.5.2 Medical assessment

In addition to the diagnostic investigations for tumour stage and tumour resectability, operability of the patient should be assessed ruling out the presence of concomitant diseases and general risk factors, which make anesthesia and surgery an excessive risk. Patients with oesophageal cancer are often heavy smokers and suffer from chronic obstructive or restrictive pulmonary diseases, and are often heavy alcoholic drinkers with possible liver cirrhosis. Routine evaluation of patients’ cardiovascular, respiratory, hepatic and renal functions and state of nutrition is recommended on a type R basis. Cardiac function is routinely evaluated clinically, with an electrocardiogram, echocardiography, a chest radiograph and in selected patients with stress electrocardiogram, through a radionuclide scan or with cardiac catheter examination. Respiratory function is assessed clinically, through arterial blood gas analysis and through the assessment of respiratory volumes. Hepatic function is determined mostly by the evaluation of Child classification and prothrombin time. In selected patients with a suspected alcoholic liver disease, laparoscopy is recommended on a type R basis to evaluate the presence of portal hypertension, which represents a contraindication for oesophageal surgery. It has been recently reported that the risk of postoperative death in patients with resectable oesophageal cancer is determined in decreasing order by preoperative general status (objectively and subjectively assessed as Karnofsky index and mental “cooperation”), cardiac function (based on cardiologist’s impression), hepatic function (evaluated by the aminopyrine breath test or the presence of cirrhosis) and respiratory function (assessed by vital capacity and arterial partial pressure of oxygen). Advanced age alone is not associated with an increased postoperative mortality. Calculation of a composite risk score based on the relative impact of each individual parameter allowed to establish a “low”, “moderate” and “high” risk group. Inclusion of the risk score in the process of patient selection and choice of the surgical procedure resulted in a decrease of the postoperative mortality rate in the same institution from 9.4% (in the period 1982-1993) to 1.6% (in the period 1994-1996) (Bartels 1998). Calculation of individual risk score and inclusion of such score in preoperative decision-making process may be helpful.

4.6 Restaging procedures

4.6.1 Tumour response evaluation after combined treatment

The value of restaging is different according to the treatment plan. If definitive chemo-radiation has been performed, its role is to rule out whether the patient has achieved a complete remission. This information is useful for the definition of prognosis since only patients in complete remission have some chance of cure. If treatment plan includes surgery after neoadjuvant therapy restaging procedures are aimed at the exclusion of (still) unresectable tumours/metastatic disease or of patients who have achieved a complete remission (for which resection could be unnecessary). Unfortunately an accurate and objective assessment of tumour response after induction therapy is difficult. Accuracy in determining tumour extension suffers from the same limitations as tumour staging and from those related to loco-regional treatment. Assessment of tumour response is recommended on a type R basis with radiological and endoscopic examination. General restrictions of these methods are the difficulty in distinguishing viable tumour from necrotic or fibrotic tissue. The accuracy of CT scan after neoadjuvant treatment raises 54%. The accuracy of Endoscopic Ultrasound (EUS) in the evaluation of response to treatment ranges from 27%-82% and overstaging is common after chemoradiotherapy. Position emission tomography (PET) is unique in its ability of visualize areas of increased metabolic activity within tissues. [18F] fluorodeoxyglucose (FDG) is preferentially taken up by cells with a high rate of glucose utilization, and this includes most malignant cells. Various pilot studies have shown the value of FDG PET or PET-CT for measurement of treatment response and found FDG PET-CT to be more accurate than CT and EUS. In a prospective observation study early PET- CT (prior to and 2 weeks after chemotherapy) was able to indentify those adenocarcinomas which will not show major histologic response to preoperative chemotherapy (Lordick 2007). Thereby, investigators intended to guide therapy with early stopping or changing preoperative chemotherapy. However, this approach is still under discussion. Some studies have questioned the reproducibility of the results of PET-CT, at least during or after radiochemotherapy (Fencl 2012). Moreover, it is has been shown that intensification of preoperative therapy by adding radiotherapy to chemotherapy may not change the poor prognosis of patients with non-responding tumours (zum Büschenfelde 2011).

4.6.2 Local tumour recurrence evaluation

Endoscopic ultrasound has a sensitivity of 95% and a specificity of 80% in detecting anastomotic recurrences (Lightdale 1994). The role of extended staging with endoscopy, EUS, and CT during follow-up depends on the therapy which had been applied. In case of endoscopic resection of early carcinomas close reevaluation of the oesophageal mucosa is recommended, because a second resection of recurrent cancer can be performed with curative intent. In patients with local recurrence after chemoratiotherapy plus surgery therapy will be palliative and therefore, close follow-up is not recommended.

5. PROGNOSIS

5.1 Prognostic and predictive factors

5.1.1 Prognostic factors

The presence of macroscopic disease (R2) and of microscopic residual tumour (R1) after surgery is the most important prognostic factor. The probability of 5-year survival is 40% for R0 patients and drops to 5-15% for R1 and 0% for R2 cases (Siewert 1994; Hermanek 1995). Tumour infiltration into organ wall is one of the most important prognostic factors and there is a good correlation between the T category and survival. Intramural metastases may have a prognostic significance (Takubo 1990). Although nodal involvement is related to tumour infiltration the N category remains a prominent prognostic factor by itself. Patients with involved regional lymph nodes (pN1-3) have a significant higher risk of distant recurrence than their counterparts with indentical T category but tumour free nodes (pN0) (Peyre 2008). Patients with metastases to non-regional lymph nodes have a worsen prognosis than patients with invaded regional lymph nodes only. In squamous cell carcinoma, both the number of positive lymph nodes (more than four positive lymph nodes in american or japanese reports or more than seven invaded lymph nodes in european reports) and the ratio of invaded to removed lymph nodes (favourable ratio <20%) correlate with survival in multivariate analysis (Siewert 1994; Roder 1994; Korst 1998; Kawahara 1998). Micrometastases to regional lymph nodes (defined as individual tumour cells or small clusters of cells detected in lymph nodes examined by immunohistochemical analysis with monoclonal antibodies) are prognostically equivalent to metastasis; patients with immunostained tumour cells in their lymph nodes have relapse-free and overall survival rates similar to those of patients with histopathologically proven involved nodes (Izbicki 1997; Natsugoe1998). For patients with pN0 tumours the prognosis depends on the T category. Similar 5-year survivals have been reported for patients with T1N0 and T2N0 disease, while the survival of patients with T3N0 disease more closely parallels that of patients with N1-3 disease (Killinger 1996; Korst 1998). In oesophageal adenocarcinoma prognosis is related to tumour wall infiltration and ratio of infiltrated to removed lymphnodes (<30% vs. at least 30%). The 5-year survival rate for patients with an unfavourable lymph node infiltration ratio is 0% (Hölscher 1995). The prognostic significance of the tumour type (adenocarcinoma versus squamous cell carcinoma) and of histologic differentiation remains controversial. In resected patients outcome seems related to stage, while histologic type is not an independent variable (Lieberman 1995). Possibly grading has some prognostic significance, but its independent significance is hampered by poor histologic reproducibility and tumour heterogeneity (Klimstra 1994). DNA content has been shown to be a prognostic factor in a few multivariate analyses, however a consensus is lacking regarding the prognostic significance of aneuploidy in tumours of the oesophagus. The significance of molecular markers such as over-expression of EGFR and TGF alpha, expression of bcl-2 protein, cyclin D, catenin or of chromosomal losses (17p or 18q) has yet to be validated. P53 aberrations are very common but they do not seem independently predict prognosis (Coggi 1997; Hardwick 1997). Weight loss of 10-15% and overall performance status are two additional valuable prognostic factors. A couple of studies showed that special parameters from 18F-FDG PET (standard uptake value or total lesion glycolysis of primary tumour) showed prognostic significance which persisted in multivariate analysis in some of the studies (Foley 2014).

5.1.2 Predictive factors

Numerous factors have been investigated for their role to predict prognosis after specific therapies. None of them is accepted as predictive factor and may be used for guiding therapy of oesophageal cancer, by now.

6. TREATMENT

6.1 Localised squamous cell carcinoma

6.1.1 Cervical oesophageal cancer
6.1.1.1 Overall treatment strategy

Aim of treatment is definitive cure. With regard to different international guidelines (NCCN clinical practice guidelines (Ajani 2015), German S3-guideline (Porschen 2015; Allum 2011) chemoradiotherapy is the preferred modality for cervical oesophageal cancer on a type C basis. Salvage surgery, if needed, may represent a therapeutical option on a type 3 level of evidence (Soto Parra 1997). Primary surgery with and without preoperative chemoradiotherapy represents a secondary treatment option on a type C basis in local and locoregional tumours for resectable disease and operable patients, but at the cost of loss of the oesophagus and the larynx. Postoperative radiation therapy is not recommended, postoperative chemo/radiotherapy depends on risk factors. For locally advanced unresectable patients or inoperable patients the standard treatment in medically fit patients is a combined approach of chemo-radiation on a type R basis (Herskovic 1992; al-Sarraf 1997; Cooper 1999). Treatment for advanced oesophageal cancer in patients in poor general conditions must be individualized based on stage, characteristics of the tumour, patient medical conditions and patient preferences.

6.1.1.2 Surgery of cervical oesophagus

The surgical therapy of cancers of cervical oesophagus is complex and associated with high morbidity and mortality. Therefore, it shall be performed only in specialised centers. Surgery is mostly based on the site of origin of the primary tumour, its local extension, and lymph node status. Submucosal spread along the oesophagus is possible up to 3 cm in cancers of the hypopharynx and up to 5 cm in cancers of the cervical oesophagus and should be looked for during endoscopy. Due to this tendency towards submucosal spread, a wide proximal resection is needed. The need of a wide margin determines whether laryngectomy, in addition to oesophagectomy, should be considered. Therefore, site and extension of cancer should dictate the size and type of pharyngo-laryngo-oesophageal resection, which in turn should dictate the type of reconstruction procedure. Pharyngo-laryngectomy and total oesophagectomy is the standard option on a type C basis for the great majority of tumours of the cervical oesophagus. Pharyngo-laryngo-oesophagectomy includes also a total thyroidectomy, parathyroidectomy, and bilateral functional neck dissection with preservation of the jugular veins, spinal nerves, and sternocleidomastoid muscles. Nodal resection includes submandibular deep and superficial jugular, paratracheal, perioesophageal, recurrential, and supraclavicular lymphnodes in continuity with the pharyngo-laryngo oesophageal block. Sometimes it is possible to preserve one or both upper poles of the thyroid gland in order to prevent hypothyroidism and possibly also hypoparathyroidism. To avoid calcium metabolism alterations, the parathyroid glands may be retrieved from the operative specimen and reimplanted, after histological confirmation, among the muscular fibers of the supinator muscle of the forearm. Pharyngo-laryngectomy and segmental cervical oesophagectomy are suitable for individual clinical use on a type R basis for cancers involving the hypopharynx and for selected small tumours involving the most proximal part of the cervical oesophagus when a sufficient length of uninvolved oesophagus (3 cm) guarantees that the distal margin of resection is free from cancer.
In clinical praxis this extended surgical approach is rarely used. Mostly these patients underwent a definitive radio-chemotherapy.
A larynx preserving resection is suitable for individual clinical use on a type R basis only in selected tumours involving the most distal part of the cervical oesophagus. However, it should be considered that lymphnode metastases are common in the recurrent laryngeal nerve chains and therefore early neoplastic recurrence is frequent at this level. Furthermore, the functional results after larynx preserving operations are far from optimal due to the possible occurrence of speech and swallowing alterations, which may be related to alterations of the pharyngo-oesophageal coordination or to injury of the recurrent laryngeal nerve: despite larynx preservation, a temporary or definitive tracheostomy, and even a delayed laryngectomy may nevertheless become necessary. Transthoracic total oesophagectomy is the standard option on a type C basis when the tumour extends below the level of the thoracic inlet, and in the presence of a synchronous tumour of the thoracic oesophagus. Visceral reconstruction technique (i.e., gastric pull up or colon interposition or free jejunal loop autotransplant) should be the standard option on a type C basis in the substitution of the cervical oesophagus. These techniques allow a one-stage operation to be performed; oral feeding is resumed early and good functional results are obtained at the expense of acceptable morbidity and mortality rates. The first choice standard option for reconstruction after total pharyngo-laryngo-oesophagectomy is the stomach on a type C basis, as it allows to cover long defects, it is suitable also for patients with cancer spread or synchronous cancers in the thoracic oesophagus, and entails lower postoperative morbidity and mortality rates than colon interposition. Colon interposition is used in patients who had previously undergone gastric operations or with concomitant gastric diseases that make the stomach unsuitable. In cases of segmentary resection of the cervical oesophagus, the reconstruction is performed using a free jejunal loop autotransplant with vascular microanastomosis.

6.1.1.3 Definitive chemoradiotherapy

Definitive chemoradiation is a valid treatment option for curative therapy of patients with localised squamous cell carcinoma of the cervical oesophagus (type 2 level of evidence). Treatment schedule includes cisplatin + fluorouracil for 2-4 cycles and concomitant radiation therapy. Most retrospective series used radiation doses of 50 Gy – 66 Gy in conventional fractionation, which were above those in thoracic oesophageal cancer (Gkika 2014; Grass 2015; Burmeister 2000). Grade IV toxicity has been reported in up to 14% of patients (al-Sarraf 1997). Long-term survival rates of 17%-55% can be achieved depending on the number of patients with clinical stage I und IIA carcinomas included into the studies. Although there are no randomised controlled trials in cervical carcinoma, these results compare favourable with the survival rates of 14%-47% in series with chemoradiotherapy plus surgery.

6.1.2 Thoracic oesophageal cancer
6.1.2.1 Overall treatment strategy

Aim of treatment is definite cure. Endoscopic resection is the treatment of choice in early carcinomas (Tis-T1m) on a type 1 level of evidence (Guo 2014). Surgery (with or without preoperative treatment) is standard treatment on a type 1 basis (Flood 1995; Fink 1995; NCCN 2015) in local and locoregional tumours and operable patients. The aim of potentially curative surgery is the achievement of an R0 resection, since R1-R2 resections are to be considered palliative procedures. R0 resection is determined by T depth and by infiltration of surrounding structures. Resectability rate varies from 20% for T4, to 50% for T3 and 80-90% for T1-T2 squamous cell carcinoma (Siewert 1994). Preoperative staging is critical for the prediction of resectability, but non-invasive staging is not completely adequate in determining resectability. It may be impossible to predict resectability prior to intraoperative evaluation (Roth 1994). The overall probability of achieving an R0 resection for advanced tumours is superior in subcarinal tumours. Tumours of category T1 and T2 should be considered for radical surgery, because preoperative chemoradiotherapy did not show improved survival compared to surgery alone (Mariette 2014). Mortality rate is 2-10% in specialised centers, but may exceed 20% in less experienced centers and patients with locally advanced squamous cell carcinomas. General medical assessment for accurate patient selection is required. Long-term survival of resected stage I is 70%, it ranges between 10%-35% in stage II, <15% in stage III and <5% in stage IV. Long-term results with surgery seem more favourable in recent series, since a more accurate preoperative staging and patient selection have lead to an increased rate of radical resection and to a decreased rate of postoperative deaths (Markar 2015). For locally advanced resectable (see paragaph 6.3.4) tumours chemoradiation followed by surgery is recommended based on recent phase III trials and a couple of meta-analyses (van Hagen 2012; Tepper 2008; Sjoquist 2011; Kranzfelder 2011). Definitive chemoradiation is the treatment of choice for inoperable patients or those declining surgery. Moreover, patients with increased risk at operation may be treated with definitive chemoradiotherapy (Allum 2011, Porschen 2015).

6.1.2.2 Early carcinomas (Tis, mucosal T1N0)

Although most of the trials have been performed in barrett´s carcinoma it can be concluded that endoscopic resection can be regarded as standard therapy also in superficial squamous cell carcinoms. Endoscopic resection fulfills the criteria of curative therapy in tumours with low risk features (mucosal tumours of m1 and m2 category, grading G1/2, no invasion of vessels = V0 L0 and no ulceration) and in case of tumour free resection edges. So this procedure is primarily a diagnostic one. Aim of treatment is a R0 en-bloc resection. This is best achieved with endoscopic submucosa dissection rather than with mucosal resection (Cao 2009). With this technique complete resection is possible in up to 95% of the lesions, even of those above 15 mm in size. If R0 resection cannot be achieved or if the tumour does not fulfill low risk criteria, surgical resection needs to be performed, whenever possible.

6.1.2.3 Surgery of thoracic oesophageal cancer

Surgery of patients with intrathoracic oesophageal cancer should be performed in centers of excellence with a high procedural volume, because this showed to improve clinical outcome in retrospective cohort studies (Munasinghe 2015). In patients with resectable oesophageal carcinoma with high operative risk for transthoracic oesophagectomy, an option on a type C basis is transhiatal oesophagectomy with gastric pull-up and abdominal and inferior mediastinal perioesophageal lymphadenectomy. The application of minimally invasive techniques to the dissection of thoracic oesophagus (thoracoscopic oesophagectomy) is investigational; the aim of the procedure is to improve radicality in comparison to transhiatal blunt oesophagectomy while decreasing respiratory morbidity and mortality rate in comparison to thoracotomy. Thoracoscopic oesophageal resection is feasible, in selected centers, in the absence of wide pleural adhesions, but it does not seem to offer clear advantage over traditional surgery, since morbidity and mortality rates are comparable and longer follow-up are required. This technique deserves further investigation in dedicated centers (Peracchia 1997; Osugi 2005; Palanivelu 2006). Standard treatment for low operative risk patients with supra- and juxtacarinal cancer of the thoracic oesophagus is transthoracic almost total oesophagectomy, gastric pull-up with abdominal and extended (2 field-1) or total mediastinal (2 field-2) lymphadenectomy on a type C basis. The standard approach is through a right posterolateral thoracotomy in the 5th interspace, a median supra-umbilical laparotomy, and a cervical incision. The advantage of this approach is the ability to perform a complete two-field (mediastinal and upper abdominal) lymphadenectomy and do the entire dissection under direct vision. A left neck exposure is preferred for the oesophagogastric anastomosis, since this reduce the risk of injury of the recurrent laryngeal nerve during the dissection. The gastric pull-up is the preferred reconstruction technique: colon interposition is a viable option in case of previous gastric surgery, in case of total oesophago-gastrectomy or in case of short gastric tube (DeMeester 2001; Deschamps 1995). 3-field lymphadenectomy (including abdominal, mediastinal and cervical nodes) is commonly praticed in Japan; in patients with supra- and juxta-carinal squamous cancers of the oesophagus, this extended lymphadenectomy may reduce locoregional recurrence and improve long-term survival rate (Tachibana 2003). In European centers the three-field lymphadenectomy is limited to upper oesophageal cancer for the high risk of morbidity related to low improvement in survival. In a recent multicenter study is reported that during oesophagectomy for cancer, the number of removed lymph nodes is an independent predictor of survival. A minimum number of 16 examined nodes is mandatory to maximize this survival benefit (Altorki 2008; Peyre 2008).
However, since widening of lymphadenectomy to the upper mediastinal nodes and mostly 3-field lymphadenectomy, carries a significant increase of morbidity, mostly for a higher rate of recurrent nerve palsy and higher respiratory morbidity, 3-field resections are to be considered suitable for individual clinical use for selected low risk patients in centers particularly devoted to this kind of surgery on a type 3 level of evidence (Kato 1991a). Standard treatment for low risk patients with sub-carinal cancers is transthoracic subtotal oesophagectomy, gastric pull up with upper abdominal and standard mediastinal lymphadenectomy. Dissection of cervical nodes in these patients is questionable, due to the lower incidence of cervical node metastases in patients with cancer of the subcarinal oesophagus and due to little differences in 5-year survival between patients undergoing a 3- or a 2-field dissection, even if these differences increase in patients with middle thoracic oesophagus (39% vs. 57% for middle oesophagus, 39% vs. 48% for lower oesophagus). It might be speculated that the introduction of new staging modalities, such as FDG PET, may increase the accuracy of clinical staging by revealing positive nodes in the neck. The standard approach is through a right posterolateral thoracotomy in the 5th interspace, a median supra-umbilical laparotomy. Data from literature indicate that the primary oesophagectomy can be performed with a low mortality, below 5% in high-volume centres and less than 2% in centers of excellence. Postoperative mortality results over 10% in low-volume centres (Casson 2005). Minor and major postoperative complications range from 40 to 80 percent depending on the patient population, the presence of associated comorbidity, the extent of resection and particularly in low-volume institutions (Lerut 2005). An agreement on the anatomic classification of the different extent of lymphatic dissection for cancer of the thoracic oesophagus has been recently found. The abdominal compartment (compartment I) encompasses all nodal stations limited inferiorly by the superior pancreatic margin, superiorly by the oesophageal hiatus, and laterally by the hilus of spleen, the hepatoduodenal ligament and the right gastric artery. The aorta is the posterior limit. In the mediastinal compartment (compartment II) 3 different levels of lymphadenectomy are currently described: the socalled standard lymphadenectomy, with removal of para-oesophageal, subcarinal and right para-bronchial nodes. The 2-field 1 or “extended” lymphadenectomy where dissection is extended to the right apical nodes (right paratracheal of the brachio-cephalic trunk and right recurrential nodes) and the socalled 2-field 2 or “total mediastinal” where dissection also involves the left paratracheal and recurrential nodes. The cervical compartment (compartment III) involves the deep internal nodes (recurrential nodes), the deep external nodes (around the internal jugular vein and inferiorly in continuity with the recurrential nodes), the deep lateral nodes (nodes of the accessory spinal nerve in the inferior part of the neck) and the supraclavear nodes. The 3-field lymphadenectomy is the widest extension of lymphadenectomy for cancer of the thoracic oesophagus.
It can be defined as the removal of abdominal and cervical nodes with an extended or total mediastinal lymphadenectomy. 2-field lymphadenectomy means the removal of abdominal nodes together with an extended (2-field 1) or total (2-field 2) mediastinal lymphadenectomy. More extended lymphadenectomy may improve survival as well in squamous cell carcinomas with a limited number of metastatic nodes (fewer than four positive nodes or involved node ratio <20% or metastases confined to one or two of the three anatomic compartments) (Roder 1994; Altorki 1997; Akiyama 1994; Nishimaki 1998; Kawahara 1998; Kato 2007). The 5-year survival of all resected patients is 24% and of R0-resected patients is approximately 40% either in European, Japanese or American reports, independently of the histologic type. The probability of 5-year survival of an R0-resected stage I squamous cell carcinoma is 70% (90%-100% for T1 mucosal, 50% for T1 submucosal) and it drops to 20-50% for IIa-IIb patients, to 10-20% for stage III patients and to 10% for nodal stage IV patients. These European figures have been reported for patients treated with en bloc resection and 2-field lymphadenectomy (Siewert 1994; Roder 1994). Altorki and Skinner reported similar survival results after en bloc oesophagectomy with 2-field or 3-field lymphadenectomy and suggested a survival benefit from 3-field lymphadenectomy such an aggressive surgical approach for stage III or N1 squamous cell or adenocarcinoma (4-year survival of an R0-resected stage III is around 35%) (Altorki 1997). Globally the difference in terms of survival between a 2-field and a 3-field dissection in squamous cell carcinoma, as reported recently from Japan, ranges from 10% to 15% (Akiyama 1994; Nishimaki 1998). Despite these published results, 3-field lymphadenectomy is not actually considered a standard procedure in western countries. Most patients with locally advanced tumours, who might theoretically benefit from 3-field lymphadenectomy, are usually treated with neoadjuvant treatment protocols. Reconstruction of the alimentary tract is performed through gastric pull-up, since it guarantees good functional results with a safe and quick operation. Lymphadenectomy of the lesser gastric curvature and of the left gastric artery is performed by the construction of a gastric tube. If the stomach is unfit due to previous surgery or concurrent diseases, a pedicled isoperistaltic colonic loop or a jejunal loop should be considered. The transposition path of choice is the posterior mediastinum as it is the most direct, and guarantees less morbidity and better postoperative functional results. The alternative retrosternal transposition route is preferred in case of an R2 resection in order to avoid the involvement of the transposed viscus either by local recurrence or by postperative irradiation.
A transthoracic oesophagectomy is today the preferred approach for thoracic oesophageal cancer allowing for optimal resection of the tumour and the surrounding lymph nodes. However the percentage of cardiopulmoary complications associated with this conventional oesophagectomy is high. Therefore minimally invasive oesophagectomy is under discussion A randimized trial from the Netherlands show reduced morbidity and mortality after minimally approach (Biere 2012). Short-term oncologic results of this trial for minimally invasive oesophagectomy are comparable with oncologic results after open oesophagectomy. Results of the French MIRO trial discussed at the ASCO meeting 2015 show a reduced morbidity and especially reduced frequency of pulmonary complications after laparoscopic mobilization of the stomach combined with open thoracotomy in comparison to conventional open oesophagectomy. These results were confirmed by a nationwide French study published in Annals of Surgery (Messager 2015) with lower morbidity and mortality after hybrid technique compared with open surgery.

6.1.2.4 Concepts of radiotherapy

In view of the common observation that radiation therapy for oesophageal cancer is a complex treatment, referral to high-volume centres is recommended on a type R basis. In the neoadjuvant setting, the standard RT dose is 45.0-50.4 Gy, given in a conventional fractionation of 1.8 Gy per day single fraction dose with concurrent cisplatin-5FU chemotherapy (Herskovic 1992; Cooper 1999). The Cross trial (van Hagen 2012; Shapiro 2015) provided type-1 evidence in support of a lower total dose (41.4 Gy/1.8 Gy per fraction) delivered with concurrent weekly CBDCA Auc 2 and Paclitaxel 50 mg/m2. In the definitive setting, dose escalation to 64 Gy didn’t translate into improved survival (Minsky 1999, Minsky 2002). In selected patients, particularly in case of cervical oesophageal lesions, higher total dose may be considered; however, given the evidence available, the prescription of doses above 60 Gy as well as the use of altered fractionation scheme have to be considered investigational. Treatment volume selection and delineation have to be based on a combination of all available imaging, with CT and EUS as mandatory and FDG PET as recommended modalities. The gross tumour volume (GTV) is a composite delineation consisting of primary tumour (GTV tumour) and involved lymph nodes (GTV nodal). Pathologic observations (Gao 2007) reported that more than 90% microscopic intraepithelial or subepithelial tumour spread beyond the gross primary tumour are found within 3 cm in proximal and distal directions for both squamous cell carcinoma of the mid/low oesophagus and for adenocarcinoma of the GE junction (in the latter, 94% of distal tumour spread within 5 cm). Therefore, a GTV-CTV margin of 3.5 cm in the cranio-caudal direction is generally considered to be adequate, except for adenocarcinoma of the GE junction where a 5 cm caudal margin is advocated (type R basis). The CTV should be extended to include all pathologic lymph nodes (GTV nodal) and the lymphatic stations between these volumes. Secondary lymph node involvement is an early event in the natural history of oesophageal cancer independently from the T-stage category (Isono 1991) and the location of the disease (Ding 2012). As underlined by pooled surgical data (Rice 2010), the number of pathologic lymph nodes carries a negative prognostic significance. The elective lymph node drainage pattern corresponds to the specific tumour location. In case of cervical tumours, supraclavicular, para-oesophageal, pre-tracheal, and a-p window lymph nodes should be included in the elective CTV. In case of proximal thoracic lesions, pre- and sub-cranial nodes could also be considered. In case of mid-oesophageal tumours, para- and pre-tracheal, a-p window, pre- and sub-carinal, and higher and lower para-oesophageal nodes should be included in the elective CTV. In case of type 1 Siewert EGJ tumours, lower para-oesophageal, supra-diaphragmatic, posterior mediastinal, paracardial, infra-diaphragmatic, and nodes along the left gastric and celiac arteries should be included in the elective CTV (Matzinger 2009) (type C basis). However, given the observation that the incidence of isolated outfield regional failure is low (below 10%) across prospective trials of “involved-field” radio-chemotherapy and the lack of evidence of a survival gain by an elective nodal irradiation (ENI) approach (Qiao 2008; Ma 2011) (type 2 evidence) some guidelines (Gao 2010) do not support an extensive inclusion of unaffected lymph node stations in target volume. Whenever available, strategies for individualized identification of target motion are strongly encouraged. As recommended by ICRU 62, an internal target volume (ITV) should be included in the treatment planning process (general consensus on a type C basis). For proximal and mid-oesophageal tumours, experimental evidence (Dieleman 2007; Yaremko 2008) (type-3 evidence) suggests that the following margins would provide tumour motion coverage in 95% of the patients’ population: 7-8 mm in the dorso-ventral direction, 5-7 mm in the medio-lateral direction, 10 mm in the cranio-caudal direction. In case of lower oesophageal and EGJ tumours, larger margins are suggested (1 cm radial margin, 1.5 cm distal margin, 1 cm proximal margin) (Matzinger 2009) (type C basis). Therefore, the herewith provided margins are to be considered for CTV-ITV expansion in the absence of a personalized tumour motion assessment (i.e., with 4D-CT), which is the recommended planning modality. According to ICRU 50 and 62, the planning target volume (PTV) is then determined by the ITV volume plus a 5 mm margin (unless the treating center has identified its own margins to take into account setup uncertainties). In the treatment planning process, dose constraints to organs at risk (spinal cord, lungs, heart, liver, kidneys, stomach, duodenum, and small bowel) should follow international recommendations (Quantec project) (type C basis). The planning CT has to be acquired with the patient in the supine position holding arms above the head and a knee support. Slice thickness should be of 3 mm, the use of IV contrast for planning purposes is recommended. Minimum 3D treatment planning following ICRU 50 definitions is recommended. Usually, treatment starts with AP-PA-fields followed by an AP-field with two posterior oblique fields or with the 3-field technique from the start, which is preferable. 3D-conformal techniques may also be used to boost the tumour. In case of intensity modulated radiotherapy (IMRT) availability, its use should be encouraged for the treatment of oesophageal cancer, provided that proper quality assurance and centre experience are guaranteed. Although the use of IMRT may be still regarded as investigational, type-3 evidence (Lin 2012) supports its consideration over 3D-CRT: overall survival, locoregional control, and noncancer-related death were significantly better after IMRT than after 3D-CRT in a single-institution analysis of 676 nonrandomized patients (stage IB-IVA) (Greene 2002) treated with radio-chemotherapy. Moreover, a recent secondary analysis of a phase 2 randomized trial performed in locally advanced NSCLC treated with RTCT (>60 Gy) showed that IMRT was associated with a reduced risk of grade ≥3 pneumonitis (3.5% vs. 7.9%; p=0.039) and with a lower volume of the heart receiving radiation doses compared with 3DCRT, providing further evidence (Speirs 2016) (type 3 evidence) in favour of routine IMRT use in thoracic irradiation. Image guided radiotherapy (IGRT) is strongly encouraged given the potential tumour motion and displacement of oesophageal lesions, particularly if IMRT-generated steep dose gradients are employed. Prospective studies (Lordick 2007; zum Büschenfelde 2011) mainly developed in the context of upfront neoadjuvant chemotherapy showed the prognostic discrimination of a metabolic response showed at an “early” FDG PET (type-2 evidence). Taking also into account the observation that locoregional, in-field recurrences represent the predominant pattern of failure after concomitant RTCT (86% of locoregional recurrences occurred at the site of the primary tumour in CROSS trial), strategies of FDG-PET guided RT adaptation or of dose intensification to the biological target volume (BTV) are rationale, but at present remain investigational in the absence of prospective validation.

6.1.3 Localised tumours (submucosal T1 and T2)

Primary surgery is the standard of care in localized squamous cell carcinoma because a French phase III study did not show a benefit for the patients by adding preoperative chemoradiotherapy (Mariette 2014). This negative result may be caused by a sigificantly increased postoperative mortality rate in the multimodal therapy group (11.1% vs. 3.4%), which may have prevented to prove superiority regarding overall survival. The rate of local recurrences was significantly reduced by preoperative chemoradiotherapy (28.6% vs. 44.3%) although R0-Resection rate was almost identical. Moreover, the long-term prognosis of patients with surgery and involved lymph nodes (pN1-3) was poor due to recurrence rates of about 70% after R0 resection. However, the accuracy of predicting involvement of regional lymph nodes prior to surgery it limited.

6.1.3.1 Locally advanced tumours (T3-4 any N M0 or T2 N1-3 M0)
6.1.3.1.1 Pre- and post-operative chemotherapy

The prognosis of patients with locally advanced oesophageal cancer is poor due to not completely resectable tumours and high recurrence rates after R0 resection even in specialised centers (Peyre 2008). Numerous phase III trials have been performed to compare primary surgery with preoperative chemo- or chemo-radiotherapy and surgery and most of the patients included into these trials had locally advanced resectable carcinoma. A phase III trial from Japan proved preoperative chemotherapy with cisplatin and 5-fluorouracil to be superior to the same postoperative chemotherapy regarding survival and toxicity (Ando 2012). Randomizing more than 160 patients in each group, the authors reported on a significantly improved overall survival (5-year OS 55% vs. 43%, p=0.04) Therefore, adjuvant chemotherapy shall not be applied in squamous cell oesophageal cancer. Most of the studies with preoperative chemotherapy versus surgery have been performed in mixed patient populations. From meta-analyses of these trials it appears that preoperative chemotherapy in squamous cell carcinoma does not improve survival compared to surgery alone (Sjoquist 2011).

6.1.3.1.2 Preoperative chemoradiotherapy

Numerous studies have been published to compare preoperative chemoradiotherapy with surgery alone in oesophageal cancer. Most of these studies were too small to detect a significant advantage in overall survival, but they showed improvement in resection rates or local tumour control. To overcome this statistical problem a couple of meta-analyses have been performed which concordantly resulted in a significant survival advantage for preoperative chemoradiotherapy rather than preoperative chemotherapy compared to surgery alone (Sjoquist 2011; Kranzfelder 2011). Moreover the CROSS study (van Hagen 2012) proved superiority of multimodal therapy over surgery and this was particularly seen with squamous cell carcinoma (p=0.011 in SCC vs. p=0.049 in adenocarcinoma). Therefore, preoperative chemoradiotherapy is accepted as standard therapy in locally advanced thoracic oesophageal cancer, particularly that of squamous cell histology (Ajani 2015; Porschen 2015).

6.1.2.1.3 Defintive chemoradiotherapy

Two European Groups published a comparison of trimodality therapy (chemoradiotherapy and surgery) with definitive chemoradiation. A phase III trial from France (Bedenne 2007) randomised patients with objective tumour response to chemoradiotherapy (Cisplatin/FU, 40-45 Gy) in a group which continued chemoradiotherapy (60-66 Gy) versus a group undergoing surgery. Treatment associated mortality with surgery was significantly higher, but overall survival was not different (Two-year survival rate 34% with surgery vs. 40% with definitive chemoradiation, p=0.44). A German study (Stahl 2005) randomised patients with locally advanced SCC in chemoradiotherapy (Cisplatin/Etoposide, 40 Gy) followed by surgery or definitive chemoradiotherapy (60-66 Gy). The study showed that omitting surgery was not inferior regarding overall survival (primary endpoint), neither in the ITT evaluation (2-year survival rate 40% vs. 35%, log-rank p for equivalence = 0.007) nor in patients with tumour response to induction chemotherapy (3-year survival rate 52% vs. 54%). Again, treatment associated mortality was higher in the trimodality group (12.8% vs. 3.5%). However, in both trials surgery improved the rate of local tumour control and the need for local interventions against dysphagia was increased in patients without surgical treatment. A meta-analysis included 6 randomised trials comprising 929 patients, most of them with squamous cell carcinoma (Pöttgen 2012). In these trials definitive radio(chemo)therapy was compared to surgery, with and without preoperative therapy. Overall survival was equivalent between these treatment strategies (HR for equivalence 0.98, 0.8-1.2; p = 0.84). However, there was a trend to more cancer related deaths with definitive radio(chemo)therapy (HR 1.19, 0.98-1.44; p = 0.07) predominantly due to a higher risk of loco-regional tumour progression without surgery. Radiotherapy doses of 50.4 to 66 Gy may be combined with chemotherapy combinations like Cisplatin/5-FU, Cisplatin/Docetaxel, Carboplatin/Paclitaxel or FOLFOX (van Hagen 2012; Conroy 2014).
In conclusion, preoperative chemoradiotherapy is the treatment of choice in patients with locally advanced, resectable squamous cell carcinoma of the thoracic oesophagus (Allum 2011; Ajani 2015; Porschen 2015). Definitive chemoradiotherapy is an alternative option in these patients, particularly those with tumours located in the upper third of the oesophagus and with increased operative risk.
Recently, response-related strategies have been reported in oesophageal cancer (Tachimori 2009; Ariga 2009). The principle is to start with definitive chemoradiotherapy (radiation doses of 50-60 Gy) and to perform extensive restaging 6 to 8 weeks after the end of radiotherapy, including (PET)-CT scans and endoscopy with multiple biopsies in the region of the initial tumour. Patients with evidence of avid carcinoma may proceed to surgery, if medically operable (“early salvage” in tumours resistant to chemoradiotherapy). Those patients with clinical complete response will undergo a surveillance programme. In case of local tumour progression a delayed surgery was performed (“late surgery” in tumours sensitive to initial chemoradiotherapy). Because prospective randomized studies are lacking, so far, this is not a standard procedure. However, long term survival rates of 23% to 41% in patients with early salvage and those of 30% to 51% in patients with late salvage have been reported (Wang 2014; Ariga 2009; Marks 2012) and 25% to 30% of the patients showed long term recurrence free survival after CRT without the need of surgery. Long term prognosis in this situation is correlated with the indication for salvage surgery (late salvage), complete tumour resection, N and M category (pN0, M0) and the extend of lymph node dissection (Wang 2014).

6.1.4 Unresectable tumours

For patients with good performance unresectable squamous cell carcinoma a combined chemoradiation approach is recommended on a type 1 level of evidence (Herskovic 1992; al-Sarraf 1997; Cooper 1999). The 5-year survival in the combined approach may reach 30% as compared to 0% for the radiation treatment arm alone. Treatment is based on the association of cisplatin + 5-fluorouracil, cisplatin + docetaxel, carboplatin and paclitaxel or FOLFOX and concomitant radiation therapy (50-66 Gy). Severe toxicity is to be anticipated in 40% of cases. In 20% of patients it may be life threatening for perforation, fistula formation and myelodepression. A surgical resection after preoperative chemoradiotherapy in responding patients is suitable for individual clinical use on a type 3 level of evidence. Initial combined radio-chemotherapy lead to a R0 resection rate around 50-70%, particularly in squamous cell oesophageal cancer, but may also increase postoperative morbidity and mortality (15%-20%).
If complete resection is not possible despite high experience of a surgical center, further therapy needs to be discussed in an interdisciplinary tumour board. In case of intraoperatively proven R1 resection, surgery should be extended to reach complete tumour resection with tumour free margins (R0 resection). If R1 resection turns out after surgery or if macroscopic tumour has been left at surgery then additive chemoradiotherapy is recommended an a type R basis for patients with good performance status after surgery (Porschen 2015).

6.1.5 Local-regional relapsed disease

Local recurrence of early cancer after endoscopic resection may be treated by another endoscopic resection, when low risk parameters are still valid (link early carcinomas). Anastomotic recurrences after surgery can be submitted to resective treatment in low risk patients. However most local relapsing diseases are part of extensive mediastinal recurrence and are excluded from a surgical approach. Chemoradiotherapy is a valid treatment option, particularly when patients were not pretreated by radiation, though radiation dose might be limited to 45 to 50 Gy because of gastric mucosa in the treatment field. Long-term survival may be achieved in up to 40% of these patients (Jingu 2012).
In patients relapsing after surgery and chemoradiation, treatment aim is palliation. Treatment must be individualized based on local tumour characteristics, patient medical conditions and patient preferences. Endoscopic palliation is standard option on a type C basis (Ponec 1997) in the presence of dysphagia. The complication rate of endoscopic procedures after radiation therapy is higher. Palliative chemotherapy and/or palliative radiation in patients not previously treated with radiotherapy are investigational. Surgery is an option for a localised relapse after chemoradiation.

6.1.5.1 Metastatic disease (stage IV)

Chemotherapy is an option on a type R basis for medically fit patients with metastatic disease (Allum 2011; Porschen 2015), although there is no prospective comparison of palliative chemotherapy versus best supportive care in oesophageal squamous cell carcinoma. Regimens employing cisplatin and 5-fluorouracil or cisplatin and a vinca alkaloid are more frequently used (Grünberger 2007). With such combinations, the response rate for patients with locoregional disease is significantly higher (around 45% to 55%) than that for patients with metastatic disease (25% to 30%). In a single randomized phase II trial single-agent cisplatin produced a lower response rate than did a cisplatin/5-FU combination (18% vs. 35%), but a significant survival advantage has not been reported (28 weeks vs. 33 weeks). This might be related to the higher incidence of toxic deaths in the combination arm, using an intensive 3-weeks schedule (Bleiberg 1997). The combination of Cisplatin and Vinorelbine appears more convenient and less toxic, but survival is also poor with this combination (median survival time 7 months) (Conroy 2002). There have been no prospective, randomized comparisons of different combination regimens. Therefore, even if no standard chemotherapy can be recommended, Cisplatin based combination chemotherapy may be offered medically fit, younger patients with metastatic squamous cell carcinoma (Flood 1995; Kelsen 1995b; Bleiberg 1997; Conroy 2002). Additionally, supportive care (treatment of dysphagia) is stronlgy recommended in these patients.

6.1.6 Patients in poor general conditions

Treatment for advanced oesophageal cancer in patients in poor general conditions must be individualized based on stage, characteristics of the tumour (location and shape), local expertise, as well as patient medical conditions and patient preferences. The aim of palliative treatment is rapid relief of dysphagia without the need for long hospital treatment. Single procedures are often combined according to tumour evolution. Major treatment options to improve dysphagia are radiotherapy (brachytherapy or extern beam radiotherapy) or endoscopic treatments (stent placement, dilatation, endoscopic laser treatment).

6.1.7 Treatment of synchronous tumours

Squamous cell carcinoma of the oesophagus develops as a result of multistep carcinogenesis. The concept of field carcinogenesis is applicable to the oesophagus as to the entire upper aerodigestive tract. Patients with squamous cell carcinoma of the upper aerodigestive tract, including the oesophagus, have a common antecedent of smoking and/or ethylism and are likely to have multiple clinically and histologically evident premalignant lesions or already malignant lesions. Treatment of such patients is highly individualised being related to patient’s conditions, site and histology of synchronous tumour.

6.1.8 Palliative endoscopic intervention to improve dysphagia
6.1.8.1 Palliative dilation

Palliative dilation is suitable for individual clinical use on a type R basis in patients with an extremely short life span. The advantages of dilatation are that it is simple, cheap, easily available and suitable for many tumours irrespective of site and characteristics. The procedure achieves good relief of dysphagia with an overall complication rate < 10%, but the duration of symptom relief is short. Since the functional benefit is of short duration (2-4 weeks) it is usually the first step in many palliative techniques in patients with a longer life expectancy.

6.1.8.2 Endoscopic stenting

Endoscopic stenting is standard option on a type C basis in patients in poor general condition especially those with obstructive tumours or those whose cancer is complicated by a mediastinal or tracheoesophageal fistula (Ponec 1997). Improvement in survival has not been shown by endoscopic techniques, but their relative safety, efficacy in controlling symptoms, and the possibility to use them in an outpatient setting makes them valuable tools in the palliation of patients with advanced or recurrent oesophageal carcinoma. Lesions most suitable for palliation by stenting are long (5 cm) infiltrating tumours, extrinsic strictures, and tumours located more than 2 cm below the superior oesophageal sphincter. Proximal tumours of the cervical oesophagus cannot be treated with traditional stents but only, in selected patients, with self-expandable ones. The functional success rate with conventional rigid plastic stents is approximately 70%, only 10-50% of patients succeed in eating solids. Implantation of plastic endoprostheses is associated with relatively high procedure-related complication rate (5%-20%), and mortality rate (5%-12%). Early complications include perforations, bleeding and tube dislocation. Late complications are obstruction, dislocation and pressure necrosis. Contraindications are non-stenosing tumours (unable to sustain the prosthesis) and angulated or undilatable tumours. The recently introduced metallic self-expanding stents have significantly improved the possibilities of palliation of malignant dysphagia and oesophagorespiratory fistulas. Three recent small randomized trials that compared the placement of rigid plastic tubes with that of covered or uncovered self-expanding metal stents showed that the use of the latter is associated with fewer major complications (0%-16% vs. 21%-47%), fewer procedure-related mortality (0% vs. 16%) and shorter hospital stay. Only prior treatment may increase the risk of specific device-related complications with respect to the oesophagus (Siersema 1998). Technical success and improvement in dysphagia score were similar in both groups (Knyrim 1993; Siersema 1998; De Palma 1996). A recent trial compared endoscopic laser therapy with plastic-covered self-expandable metal stents or with uncovered self-expandable metal stents (Adam 1997). Early complications are similar in three groups and low (10% of cases), but the median improvement of dysphagia score at 1 month is better after positioning a self-expanding metal stent than after laser therapy and the duration of palliation after laser ablation is short (4 weeks) and in 100% of cases a laser retreatment is required at regular intervals. Although safer and easier to place, expandable stents are not without late complications.
Uncontrolled studies compared different self-expanding metal stent types (Wallstent, knitted nitinol, plastic-covered or uncovered) showing that palliation is good and equal and that morbidity may be relatively high and different. Expansile forces, flexibility, stent diameters and presence of plastic covering seem to be relevant for indication, early complication rate and stent dysfunction. Uncovered Wallstent has a diameter of 20-25 mm, it has high expansile force and is stiff. It seems to cause more early severe complications (10%-30%) such as perforation, hemorrhage and severe chest pain, high procedure-related mortality (up to 16%), in case of migration or misplacement it is impossible to relocate. It is indicated in case of very tigh stricture. Wallstent dysfunction and reintervention rate are low (<10%). Uncovered knitted nitinol stent has a diameter of 18 mm, lower expansile force and high flexibility. It can be repositioned and removed and mortality rate and early complication rate are low (<10%); in contrast, late obstruction by permeation of the uncovered prosthesis by tumour ingrowth inside the stent or by food-bolus impaction are frequent (30%) and reintervention rate is necessary in over 30% of cases. The use of laser ablation or photodynamic therapy to treat tumour ingrowth through uncovered expandable stents seems safe and effective and is suitable for individual clinical use on a type 3 level of evidence (Adam 1997; Scheider 1997). Covered stents are being developed to overcome the problem of tumour ingrowth. Stent migration was major problem after positioning plastic-covered Wallstent; it was reported in 30% of patients with low oesophageal tumours. Rates of early and late complications as well as reintervention rate are similar after positioning knitted nitinol stents or plastic-covered Wallstents. New conical plastic-covered stents, resistant to distal migration, are under study. Therefore, the use of either plastic-covered or uncovered or knitted nitinol self-expanding metal stents is suitable for individual clinical use on a type 2 level of evidence depending on type and level of stenosis and medical expertise (Knyrim 1993; Siersema 1998; De Palma 1996; Adam 1997; Schmassmann 1997). Some of the new self-expandable stents have a soft wall and may easily adapt to oesophageal peristalsis, allowing its placement also in patients with strictures of the upper cervical oesophagus. Covered self-expandable stents should nowadays be considered the standard option on a type C basis for endoscopic palliation of malignant oesophageal fistulas and perforations (Morgan 1997). Fistulas close to the upper oesophageal sphincter may be closed with placement of parallel coverd metallic stents in the oesophagus and trachea on a type R basis. The addition of conventional radiotherapy (55 to 65 Gy) to endoscopic dilatation or intubation prolongs survival (from 3 to 7 months) as well as improves dysphagia and nutritional parameters in untreated patients with advanced oesophageal cancer without associated oesophagorespiratory fistula. Radiotherapy associated to endoscopic treatment is suitable for individual clinical use on a type 2 level of evidence (Kharadi 1997).

6.1.8.3 Endoluminal brachytherapy

Although stenting offers fast improvement of dysphagia a prospective randomized study from the Netherlands showed that single-dose brachytherpy was significantly superior regarding sustained and complication free relief from dysphagia in patients with oesophageal cancer (Homs 2004). Therfore, this option should be offered to suitable patients with high-grade dysphagia and poor medical condition preventing other tumour specific therapy.

6.1.8.4 Palliative Radiation therapy

Radiation therapy is suitable for individual clinical use on a type R basis. External irradiation (EBRT) is truly non invasive compared to endoscopic palliative procedures. About 50%-80% of patients will experience an improvement of dysphagia; a disadvantage is that relief of dysphagia only occurs within 4-6 weeks and the median duration is usually short-lived (3 to 6 months). It might not offer fast relief when the lumen is totally obstructed (Reed 1995). The presence of a tracheobronchial fistula is no more considered an absolute contraindication to radiotherapy or to concomitant radio-chemotherapy, since closure of fistula was observed in patients responding to treatment (Ahmed 1998). About 10-20% of patients experience early complications such as oesophagitis, stenosis and fistula formation. Only 20-30% of cases will remain asymptomatic for dysphagia until death due to fibrosis and/or local recurrence. The majority of patients require an alternative palliative procedure. Brachytherapy alone is a palliative modality. It is more rapid than EBRT in locally controlling tumour growth and in relieving dysphagia. About 70%-100% of patients with adenocarcinoma or squamous cell carcinoma will experience an improvement of dysphagia within 2 weeks, for an average duration of 5-6 months; median survival was reported to be around 6 months. The only complications are mild to moderate oesophagitis (50% of patients) and fibrotic strictures needing dilatation (25% of patients). Brachytherapy alone is suitable for individual clinical use on a type 3 level of evidence in patients recurring after EBRT or with a life expectancy smaller than 6 months. The optimal dose-fractionation scheme is unknown; either fractionated high dose rate (16-18 Gy in two-three fractions given weekly in untreated patients or 10-14 Gy, one or two fractions, after EBRT) or low dose rate (25-40 Gy, 0.4-1.0 Gy/hr in untreated patients or 20-25 Gy in a single course at 0.4-1 Gy/hr, after EBRT) are suitable for individual clinical use on a type 3 level of evidence (Gaspar 1997a; Sur 1998). Although stenting offers fast improvement of dysphagia a prospective randomized study from the Netherlands showed that single-dose brachytherpy was significantly superior regarding sustained and complication free relief from dysphagia in patients with oesophageal cancer (Homs 2004). Therfore, this option should be offered to suitable patients with high-grade dysphagia and poor medical condition preventing other tumour specific therapy.

6.1.8.5 Laser therapy

Nd:YAG laser therapy is suitable for individual clinical use on a type R basis in cases with non-angulated, fungating, non circumferential infiltrating lesions with a length less than 5 cm located in the mid-distal oesophagus. Contraindications to laser treatment are ulcerating/necrosing tumours and neoplastic fistula. Laser induces a coagulation necrosis or tissue vaporisation in a single or in multiple treatment courses. It is preferable to perform the procedure in a retrograde fashion since the risk of perforation is lower after dilation. Laser ablation is effective in eliminating dysphagia in 70%-80% of cases for 4-5 weeks. A prospective trial compared endoscopic laser therapy with plastic-covered self-expandable metal stents or with uncovered self-expandable metal stents (Adam 1997). Early complications are similar in three groups and low (10% of cases), but the median improvement of dysphagia score at 1 month is better after positioning a self-expanding metal stent than after laser therapy and the duration of palliation after laser ablation is short (4 weeks) and in 100% of cases a laser retreatment is required at regular intervals. External beam radiotherapy after laser therapy enhances palliation since it prolongs interval between endoscopic laser treatments from 5 to 9 weeks. A randomized trial demonstrated an advantage in delaying recurrent dysphagia when laser treatment was associated to brachytherapy. Either external beam radiotherapy or brachytherapy after laser recanalization are suitable for individual clinical use on a type 2 level of evidence (Sander 1991; Sargeant 1997).

6.2 Adenocarcinoma of lower oesophagus and oesophagogastric junction (EGJ)

6.2.1 Overall treatment strategy

Aim of treatment is to definite cure. Endoscopic resection is the treatment of choice in early carcinomas (Tis-T1m) on a type 1 level of evidence. The prognosis of localized adenocarcinoma is superior to that of squamous cell carcinoma; 5-year survival rates superior to 50% have been reported in surgical series with a high prevalence of early tumour stages (Siewert 1997). There is evidence suggesting that neoadjuvant chemoradiotherapy is superior to neoadjuvant chemotherapy (Gebski 2007; Stahl 2009; Ronellenfitsch 2013a). Preoperative radiotherapy shall not be performed. Postoperative therapy depends on tumour spread and site, nodal status, histology and R-status. In general, non-R0-situations may be treated with adjuvant chemoradiotherapy on a type C basis. Completely resected adenocarcinomas, clinical stage T3-4 N0 or Tany N+ might benefit from adjuvant chemotherapy alone or combined with radiotherapy on a type C basis. The aim of palliative treatment is rapid relief of dysphagia without the need for long hospital treatment. Single procedures are often combined according to tumour evolution.

6.2.2 Early carcinomas (Tis, mucosal T1N0)

Endoscopic resection is the standard of care in patients with high-grade intraepithelial dysplasia or mucosal adenocarcinoma in Barrett’s oesophagus. Endoscopic resection fulfills the criteria of curative therapy in tumours with low risk features (mucosal tumours, grading G1/2, no invasion of vessels = V0 L0, no ulceration, and no signet ring cells) and in case of tumour free resection edges. Moreover, adenocarcinomas with superficial infiltratrion of the submucosa (sm1 <500 µm) with low risk features (G1/2, L0, V0, no ulceration, size <20 mm) may be treated with curative intent by endoscopic resection (Porschen 2015). So, this procedure is primarily a diagnostic one. Aim of treatment is to perform a R0 en-bloc resection. This is best achieved with endoscopic submucosa dissection rather than with mucosal resection (Cao 2009). With this technique complete resection is possible in up to 95% of the lesions, even of those above 15 mm in size. Several cohort studies showed that endoscopic resection in patients with low risk situation is equivalent to surgical resection with lower morbidity and mortality (Pech 2014). If R0 resection cannot be achieved or if the tumour does not fulfill low-risk criteria, surgical resection needs to be performed, whenever possible.

6.2.3 Surgery in adenocarcinoma of the oesophagus and oesophagogastric junction (EGJ)

A recently published systematic review of comparative studies that analyzed the outcome of surgical treatment of adenocarcinoma of the oesophagogastric junction shows that there is no consensus concerning the optimal approach for EGJ tumours (Haverkamp 2014). The choice of surgical techniques is discussed controversial, with particular uncertainty about the appropriate extent of resection in the oesophagus and the stomach, the extent and the sites of lymphadenectomy, and the optimum surgical approach (Mariette 2011).
In type I Adenocarcinoma of the EGJ two principal approaches are under discussion. The right thoracic approach is the onr with anastomis at the top of the thorax or in the cervical area with systematic mediastinal lymphadenectomy and the transhiatal approach with a cervical anastomosis without thoracotomy and without systematic mediastinal lymphadenectomy. A randomized trial published by Omlo et al has compared transthoracic with transhiatal approach (Hulscher 2002). A non-significant pattern of improved 5-year overall survival was noted in the transthoracic group compared with the transhiatal group (39% vs. 29%), and in diseass free survival (39% vs. 27%). A subgroup analysis indicated a gain in 5-year survival of 17% in the transthoracic group for type I cancer. The longterm results confirmed this data with a gain in survival of 14% for type I EGJ cancer (Omloo 2007).
In type II EGJ cancer (so called “cardia cancer”) most surgeons propose a transhiatal extended gastrectomy with D2 lymphadenectomy (abdominal approach) and lymphadenectomy of the lower mediastinum. If a free margin cannot be achieved with a transhiatal extended gastrectomy a transthoracic oesophagectomy with proximal gastrectomy and reconstruction with pull up of the stomach is indicated. A randomized trial of type II and type III EGJ cancer compared transhiatal extended gastrectomy with a left thoracophrenolaparotomy (Sasako 2006). This study and the published long term results showed comparable R0 resection rate and a not significant prognostic advantage of the transhiatal extended gastrectomy (Kurokawa 2015). Therefore and in recommendation of the better quality of life after gastrectomy compared with oesophagectomy (Haverkamp 2014; Fuchs 2016) the abdominal approach seems to be the first choice approach. In case of very enlarged type II cancer an oesophgogastrectomy with colon interposition can be indicated.
In type III EGJ cancer (subcardial cancer) a transhiatal extended gastrectomy with D2 and lowermediastinal lymphadenectomy is recommended.

6.2.4 Localised tumours (submucosal T1 and T2)

In patients with submucosal tumour infiltration (T1sm), lymphatic spread has been reported in 16% to 41% (Hölscher 1997; Lee 2013). Lymph node involvement is even more likely (up to 60%) in tumours infiltration the muscularis propria (category T2). In these patients surgical resection and regional lymphadenectomy is recommended. Primary surgery is the standard of care because prospective comparisons with multimodal therapy are lacking. Like in squamous cell carcinoma the rate of distant recurrences after complete resection correlates with involvement of regional lymph nodes (pN1-3) and recurrences of about 60% have been reported for tumours of category pT2N+ after R0 resection compared to about 30% without lymphatic spread (pT2N0) (Peyre 2008). In experienced centers with low rates of postoperative mortality the survival rates at 5 years will reach 76% and 42% in patients with pT1N0 and pT2N0 category, respectively. This drops down to less than 30% in patients with lymphatic spread (pT1-2 N1-3) (Peyre 2008). So, high-risk patients with regional lymph node involvement may be candidates for preoperative treatment. However, the accuracy of predicting involvement of regional lymph nodes prior to surgery is limited (see paragraph 4.3.3).

6.2.5 Locally advanced tumours (T3-4 any N M0 or T2 N1-3 M0)
6.2.5.1 Perioperative chemotherapy

The prognosis of patients with locally advanced oesophageal cancer is poor due to not completely resectable tumours and high recurrence rates after R0 resection even in specialised centers (Peyre 2008). Numerous phase III trials have been performed to compare primary surgery with pre/perioperative chemotherapy plus surgery or preoperative chemoradiotherapy plus surgery and most of the patients included into these trials had locally advanced resectable carcinoma. Three randomized studies with chemotherapy adjunctive to surgery have been reported which included mostly patients with oesophagogastric adenocarcinoma. The MAGIC trial (Cunningham 2006) included 90% adenocarcinomas, but only 25% were located in the oesophagus or EGJ. Preoperative chemotherapy with epirubicin, cisplatin and capecitabine (ECX regimen, 9 weeks prior to and 9 weeks after surgery) increased the 5-year survival rate to 36% compared to 23% with surgery alone. A French cooperative study randomized patients with adenocarcinoma, only and 75% were located in the oesophagus or EGJ (Ychou 2011). Also in this trial the long-term prognosis was improved by peroperative chemotherapy (cisplatin/fluorouracil, 6-9 weeks prior to and 9-12 weeks after surgery) by 14% (5-year survival rate increased from 24% to 38%). Of note, only 50% of the patients were able to start the postoperative chemotherapy and only 40% did receive it completely, as written in the protocol. Thus, the value of the postoperative part of perioperative chemotherapy is uncertain. A European phase III trial (EORTC 40954) investigated preoperative chemotherapy (without a postoperative part) compared to surgery in extensively staged locally advanced adenocarcinomas (Schuhmacher 2010). About one third of the patients had tumours in the EGJ. In this small trial preoperative chemotherapy significantly increased the rate of complete tumour resection (82% vs. 67%; p=0.036), but there was no improvement of overall survival (2-year survival rate 73% vs. 70%; p=0.46). From these trials the German S3-guideline concluded perioperative chemotherapy in locally advanced oesophago-gastric cancer shall be applied on a 1b level of evidence, but preoperative chemoradiotherapy is equally recommended (Moehler 2011).

6.2.5.2 Preoperative chemoradiotherapy

Up to 25% of recurrences after perioperative chemotherapy and surgery in oesophagogastric adenocarcinomas will occur locoregionally (Ott 2009). This has prompted investigators to include radiotherapy into the concept of perioperative therapy to reduce the risk of local recurrence. Most of the studies were performed with preoperative chemoradiotherapy. As a result the British Guideline (Allum 2011) stated that chemoradiotherapy followed by surgery should be preferred in locally advanced adenocarcinomas of the EGJ. This recommendaton is based on subgroup analyses of randomized trials like the CROSS study (van Hagen 2012). Although results in patients with adenocarcinoma were less impressive than in those with squamous cell carcinoma, superiority of multimodal therapy over surgery alone regarding overall survival was proven in this pahse III study (p=0.049 in adenocarcinoma). Moreover, meta-analyses dealing with this question showed that the advantage in long-term survival appears to be more pronounced with preoperative chemoradiotherapy (HR 0.70-0.75) than with pre/perioperative chemotherapy (HR 0.83-0.88) (Sjoquist 2011; Ronellenfitsch 2013b). Two randomized trials directly compared preoperative chemo- with chemoradiotherapy in oesophagogastric cancer. The Australian study (Burmeister 2005) included about 160 patients with oesophageal adenocarcinoma (60% of all patients). A short term of chemoradiotherapy (one cycle cisplatin/fluorouracil combined with 35 Gy) significantly increased the rate of R0 resection (80% vs. 59%; p <0.001), but progression free survival was improved only for patients with squamous cell carcinoma (HR 0.47) and not for adenocarcinoma (HR 1.02). Also in multivariable analysis, histology proved to be a prognostic factor. The German POET study (Stahl 2009) included exclusively patients with adenocarcinoma of the EGJ. This trial randomized 126 patients. Intensive preoperative chemotherapy (12 weeks) and chemoradiotherapy (3 weeks, 30 Gy) induced a strong trend for improved survival compared to chemotherapy alone (15 weeks) (3-year survival rate 47% vs. 28%, p=0.07[S1] ).
In conlusion, preoperative chemoradiotherapy is accepted as one European standard therapy in locally advanced adenocarcinoma of the EGJ (Moehler 2011; Allum 2011; Porschen 2015).

6.2.5.3 Adjuvant chemotherapy

A couple of phase III trials have been performed in gastric cancer investigating the role of adjuvant chemotherapy after tumour resection. An International Collaboration Group (GASTRIC) summarized data of all randomized trials which have been closed before 2004 (GASTRIC 2010). This group managed to include individual patient data from more than 3,800 patients out of 17 studies (60% of all trials). As a result adjuvant chemotherapy was associated with a statistically significant benefit in terms of overall survival (HR 0.82; 0.75-0.90; p<0.001), but the absolute benefit in long-term survival was small (5.6%). The studies included into this analysis randomized up to 30% of patients with adenocarcinomas of the EGJ. However, a seperate analysis of this subgroup of patients was not performed. Consequently, the role of adjuvant chemotherapy in patients with primary complete resection of oesophagogastric adenocarcinoma is uncertain.

6.2.5.4 Adjuvant chemoradiotherapy

Based on results of an US Intergroup trial (Macdonald 2001; Smalley 2012) the NCCN guideline recommends the use of adjuvant chemoradiotherapy in completely resected oesophagogastric adenocarcinomas. In this study about 20% of the 556 randomized patients had adenocarcinomas of the EGJ. Only 64% of the patients completed adjuvant chemoradiotherapy. Three year relapse free survival increased from 31% with surgery alone to 48% in the chemoradiotherapy group (p<0.001). This trial has been critisized because most of the patients had inadequate surgery (no lymph nodes dissection in 54% of the patients) according to international standards. A meta-analysis including 13 studies investigated the role of adjuvant radiotherapy with or without chemotherapy in patients with gastric cancer (Ohri 2013). This analysis confirmed the correlation of treatment effect by adjuvant radiotherapy and the extention of lymphadenectomy. A significant effect of adjuvant chemoradiation on survival was only seen in patients without lymph node dissection (D0: HR 0.73, 0.56-0.95; p=0.02) and a trend for improved survival was shown in patients with limited dissection (D1: HR 0.79, 0.62-1.01; p=0.06). Again, it is difficult to evaluate the number of patients with EGJ tumours in these trials and a subgroup analysis has not been performed.
Therefore, European guidelines recommend adjuvant chemoradiotherapy only for patients with high risk for tumour recurrence, e.g., those with limited surgery or extended lymph node involvement (Allum 2011, Porschen 2015) who have not received preoperative therapy.

6.2.5.5 Inoperable patients

For inoperable patients with good performance status a combined chemoradiation approach may be chosen with curative intention. Retrospective series showed that long-term tumour free survival is possible in about 30% of these selected patients (Tougeron 2012). Usually radiation doses of about 50 Gy were combined with cisplatin-based combination chemotherapy in these studies. From a propensity-based matching with patients undergoing preperative chemoradiotherapy and surgery it appers that patients with adenocarcinomas who declined surgery may have the same prognosis after chemoradiotherapy without surgery (Taketa 2013). Althoug this analysis may be biased by patients with good response to chemoradiation in the group without surgery, it offers a rationale to use definitive chemoradiotherapy in patients unable to undergo surgery. If the treatment intention is palliation, combined chemoradiotherapy does not offer advantage compared to radiotherapy alone in oesophageal adenocarcinoma.

6.2.5.6 Metastatic disease (stage IV)

Palliative therapy of patients with oesophageal adenocarcinoma should be handled according to gastric carcinoma (Moehler 2011; Allum 2011; Ajani 2015). Combination chemotherapy prolongs survival and quality of life compared to best supportive care and therefore, shall be offered to all patients, who qualify for tumour specific therapy (Al-Batran 2010). A cisplatin/fluoropyrimidine-containing two or three-drug regimen is reflecting the standard of care, although in unselected patients modern combinations were able to prolong median survival time by about 4 weeks, only (GASTRIC 2013). Numerous combinations have been investigated in randomized studies. The practical use of a specific chemotherapy depends on the individual patient situation and the experience of the treating center. When a platinum analogue is not possible to apply (impaired renal function or existing polyneuropathy) there is evidence to use platinum-free combinations like the FOLFIRI regimen (Guimbaud 2014) or a taxane/fluoropyrimidine combination (Thuss-Patience 2011). To retain the efficacy of a combination it appears important to apply the full dose of all cytotoxic drugs conducting dose reductions in case of intolerable toxicity only (Thuss-Patience 2011). Adding targeted therapy to chemotherapy has been widely investigated in oesophagogastric adenocarcinoma. By now, only trastuzumab combined with cisplatin/fluoropyrimidne in patients with tumours showing overexpression of her2 protein or amplification of Her2 gene (about 25% of EGJ adenocarcinomas) has proven superiority compared to chemotherapy alone (Bang 2010). In this selected patient group median survival time was increased from 11 months to 14 months (HR 0.74, 0.60-0.91), p<0.005). Therefore, combined chemo/antibody therapy shall be applied as first palliative treatment to patients with advanced, unresectable Her2-positive EGJ adenocarcinoma. Whether other combinations of chemotherapy added to trastuzumab may be equally effective is still under discussion.
Second line chemotherapy after failure of a platinum-combination has also proven superiority above best supportive care. Monotherapy with a taxane (paclitaxel or docetaxel), irinotecan, or the VEGF receptor-2 inhibitor ramucirumab showed significant improvement of survival in this situation (Ford 2014; Fuchs 2014). In these phase III trials median survival times of about 5 months were reported. More recently, the combination of paclitaxel and ramucirumab was able to increase median survival time to almost 10 months in pretreated patients, which was significanlty superior to paclitaxel alone (HR 0.81, 0.68-0.96; p=0.02) (Wilke 2014). This combination therapy may be considered a new standard second-line treatment for advanced gastroesophageal adenocarcinomas.

6.2.5.7 Metastasectomy

There is no data that resection of metastases other than regional lymph nodes may change the prognosis of patients with oesophageal carcinoma. Therefore, patients with known distant metastases shall not be considered for surgical resection. However, limited distant metastases which will be detected by chance at surgery may be resected combined with the primary tumour (Porschen 2015).

7. LATE SEQUELAE

7.1 Treatment of late effects and sequelae

Voice restoration after pharyngo-laryngo oesophagectomy and gastric pull-up is a major problem for many patients since very few of them develop an imitation of the oesophageal speech and the majority can only use an electrolarynx for communication. Voice restoration can be obtained by means of tracheo-gastric puncture and placement of a Bloom-Singer prosthesis. A patient’s strong determination to learn a verbal communication method was considered mandatory in the selection of patients for this procedure. Voice quality of these patients is worse than that of patients undergoing simple laryngectomy because of the lower pitch and intensity. Late postsurgical complications may be anastomotic strictures (up to 20%-25%) due to cicatricial fibrosis or to acid and or bilious pancreatic reflux. Fibrotic strictures can be observed in 50% of patients undergoing radiation therapy after surgery. Oesophageal dilation is recommended on a type C basis.
As a consequence of the advanced stage at diagnosis of oesophageal cancer and the poor survival with the available treatments, it is difficult to implement a policy of chemoprevention after the treatment of primary oesophageal cancers.

8. FOLLOW-UP

8.1 General principles and objectives

Cancer of the oesophagus has a high propensity for locoregional relapses and visceral metastases. Beside local recurrence in patients with endoscopic resection of mucosal carcinoma, early detection of locoregional or distant relapse is of little value being effective salvage treatment not available. Metachronous head and neck cancers and lung cancers occur in 15 to 20% of patients surviving at least one year after treatment for oesophageal cancer. After treatment, patients should have clinical follow-up visits every 2 to 4 months. The optimal interval between contacts and its duration is not established being in function of the general conditions of the patient. During the clinical examination, weight measurement, nutritional conditions and assessment of swallowing are essential since such impairments may be due to previous treatment. Full column and double contrast upper gastrointestinal barium swallow, endoscopy with biopsy, CT scan and endosonography (EUS) are optional. Both CT scan and EUS are limited by imaging artefacts. Second primaries are detected by clinical examination of the oral-cavity, pharynx and larynx, and by chest X-ray.

INDEX

 

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Prof. Ermanno Ancona (Author)
University of Padua (Italy)
email: ermanno.ancona@unipd.it

Dr. Pierluigi Bonomo (Author)
Radiotherapy Department
University Polyclinic “Careggi”, Firenze (Italy)
email: bonomop@aou-careggi.toscana.it

Prof. Volker Budach (Reviewer)
University Hospital Charite, Berlin (Germany)
email: volker.budach@charite.de

Dr. Gemma Gatta (Consultant)
Italian National Cancer Institute, Milan (Italy)
email: gatta@istitutotumori.mi.it

Prof. Andreas Kaiser (Author)
University Hospital Charite, Berlin (Germany)
email: andreas.kaiser@charite.de

Dr. Lisa Licitra (Editor)
Start Clinical Editor, Italian National Cancer Institute, Milan (Italy)
email: lisa.licitra@istitutotumori.mi.it

Prof. Dr. Stefan Paul Mönig (Author)
Department of General, Visceral and Cancer Surgery
University Hospital Cologne (Germany)
email: stefan.moenig@uk-koeln.de

Prof. Michael Stahl (Author)
Kliniken Essen-Mitte, Essen (Germany)
email: m.stahl@kliniken-essen-mitte.de