User:Anthonyhcole/Esophageal cancer1
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Esophageal cancer: A Review of epidemiology, pathogenesis, staging workup and treatment modalities (Not systematic. Seems clumsey and shallow.)
(UK/Ireland) Guidelines for the management of oesophageal and gastric cancer
Esophageal cancer: staging system and guidelines for staging and treatment
Current management of esophageal cancer
Definition[edit]
"Oesophageal cancer is a malignant, usually epithelial neoplasm most commonly showing squamous, glandular (adenocarcinoma), or neuroendocrine differentiation and arising in the oesophagus. Other, rarer types of malignant neoplasms can be encountered (adenoid cystic carcinoma, adenosquamous carcinoma, muco-epidermoid carcinoma, mixed adenoneuroendocrine carcinoma, various sarcomas, and melanoma). Only squamous cell carcinoma and adenocarcinoma are addressed here as they account for most oesophageal malignant neoplasms."
— WHO World Cancer Report
Should Howel–Evans syndrome ("focal non-epidermolytic palmoplantar keratoderma with carcinoma of the esophagus") be listed, or is it covered by the above?
"Adenocarcinoma of the oesophagus is a malignant epithelial neoplasm with glandular differentiation arising predominantly from Barrett mucosa and typically encountered in the lower third of the oesophagus."
— WHO World Cancer Report
(In relation to stomach cancer) "The gastric antrum (distal stomach) is the most common site of gastric carcinoma. Carcinomas of the oesophago-gastric junction have been most commonly reported in populations in North America and Europe, associated with gastrooesophageal reflux disease and other characteristics similar to adenocarcinoma arising in Barrett oesophagus, and are unrelated to H. pylori infection. However, in parts of Asia, for example in China, but also for a subset of tumours diagnosed in North America and Europe, neoplasms of the proximal stomach arise in a setting of chronic atrophic gastritis with H. pylori infection and are similar to distal gastric cancer. Adenocarcinomas located entirely below the oesophago-gastric junction are considered gastric in origin, and for these tumours the use of the ambiguous and often misleading term “carcinoma of the gastric cardia” is discouraged in favour of “carcinoma of the proximal stomach”.
— WHO World Cancer Report
(In relation to head and neck cancer)
Types of esophageal cancer[edit]
"The two most common histological types of esophageal carcinoma include [sic] SCC and adenocarcinoma. Less than 1% to 2% of all esophageal cancers are sarcomas or small cell carcinomas[10]. Rarely lymphomas, carcinoids, and melanomas may arise in the esophagus."
"(SCC) Oesophageal squamous cell carcinoma is defined as a squamous neoplasm that invades through the epithelial basement membrane into the lamina propria, submucosa, muscularis propria, or deeper. Variable amounts of keratinization are seen, manifested by cells showing brightly eosinophilic opaque cytoplasm (Fig. 5.3.3A,B). Invasion into the lamina propria begins with the proliferation of rete-like projections of neoplastic squamous epithelium. Both horizontal and vertical spread are observed. Tumours can penetrate vertically through the oesophageal wall and invade the intramural lymphatic channels and veins. "(SCC) The development of oesophageal squamous cell carcinoma is understood to be a multistep process that progresses from normal squamous epithelium to include intraepithelial neoplasia (dysplasia; Fig. 5.3.3C) and culminates in the growth of invasive carcinoma.
— WHO World Cancer Report
(AC) Adenocarcinoma in Barrett oesophagus develops through a progressive sequence of morphologically identifiable premalignant lesions termed “dysplasia”. Dysplasia is diagnosed by the presence and degree of cytological and architectural atypia [22]. Low-grade dysplasia shows pits with relatively preserved architecture, or minimal distortion, containing cells with atypical nuclei limited to the basal portion of the cell cytoplasm. High-grade dysplasia is diagnosed by the presence of marked cytological abnormalities and/or significant architectural complexity of the glands (Fig. 5.3.4A). Cytological abnormalities include nuclear pleomorphism and loss of polarity, irregularity of nuclear contour, and increased nuclear-to-cytoplasmic ratio. Architectural abnormalities of high-grade changes include crypt budding, branching, marked crowding, and, rarely, a cribriform growth pattern.
(AC)"Intramucosal adenocarcinoma (invasion into the lamina propria; T1a) show single cells or small clusters of compact back-to-back glands within the lamina propria, a cribriform or solid pattern of growth with expansion and distortion of the adjacent crypts, and a highly distorted/irregular glandular proliferation not explained by the presence of preexisting glands. The presence of necrosis and/or desmoplasia is evidence in favour of adenocarcinomas as well, although these features are rarely present in carcinomas limited to the mucosa.
(AC)"Oesophageal adenocarcinomas are typically papillary and/or tubular. Most cases are of the intestinal type in the Laurén classification (Fig. 5.3.4B), whereas some are of the diffuse type.
— WHO World Cancer Report
Signs and symptoms[edit]
Risk factors[edit]
The relationship between the development of oesophagogastric junctional cancer and chronic GORD is now well established. The risk associated with GORD is related to Barrett’s metaplasia. There is also a three- to sixfold excess risk among overweight individuals. Obesity predisposes to hiatus hernia and reflux, and hence contributes mechanically to increase risk. However, data from a number of studies demonstrate an effect independent of reflux. Lindblad and colleagues have reported a 67% increase in the risk of oesophageal adenocarcinoma in patients with a body mass index (BMI) >25, and this increases with increasing BMI. This effect was noted irrespective of the presence of reflux symptoms. The increased risk was only found in obese women (BMI >30), whereas in men it was observed in both overweight (BMI 25—29.9) and obese (BMI >30) individuals. The Million Women study confirmed this effect, with 50% of cases of oesophageal adenocarcinoma in postmenopausal women being attributed to obesity. Further evidence is accumulating to support different types of obesity, with the ‘male pattern’ of abdominal obesity (central and retroperitoneal) more likely to be associated with malignant transformation. This acts as a potent source of growth factors, hormones and regulators of the cell cycle, resulting in a predisposition to developing the metabolic syndrome. In the general population the metabolic syndrome occurs in 10—20%, and recent evidence demonstrated that 46% of those with Barrett’s oesophagus and 36% of those with GORD have features of the metabolic syndrome. The factors released by centrally deposited fat may have an effect on the process of metaplasia transforming to dysplasia. The role of Helicobacter pylori infection in the aetiology of oesophago-gastric junctional cancer is evolving. The hypochlorhydria associated with H pylori in association with ammonia production from urea by the bacteria may protect the lower oesophagus by changing the content of the refluxing gastric juice. In countries with an increase in oesophago-gastric junctional cancer, there has been a corresponding decrease in incidence of H pylori infection. Furthermore, community-based approaches to eradicate H pylori infection in the treatment of ulcer and non-ulcer dyspepsia may be inadvertently contributing to the increase in these cancers. Increases in incidence in true cardia (type II) and type III junctional cancers have parallelled the increase in type I cancers, and the natural history appears to be similar. Some consider the inflammation and metaplasia associated with cardia cancer to be caused by H pylori infection despite many cases presenting with re flux. Recently Hansen and colleagues have proposed that cardia cancer has two distinct aetiologies. In a nested case—control study, serum from a defined population cohort followed for the development of gastric cancer was tested for H pylori antibodies and for evidence of atrophic gastritis using as surrogate markers gastrin levels and the pepsinogen I to pepsinogen II ratio. H pylori seropositivity and gastric atrophy were associated with the risk of non-cardia gastric cancer. In cardia cancer there were two distinct groups. In one, serology for H pylori was negative and there was no evidence of gastric atrophy, and in the other H pylori was positive and there was evidence of atrophy. The authors concluded that the former group behaved like non-cardia cancer and were more likely to be diffuse type, and the latter like oesophageal adenocarcinoma and likely to be intestinal type. Such different characteristics would imply a different carcinogenic process at the two sites.
The main risk factors for squamous cell carcinomas (SCCs) in Western countries are smoking and alcohol consumption, whereas adenocarcinomas (ACs) predominantly occur in patients with gastro-oesophageal reflux disease and their risk is correlated with the patient's body-mass index.
(SCC)"Other carcinogens, such as nitrosamines found in certain salted vegetables and preserved fish, have also been implicated in SCC of the esophagus.
(SCC) "Major risk factors include alcohol consumption and tobacco use. Most studies have shown that alcohol is the primary risk factor but smoking in combination with alcohol consumption may have a synergistic effect and increase the relative risk." (Citing US 1994 research:) "The relative risk in men who used both heavy tobacco and alcohol was 35.4 in white males and 149.2 in black males compared to men of the same race and region who were non-smokers or drinkers."
(SCC) "Other carcinogens, such as nitrosamines found in certain salted vegetables and preserved fish, have also been implicated in SCC of the esophagus."
(AC) "Barrett oesophagus has been identified as the single most important precursor lesion and risk factor for oesophageal adenocarcinoma, irrespective of the length of the segment with intestinal metaplasia."
— WHO World Cancer Report
(SCC)"Given that alcohol consumption and tobacco use are the two major known causes of oesophageal squamous cell carcinoma, an Australian study assessed respective population attributable fractions based on 305 cases and 1554 controls. The results were 49% (95% confidence interval [CI], 38–60%) and 32% (95% CI, 25–40%) of oesophageal squamous cell carcinoma cases attributable to smoking and heavy alcohol consumption, respectively. More than 75% of the oesophageal squamous cell carcinoma burden in men could be attributed to smokers with heavy alcohol consumption."
— WHO World Cancer Report
(AC) Another risk factor for EAC is obesity, specifically in those individuals with predominately abdominal centered fat distribution. Hypertrophied adipocytes and inflammatory cells within fat deposits create an environment of low-grade inflammation and promote tumor development through the release of adipokines and cytokines[23]. Adipocytes in the tumor microenvironment supply energy production and support tumor growth and progression[22].
"The biological effects of alcohol intake on the risk of digestive tract cancers are also dependent on the genotype of the consumer; individuals with the ALDH2 Lys487 allele (and therefore a deficiency of ALDH2) experience a higher risk of oesophageal cancer for the same amount of alcohol consumed. The ALDH2 Lys487 allele is thought to modify the risk of all cancers that are caused by the metabolites of alcohol [4,5]."
" Occupational exposures, occupations, industries, and occupational circumstances classified as definite carcinogenic exposures (Group 1) by the IARC Monographs, Volumes 1–106 ... Ionizing radiation (including radon-222 progeny): Thyroid, leukaemia, salivary gland, lung, bone, oesophagus..."
"Significant radiation- associated increases in incidence occurred for multiple cancers, including those of the oral cavity, oesophagus..."
"Naturally occurring organic chemical carcinogens produced by plants that are used as herbal medicines, food, or food additives or contaminants: Dihydrosafrole and safrole (Sassafras, essential oils, spices) - Food additive, food contaminant - Metabolism to DNA-reactive sulfo-oxy metabolites → mutations - Liver, lung, oesophagus"
"Obesity, which results in major metabolic imbalance, increases the risk of several malignancies, including colon, postmenopausal breast, endometrial, kidney, liver, pancreatic, thyroid, and oesophageal cancers."
— WHO World Cancer Report
(AC)"Although familial association has been reported for patients with oesophageal adenocarcinoma, population-based studies show limited influence of familial risk, consistent with the rapid changes in incidence rates observed in many populations over a very short time period."
(AC) "Epidemiological studies have provided convincing evidence that obesity increases the risk of cancers of the oesophagus (adenocarcinoma)"
(AC) "For adenocarcinoma of the oesophagus, the increase in cancer risk probably involves an increase in the prevalence of chronic acid reflux from the stomach into the oesophagus, which damages the oesophageal epithelium."
(AC) Obesity is a strong risk factor for oesophageal adenocarcinoma, as is gastro-oesophageal reflux disease. The trend of increasing incidence rates of oesophageal adenocarcinoma parallels the growing obesity epidemic and the prevalence of gastro-oesophageal reflux disease [15]. However, in a 2012 study in the USA, incidence rates of oesophageal adenocarcinoma were 7-fold higher among White men than among Black men, despite data indicating that the prevalence of obesity is higher among Black men and women than among White men and women."
— WHO World Cancer Report
"Smoking can cause death not only from lung cancer (the main neoplastic hazard) but also from cancer of the mouth, pharynx, larynx, oesophagus..."
"The relationship between alcohol consumption and cancer risk has been known since the beginning of the 20th century. Epidemiological and biological research on the association has established that alcohol consumption causes cancers of the mouth, pharynx, larynx, oesophagus, liver, colorectum, and female breast."
"Tumour types caused by drinking alcoholic beverages include cancers of the oral cavity, pharynx, larynx, oesophagus..."
"These meta-analyses establish that a significant positive dose–response association exists between alcohol consumption and cancers of the mouth, pharynx, oesophagus..."
"When epidemiological criteria were examined for causality [12], the association between alcohol consumption and cancers of the mouth, pharynx, oesophagus, colorectum, liver, larynx, and female breast was found to be causal..."
"Evidence suggests a synergistic effect of tobacco smoking and consumption of alcoholic beverages on the risk of cancer of the oral cavity, pharynx, larynx, and oesophagus, with very high risks observed in individuals who are both heavy drinkers and heavy smokers."
— WHO World Cancer Report
"Chewing tobacco has been proven to cause oesophageal, oral, bladder, and pancreatic cancers."
— WHO World Cancer Report
(SCC) "Alcohol consumption and tobacco smoking and chewing are the strongest risk factors for the development of oesophageal squamous cell carcinoma, although these associations display marked geographical variation. Cessation of smoking substantially reduces the smoking-associated risk. Intake of hot beverages (hot maté in parts of South America; hot tea, hot coffee, or hot soups elsewhere) is similarly associated with risk of oesophageal squamous cell carcinoma, as is ingestion of caustic substances (such as occurs in suicide attempts and in accidental swallowing of household toxins by children). Certain dietary habits (low intake of fresh fruits and vegetables, fresh meat or fish, and dairy products, and high intake of barbecued meats and pickled vegetables, which may result in exposure to N-nitroso compounds) are associated with a high incidence of oesophageal squamous cell carcinoma. Use of opium, poor oral health, and poor nutrition all interact to affect outcome in oesophageal squamous cell carcinoma in high-risk areas. For example, in the Islamic Republic of Iran, opium intake is associated with poor outcome in univariate analysis but not in adjusted models [1]. Other circumstances mediating increased risk include having Plummer–Vinson syndrome (sideropenic dysphagia, including dysphagia due to oesophageal webs, glossitis, and iron-deficiency anaemia, usually in postmenopausal women), coeliac disease, and achalasia. Finally, exposure to ionizing radiation, often from treatment for breast carcinoma, is a risk factor."
— WHO World Cancer Report
Diagnosis of Barrett esophagus can be confirmed by biopsies of the columnar mucosa during an upper endoscopy. According to the requirements set forth by the United States gastroenterology societies, the biopsy specimen should contain the characteristic columnar epithelium metaplasia with goblet cells for a definitive diagnosis.
"Some studies have shown that the risk of adenocarcinoma of the esophagus may be affected by the extent of esophagus lined by esophageal metaplasia[18]. The longer the segment of esophagus affected the higher the risk of adenocarcinoma. However, given the fact that short segment esophageal metaplasia is more common in the general population, many cases of adenocarcinoma occur in patients with short-segment metaplasia. Less than five percent of patients diagnosed with adenocarcinoma of the esophagus had a prior diagnosis of BE[19]. The risk of developing esophageal cancer is 50-100 times more likely in those patients with BE[15]. However, a majority of patients with BE will not develop EAC, the annual risk in patients with BE has been reported as 0.12%."
"The inflammatory response to gastric acid reflux in Barrett disease may be responsible for the increased incidence of oesophageal cancer."
— WHO World Cancer Report
"Barrett oesophagus (BO) is a precursor of oesophageal adenocarcinoma. The magnitude of cancer risk in BO is crucial in determining whether the benefits of screening, surveillance, or treatment of BO outweigh any risks and whether such strategies are cost-effective. The published incidence of malignancy in BO varies widely, from 0 to 35.5 cases per 1000 person-years of risk (pyr) [1]. To date, most studies have been small, and publication bias in favour of studies showing high risks has been demonstrated [2]. Other design issues, such as the inclusion of unrepresentative cohorts of BO patients (e.g. patients from tertiary referral centres), inclusion of those at high risk of progression (e.g. with high-grade dysplasia at baseline), incomplete follow-up of patients, or failure to exclude early incident (most likely prevalent) cancers, have resulted in overestimation of the risks of malignant progression in BO. Differing criteria for diagnosis of BO, for example inclusion of patients without specialized intestinal metaplasia, and differing definitions of malignant progression, for example inclusion/exclusion of incident high-grade dysplasia, have also contributed to the variation in observed rates. The combined risk of oesophageal adenocarcinoma or high-grade dysplasia may provide a better estimate of malignant progression than risk of oesophageal adenocarcinoma alone, although it will overestimate risk as not all patients with high- grade dysplasia would progress to cancer in the absence of therapeutic intervention [3].
"The best estimates of risk of malignant progression in BO are provided by population-based studies with long-term follow-up for a high proportion of patients (excluding those with high-grade dysplasia at baseline) and discounting events occurring soon after diagnosis. Several such studies have recently been published [4–8]. Even in these studies, differing BO definitions, different proportions of patients with low-grade dysplasia at baseline, and differing approaches to, and completeness of, follow-up have resulted in variable estimates of malignant progression. Among patients without low-grade dysplasia at baseline, the incidence of oesophageal adenocarcinoma/high-grade dysplasia ranged from 2.2 per 1000 pyr [4] to 5.2 per 1000 pyr [6,8]; however, the higher estimates were not based on follow-up of all diagnosed cases and may have overestimated risk. Risk of oesophageal adenocarcinoma/high-grade dysplasia was 2–6-fold higher in patients with low-grade dysplasia at baseline than in those without low-grade dysplasia.
"Using currently available data, it is difficult to reach a definite conclusion about the risk of malignant progression in BO, but it is lower than previously thought and, in patients without low- grade dysplasia at baseline, appears to be lower than 5 cases of oesophageal adenocarcinoma/high- grade dysplasia per 1000 pyr.
"A meta-analysis of studies in patients with Barrett oesophagus demonstrated an incidence of progression to adenocarcinoma of about 6.1 per 1000 person-years, which reduced to 3.9 per 1000 person-years when only high-quality studies were considered [18], corresponding to a lifetime risk of about 10% in these patients. However, these results may be overestimations that reflect various types of bias in the studies. More recently, an Irish study reported a rate of 3.8 per 1000 person-years [19], whereas a Danish study showed a considerably lower progression rate of only 0.12% per year [20], although obesity is far less prevalent in the Danish population than in the United States or Irish population (see “Risk of malignant progression in Barrett oesophagus patients”).
"Chronic gastro-oesophageal reflux disease is the usual source of mucosal injury and also provides an abnormal environment during the healing process that predisposes to intestinal metaplasia and adenocarcinoma. In a large Swedish study, individuals with long-standing and severe gastro- oesophageal reflux disease symptoms had a 40-fold increased risk of oesophageal adenocarcinoma [21]. Both experimental and clinical data indicate that combined oesophageal exposure to both gastric acid and duodenal contents (bile acids and pancreatic enzymes) appears to be more carcinogenic than exposure to only gastric juice or duodenal contents. An association between alcohol consumption and oesophageal adenocarcinoma has not been well established. A reduced risk of oesophageal adenocarcinoma is associated with Helicobacter pylori infection, and particularly H. pylori strains with the CagA protein. A protective effect has been suggested after the use of non-steroidal anti- inflammatory drugs, but not all studies have supported such data."
— WHO World Cancer Report
Pathogenisis[edit]
"The mechanism of how tobacco and alcohol in combination lead to increased risk of esophageal cancer has been extensively studied. Alcohol can damage the cellular DNA by decreasing metabolic activity within the cell and therefore reduce detoxification function while promoting oxidation" [Cites a primary Indian study into oral cancer] "Alcohol is a solvent, specifically of fat-soluble compounds. Therefore, the hazardous carcinogens within tobacco are able to penetrate the esophageal epithelium easier[14]. Some of the carcinogens in tobacco include aromatic amines, nitrosamines, polycyclic aromatic hydrocarbons, aldehydes and phenols."
SCC[edit]
(SCC)"The pathogenesis appears to be linked to inflammation of the squamous epithelium that leads to dysplasia and in situ malignant change."
"SCC is the most common type of esophageal cancer worldwide. The overall incidence increases with age, reaching a peak in the seventh decade. SCC occurs equally as often in the middle and lower esophagus, with an incidence that is three times higher in blacks in comparison to whites."
Adenocarcinoma[edit]
"Adenocarcinoma of the esophagus occurs in the distal esophagus approximately three-fourths of the time[16] and has a distinct link to gastroesophageal reflux disease (GERD). Untreated GERD can progress to Barrett’s esophagus (BE), where the stratified squamous epithelium that normally lines the esophagus is replaced by a columnar epithelium. The chronic reflux of gastric acid and bile at the gastroesophageal junction and the subsequent damage to the esophagus has been implicated in the pathogenesis of Barrett metaplasia[17]. The exact nature of the metaplasia still remains to be determined."
Genetics[edit]
"(SCC) Mutation in the TP53 gene is an early event, sometimes detectable in intraepithelial neoplasia. Amplification of cyclin D1 occurs in 20–30% of these tumours. Inactivation of CDKN2A, either by homozygous deletion or by de novo methylation, appears to be associated with advanced disease.
"(SCC) The scope of molecular analyses applicable to all tumour types is indicated from studies identifying alterations in genes, proteins, and microRNAs in oesophageal squamous cell carcinoma, of which 10 or more studies in each category are available. Epigenetic abnormalities are evident from DNA methylation, histone deacetylation, chromatin remodelling, gene imprinting, and non-coding RNA regulation studies [8]. High-throughput genotyping of metastatic tumours has identified phosphatidylinositol 3-kinase (PI3K) and BRAF mutations among the somatic mutations evident [9]. In a separate study, inactivating NOTCH1 mutations were identified in 21% of oesophageal squamous cell carcinomas from the USA but only rarely in such tumours from China.
"Familial predisposition to oesophageal cancer has been studied predominantly in association with focal non-epidermolytic palmoplantar keratoderma (also known as tylosis), a rare condition in industrialized countries (low-risk populations). This autosomal dominant inherited disorder of the palmar and plantar skin surfaces is associated with oesophageal cancer. The causative locus, the tylosis oesophageal cancer (TOC) gene, maps to 17q25, with missense mutations (c.557T → C [p.Ile186Thr] and c.566C → T [p.Pro189Leu]) in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2).
— WHO World Cancer Report
"Tylosis with esophageal cancer: A genetic disorder characterized by thickening (hyperkeratosis) of the palms and soles, white patches in the mouth (oral leukoplakia), and a very high risk of esophageal cancer. This is the only genetic syndrome known to predispose to squamous cell carcinoma of the esophagus. The risk of developing esophageal cancer is 95% by age 70. The syndrome is inherited in an autosomal dominant manner. The gene has been mapped to chromosome 17q25 but has not been identified. The syndrome is also called nonepidermolytic palmoplantar keratoderma. (MedTerms.com)"
(AC) Multiple genetic alterations are involved in the development and progression of Barrett oesophagus to oesophageal adenocarcinoma, encompassing tumour suppressor genes, oncogenes, growth factor receptors, or enzymes that play important roles in diverse cellular functions such as cell-cycle control, apoptosis, cell signalling, cell adhesion and genetic stability, signal transduction, and DNA repair. Gains in the region of 8q (region of c-myc) and 20q, and losses at 3p (FHIT), 4q, 5q (APC) and 18q (SMAD4, DCC) have all been reported, with an increasing number of chromosomal alterations in the sequence from metaplasia to intraepithelial neoplasia to carcinoma. Gene silencing by promoter hypermethylation has been demonstrated frequently for the CDH1 gene (which encodes E-cadherin) and the APC, p16, MGMT, and HPP1 genes. Disorders of ARID are also noted. (AC) "Exome and whole-genome sequencing of 149 and 15 oesophageal adenocarcinomas has been recently reported [23]. A mutational signature was defined by a high prevalence of A → C transversions at AA dinucleotides. Of 26 significantly mutated genes, TP53, CDKN2, SMAD4, ARID4, and PIK3CA had been implicated previously. The new significantly mutated genes included chromatin modifying factors and candidate contributors SPG20, TLR4, ELMO1, and DOCK2 (Fig. 5.3.5). Functional analysis of the relevant mutations in ELMO1 identified increased cellular invasion."
— WHO World Cancer Report
"(AC of esophagus and oesophago-gastric junction) Although familial association has been reported for patients with oesophageal adenocarcinoma, population-based studies show limited influence of familial risk, consistent with the rapid changes in incidence rates observed in many populations over a very short time period. Intestinal metaplasia of the oesophagus develops when the squamous oesophageal epithelium is replaced by columnar epithelium during the process of healing after repetitive injury, typically associated with gastro-oesophageal reflux disease. Intestinal metaplasia can be detected in the majority of patients with oesophageal adenocarcinoma."
— WHO World Cancer Report
(SCC)"Polymorphisms in acetaldehyde dehydrogenase 2 (ALDH2) are key to individual susceptibility to upper aerodigestive tract cancer; patients with inactive ALDH2 are at high risk of oesophageal squamous cell carcinoma [3]. In Asians, polymorphisms in the ALDH gene family are associated with altered risk of oesophageal squamous cell carcinoma. The effects of these polymorphisms are synergistic with alcohol consumption and smoking. In addition, the polymorphisms in ALDH associated with oesophageal carcinoma also result in accumulation of acetaldehyde, which causes flushing upon ingestion of alcohol (the “Asian flush”) in about one third of East Asians (Chinese, Japanese, and Koreans) [4]. Genome-wide association studies in Chinese individuals have identified several susceptibility loci, encompassing 5q11, 6p21, 10q23, 12q24, and 21q22 and including genes related to those encoding ALDH and thereby linked to the association between alcohol consumption and oesophageal squamous cell carcinoma in both Chinese and Japanese people."
— WHO World Cancer Report
Protective factors[edit]
Diagnosis[edit]
(UK/Ireland)
Symptomatic presentation
The UK Department of Health has specified the‘at risk’symptoms for oesophago-gastric cancer which guide referral of patients for investigation and recommends urgent investigation to be performed within 2 weeks of referral. In the Department of Health guide patients with new-onset dyspepsia are recommended urgent referral for gastroscopy only if they are over 55 years. However, early referral for more patients even with minimal symptoms should be considered because clinical diagnosis is often inaccurate and early tumours will not be associated with typical symptoms. Approximately 70% of patients with early gastric cancer (EGC) have symptoms of uncomplicated dyspepsia with no associated anaemia, dysphagia or weight loss. It has recently been demonstrated that use of alarm symptoms to select patients for endoscopy causes patients with localised disease to be overlooked. Clinical diagnosis is very inaccurate in distinguishing between organic and nonorganic disease and therefore all patients deemed to be ‘at risk’ patients with dyspepsia should be considered for endoscopy even though the overall detection rate is only 1—3%. In summary, patients with dyspepsia who are older than 55 years of age with persistent new-onset symptoms or those with alarm features at any age should undergo an endoscopy. An endoscopy with biopsies should be considered for patients in whom there is a clinical suspicion of malignancy even in the absence of alarm features.Endoscopy
Video endoscopy and endoscopic biopsy remain the investigations of choice for diagnosis of oesophageal and gastric cancer performed by an experienced endoscopist, trained according to the Guidelines of the Joint Advisory Group on Gastrointestinal Endoscopy. It is recommended that endoscopy reporting should be in a standard manner detailing descriptions, dimensions and locations of lesions in relation to anatomical landmarks. Failure to diagnose UGI malignancy at the patient’s first endoscopy is consistently in the range of 10%, while a further 10—20% require a second gastroscopy. The principal factors associated with the need to re-endoscope are failure to suspect malignancy and (as a consequence) failure to take adequate numbers of biopsies. In oesophageal endoscopic examination the diagnostic yield to detect high risk premalignant lesions in Barrett’s reaches 100% when six or more samples are obtained using standard biopsy forceps. Multiple four quadrant biopsies of the oesophagus at 2 cm intervals along its entire length have been shown to increase diagnostic accuracy and allow differentiation of high grade dysplasia from adenocarcinoma, particularly when endoscopic mucosal abnormalities are present. Whether or not the index endoscopy should be done on or off proton pump inhibitor (PPI) therapy is controversial. Inflammation can confound the diagnosis of dysplasia, whereas one retrospective study suggested that PPIs may mask endoscopic findings. However, treatment with a PPI may also delay diagnosis or result in a misdiagnosis on first endoscopy. In particular the ability of PPIs to‘heal’ malignant ulcers or alter their appearance has not been fully appreciated. Overall, PPIs should be stopped for the first endoscopy. For subsequent endoscopies in patients known to have Barrett’s oesophagus, continuing treatment can decrease inflammation, making targeted biopsies and histological assessment easier. If the lumen is obstructed by tumour then an ultrathin endoscope (OD, 5.3—6 mm) should be used. Oesophageal dilatation for the purposes of diagnosis should be avoided due to the high risk of perforation which may deny these patients a chance of cure.Endoscopic adjuncts
Chromoendoscopy and high resolution endoscopy have been introduced in selected centres although their role has yet to be defined. Contrast enhancing and vital dyes sprayed onto the oesophago-gastric mucosa can aid in the detection of early lesions. The most well established are Lugol’s iodine for dysplastic and malignant squamous mucosa and indigo carmine for early cancer in gastric mucosa. Acetic acid chromoendoscopy enhances detection of occult neoplasia in Barrett’s. Currently, these techniques are only recommended in selected patients deemed at high risk. Furthermore, with the advent of new endoscopic modalities such as narrow band imaging and autofluorescence and with the development of magnifying (zoom) and confocal endoscopes, these techniques may be superseded. However it should be emphasised that there are no randomised data to indicate that these modern techniques are as good as conventional histopathology let alone suitable to replace it. There is increasing interest in ultrathin nasal endoscopy and non-endoscopic approaches which have the potential to be used in the outpatient setting with increased patient acceptability.Higher risk groups
Individuals at increased risk of oesophago-gastric cancer on the basis of family history (tylosis) or a premalignant condition (Barrett’s oesophagus, pernicious anaemia, intestinal metaplasia of the stomach or previous gastric surgery) may be considered for endoscopic monitoring. These decisions are complex and should be determined by balancing the magnitude of the benefits against the perceived clinical risks of the procedure and patient preferences. Patients with a family history of gastric cancer should be assessed to determine the risk of hereditary diffuse gastric cancer and referred for management at appropriate centres. The principal condition for which endoscopic surveillance may be recommended in the UK is for diagnosed Barrett’s oesophagus. Currently there are not any recommendations to screen individuals with reflux for the presence of Barrett’s oesophagus in the primary care population. However, in the annual report of the Chief Medical Officer published in 2008, minimally invasive screening tests were put high on the research agenda due to the worrying increase in the incidence of oesophageal adenocarcinoma. The recent report of spoge cytology to select for endoscopy is a novel and encouraging approach.
(UK/Ireland)
- All patients with recent-onset ‘dyspepsia’ over the age of 55 years and all patients with alarm symptoms (whatever their age) should be referred for rapid access endoscopy with biopsy
- A minimum of six biopsies should be taken to achieve a diagnosis of malignancy in areas of oesophageal or gastric mucosal abnormality
- Endoscopic findings of benign stricturing or oesophagitis should be confirmed with biopsy
- Patients diagnosed with high grade dysplasia should be referred to an UGI MDT (upper gastrointestinal multidisciplinary team) for further investigation
- High resolution endoscopy, chromoendoscopy, spectroscopy, narrow band imaging and autofluorescence imaging are under evaluation and their roles are not yet (2011) defined
(UK/Ireland)
"Diagnosis of high grade dysplasia in the oesophagus and stomach should be made and confirmed by two histopathologists, one with a special interest in gastrointestinal disease
(Europe)
"The diagnosis should be made from an endoscopic biopsy with the histology to be classified according to the World Health Organization criteria. Small cell carcinomas, which are very uncommon, must be identified and separated from SCCs and ACs and be treated accordingly."
"Routes of esophageal cancer spread"[edit]
"Esophageal cancer is notoriously aggressive in nature, spreading by a variety of pathways including direct extension, lymphatic spread and hematogenous metastasis. The lack of serosa in the esophageal wall plays an integral role in the local extension of esophageal cancer. With no anatomical barrier, the primary tumor is able to extend rapidly into the adjacent structures of the neck and thorax including the thyroid gland, trachea, larynx, lung, pericardium, aorta and diaphragm[25]. The lymphatic drainage of the esophagus is extensive. It is drained by two separate lymphatic plexuses, with one lymphatic plexus arising within the mucosal layer and a second plexus arising within the muscular layer. A majority of the lymphatic fluid from the upper two-thirds of the esophagus tends to flow upward, and the lymph from the lower third of the esophagus flows relatively downward, but all the lymphatic channels of the esophagus communicate. Therefore, lymphatic fluid from any portion of the esophagus may spread in either direction and spread to the intrathorax or intra-abdomenal lymph nodes[26]. Esophageal cancer also spreads hematogenously,, in order of decreasing frequency, to the liver, lungs, bones, adrenal glands, kidney and brain. This method of spread is more common with more advanced stages of esophageal cancer."
Metastasis[edit]
Pathology[edit]
(UK/Ireland)
The RCPath and the Pathology Section of the British Society of Gastroenterology strongly advocate that there should be standardisation of reporting guidelines of all cancers. Such an approach is intended to provide both the patient and clinican with prognostic information, allowing the clinician to determine the most appropriate clinical management and facilitate audit of diagnostic and therapeutic interventions.
- Process
The RCPath Guidelines recommend approaches to the practical handling of biopsies and endoscopic and surgically resected specimens. Histopathologists are advised to ensure all pathological material from patients referred to the MDT is reviewed and correlated with clinical and radiological information. In addition specimens of squamous and glandular dysplasia and high grade dysaplasia and early cancer in Barett’s metaplasia should be reported by two independent, named expert pathologists.
- Referral for review or specialist opinion
- Referral for treatment
All patients referred for specialist treatment must be reviewed and discussed by the MDT. The complete diagnostic pathology report must be available and the histological and/or cytological material should be reviewed prior to, and at, the meeting. This is particularly important if there is a significant discrepancy with the clinical/radiological findings. A formal report should be issued by the reviewing pathologist to the clinician or pathologist initiating the referral. Where patients have been referred for non-surgical oncology treatment, requests for specialist biomarker studies will be coordinated between the treating oncology service, their local pathology service and the referring hospital’s pathology service, as appropriate.
- Referral for specialist opinion
In cases of diagnostic difficulty, referral will be made to the Lead Pathologist of the specialist MDT, although referral to other specialists within or outside the network may be appropriate in individual cases. Cases referred for individual specialist or second opinion will be dealt with by the individual pathologist and a report issued by them. Where relevant, tissue blocks should be made available to allow any further investigations that are deemed appropriate. It is strongly recommended that slides and blocks are not posted together: if they are, then there is a danger that the entire specimen is lost for ever. All diagnostic material should be reviewed and presented at the MDT meeting so that the individual case can be discussed with full knowledge of all relevant pathological findings. External diagnoses of dysplasia, especially when further treatment is being considered (such as radical surgery, EMR, ESD or ablation therapy), should also be reviewed at an MDT meeting and the diagnosis confirmed by at least two gastrointestinal pathologists. More unusual tumours (such as lymphoma, melanoma, endocrine tumours, small cell carcinoma or gastrointestinal stromal tumour (GIST)) should be reviewed in the course of the MDT meeting.
- Data sets for reporting
The data sets have been subdivided into core and non-core data. Core data are the suggested minimum requirement for appropriate patient management, such data having been shown to be of prognostic significance. Non-core data are additional data that do not have a sufficient basis in published evidence to be a requirement, but may be of potential interest and use in patient management. The data items required for diagnostic biopsies, endoscopic resection specimens and therapeutic resections are shown in table 1. Specimen photography is invaluable in recording the macroscopic appearances of pathological specimens and aids with radiological audit. Photography should include the undissected specimen to demonstrate margins and potential defects in margins, and also the entire sliced specimen to demonstrate the quality of surgery and the extent of depth of spread of the tumour. In both oesophageal and gastric cancer, the end resection margins are also very important and should be sampled in all cases. Submucosal lymphovascular spread, in particular, can result in involvement of margins, particularly of the proximal oesophageal margin at a very considerable distance from the primary tumour. For circumferential margin assessment, there is little value in attempting to measure the distance from the tumour to the circumferential margin if there has been previous surgical dissection of the specimen for perioesophageal lymph nodes; therefore, it is recommended that all oesophagectomy specimens are left entirely in situ after surgical removal to allow the pathologist to assess circumferential resection margins accurately. The data set items may be reported in a proforma either within or instead of the free text part of the pathology report, or recorded as a separate proforma. In general the recording of both free text report and of all items in the RCPath data sets is recommended, the latter in a structured way, either directly onto such a proforma or alternatively using the same structure on the pathology report. Trusts and MDTs should work towards recording and storing the data set items as individually categorised items in a relational database, so as to allow electronic retrieval and to facilitate the use of pathology data in clinical audit, service planning and monitoring, research and quality assurance. It is anticipated that such data recording will become a requirement as part of recommendations of the UK National Cancer Intelligence Network.
Laboratories should use an agreed diagnostic coding system (eg, SNOMED). All malignancies should be reported to the local Cancer Registry.
- Grading conventions
Riddell-type classifications are recommended for the grading of all dysplasia in the UGI tract. The Revised Vienna classification of gastrointestinal epithelial neoplasia can be used but this system has not found particular favour in the UK. The WHO invasive carcinoma grade system is recommended for tumour grading.
- Staging conventions
The RCPath Guidelines have been based on the TNM 5th/6th editions. There were, however, discrepancies between the two editions and, as a result, the guidelines recommended TNM 6 for oesophageal cancer and TNM 5 for gastric cancer. However, pathological staging of oesophago-gastric junctional cancer was not defined. The Siewert classification was recommended, although this largely describes clinical features. For practical purposes, the guidelines recommended that if >50% of the tumour involved the oesophagus the tumour should be classified as oesophageal, if <50% as gastric. Tumours exactly at the junction should be classified according to their histology, so squamous cell, small cell and undifferentiated carcinomas should be oesophageal and adenocarcinomas should be gastric.
In 2009 the Union for International Cancer Control in collaboration with the American Joint Committee on Cancer published TNM 7th edition which has significantly changed the staging descriptions. The issue of oesophagogastric junctional cancer has disappeared. Tumours including the oesophagus and within 5 cm of the oesophago-gastric junction are classified
as oesophageal cancers and all others are gastric cancer. The T stage has now become consistent with T2 and T3 tumours defined for both sites; the previous T2a and T2b subgroups in gastric cancer have been removed. Nodal staging for both oesophageal and gastric cancers has been unfied with N0, N1, N2 and N3 subgroups. This revision has created significant concerns particularly as historical comparisons will now be more difficult. The RCPath has recently recommended that TNM 7 should be adopted in the UK. This will take some time to implement and the effect on practice is likely to evolve. The current consensus is that TNM 7 will become the standard for staging, but the clinical classification will continue with the Siewert system as this will influence the selection of surgical procedure. The effect on clinical trials, however, is more difficult to predict as the current large trials are based on TNM 5 and 6 criteria.
Staging[edit]
(UK/Ireland)
- Staging investigations for UGI cancer should be co-ordinated within an agreed pathway led by a UGI MDT
- Initial staging should be performed with a CT including multiplanar reconstructions of the thorax, abdomen and pelvis to determine the presence of metastatic disease
- Further staging with endoscopic ultrasound in oesophageal, oesophago-gastric junctional tumours and selected gastric cancers is recommended, but it is not helpful for the detailed staging of mucosal disease
- For T1 oesophageal tumours or nodularity in high grade dysplasia, staging by endoscopic resection should be used to define depth of invasion
- Positron emission tomography (PET)-CT scanning should be used in combination with endoscopic ultrasound (EUS) and CT for assessment of oesophageal and oesophago-gastric junctional cancer
- Laparoscopy should be undertaken in all gastric cancers and in selected patients with lower oesophageal and oesophago-gastric junctional tumours
(UK/Ireland)
Advances in therapeutic techniques including the use of multimodality treatment regimens require accurate initial staging and assessment of treatment response. Imaging techniques should provide staging assessment according to the TNM classification.
Since up to 50% of patients present with metastatic disease, initial assessment must establish the presence or absence of distant disease. Precise local staging is required to determine the depth of tumour spread in early tumours which may be amenable to endoscopic resection. In more advanced tumours accurate local staging should include depth of invasion with reference to surgical margins with clear delineation of cranio-caudal and radial margins and presence and extent of lymph node metastasis to determine the likelihood of regional control.
The principal imaging modalities for staging are multidetector CT (MDCT), EUS and PET integrated with CT (PET-CT). Although MDCT has been the initial modality to exclude gross metastatic disease, all three techniques should be used in combination to provide comprehensive staging detail.
- Technique
- Endoscopy
Endoscopy and EMR is an essential method to stage early neoplasia. It is indicated for the assessment of areas of Barrett’s with dysplasia and nodularity where invasive disease is suspected. The depth of resection is usually into the submuosa. In a comparative study Wani and colleagues found submucosa in 88% of EMR samples compared with 1% of biopsy samples, and the overall interobserver agreement for the diagnosis of neoplasia was significantly greater for EMR specimens than biopsy specimens. It allows assessment not only of depth of penetration but also of degree of differentiation and vascular and lymphatic involvement. It is superior to EUS in staging early T1 cancers.
- CT scanning
MDCT images of the chest, abdomen and pelvis are acquired at fine collimation enabling multiplanar reformats to be performed with the same resolution as axial images (slice thickness should be 2.5—5 mm). The studies should be performed after intravenous contrast unless contraindicated. One litre of water can be used as an oral contrast agent. It is optimal to give ~200 ml just prior to the scan for oesophageal cancer and 400 ml for gastric cancer. Antiperistaltic agents together with gas-forming granules can be administered prior to scanning to achieve maximum distension, although generally sufficient distension is achieved from using water alone. Tumours in dependent areas such as at the oesophago-gastric junction can be imaged prone or in the decubitus position. The use of multiplanar reformat images in addition to axial images improves the accuracy particularly for T3 versus T4 disease, due to the ability to evaluate possible invasion of tumour into its surrounding structures in multiple planes. MDCT also allows for volumetric analysis, so-called ‘virtual endoscopy’. Some recent experimental studies in small patient cohorts have shown an additional benefit of using the virtual endoscopy images together with conventional axial images. The three dimensional (3D) endoscopic view improves radiological detection of early tumours which manifest as shallow ulcers, not detected on the axial images.
- Endoscopic ultrasound
EUS should be performed by experienced endosonographers utilising the full range of modern radial and linear equipment. Outcome is experience related. Centres should perform at least 100 staging examinations annually, and each centre should have at least one fully trained endosonographer. EUS examination may be limited by stricture formation. Dilatation has a high risk of perforation. Options to assess strictured cancers include the blind tapered probe which improves the percentage of traversable tumours or the miniprobe in combination with guidewire placement under radiological screening. Nodal metastases are suggested by four echo pattern characteristics:
- size >10 mm;
- well-defined boundary;
- homogeneously low echogenicity; and
- rounded shape.
All four may only be present in 25% of cases thus significantly reducing sensitivity. EUS fine needle aspiration (FNA) cytology of potential nodal disease has been shown to improve accuracy. At least three passes with the EUS-guided FNA needle are recommended to maximise sensitivity. Although EUS alone is not suitable for M staging, combination with FNA is an accurate and safe method for assessment of solid lesions such as adrenal or liver metastases or for aspiration of ascites.
- PET and PET-CT scanning
The combination of metabolic assessment with 2-[18F] fluoro-2-deoxy-D-glucose (18F-FDG) PET and integrated CT provides both functional and anatomical data. The key advantage of the technique is that patient position is unchanged between each procedure and this allows for reliable co-registration of the PET and the CT data. Several technical issues remain to be evaluated such as the use of iodinated contrast media, CT technique, and optimal FDG dose and uptake period.
- T staging
EMR is the preferred approach for assessing mucosal and submucosal penetration in small early (T1) cancers. EUS is more accurate for T staging in more advanced lesions because of the precise visualisation of the separate layers of the oesophageal and gastric wall. MDCT is limited for early stage disease. Similarly, studies with PET-CT have reported failure to detect early stages (T1 and T2) and poorly cellular mucinous tumours. In addition, smooth muscle activity and GORD may artefactually produce false-positive results. In gastric cancer, tumour site, size and histological type affect FDG-PET detection. Distal tumours, T1 and T2 tumours, and diffuse-type cancers show consistently low rates of detection.
- N staging
The assessment of nodal disease by each technique is variable according to the anatomical relationship of lymph nodes to the primary tumour. EUS (alone or in combination with CT) has a sensitivity of 91% for detecting local nodal disease. Although PET-CT can identify local nodes, avid uptake by the adjacent tumour can obscure uptake by small volume metastatic nodes. For regional and distant nodal disease, PET-CT has been shown to have a similar or better accuracy than conventional EUS-CT (sensitivity and specificity 46% and 98% vs 43% and 90%, respectively; sensitivity and specificity 77% and 90% vs 46% and 69%, respectively). Thus a combined approach with CT, EUS and PET-CT has the highest possible yield for accurately assessing nodal status.
- M staging
Conventional imaging with EUS and CT has a wide range of accuracy for detecting metastatic disease (sensitivity 37—46%, specificity 63—80%). The addition of PET has significantly improved detection rates (sensitivity 69—78%, specificity 82—88%), and this is particularly advantageous for identifying unsuspected metastatic disease which is present in up to 30% of patients at presentation. The American College of Surgical Oncology Group trial of PET to identify unsuspected metastatic disease has demonstrated some limitations, with 3.7% false-positive and 5% false-negative rates. PET has similar limitations to CT in detecting peritoneal disease possibly due to lesion sizes of <5 mm and a low viable cancer cell to fibrosis ratio. The most recent studies with PET-CT have shown superior accuracy over PET and CT performed separately, particularly in the neck, locoregional nodes and in postoperative fields. Further evaluation (including surgical excision or biopsy) of PET/CT-positive unusual nodes or single ‘hot spots’ is recommended because of the potential risk of false positives.
- Laparoscopy
Laparoscopy is established for direct visualisation of low volume peritoneal and hepatic metastases as well as assessing local spread for operability, particularly in gastric cancer. de Graaf and colleagues have reported additional treatment information from laparoscopy in 17.1% of distal oesophageal and 17.2% of oeso-phago-gastric junctional tumours, as well as 28% of gastric cancers. The addition of peritoneal cytology has been debated, with regard to whether positive cytology in the presence of operable gastric cancer with subserosal or serosal invasion would change surgical planning. Nath and colleagues have recently shown that patients with oesophageal and junctional cancers with positive peritoneal cytology have a poor prognosis, with a median survival of 13 (range 3.1—22.9) months. The authors concluded that such patients should not proceed to radical surgery and be considered for palliative intervention.
- MRI
There is no clear evidence that MRI offers any advantage over CT and EUS in the local staging of oesophageal or gastric cancer. The majority of studies to date have used either low field strength magnets or ex vivo analysis. There has been some recent development using a high resolution technique with an external surface coil for local staging of oesophageal cancer which shows promise, although the work requires substantiating in a larger clinical series. MRI is also useful in the characterisation of indeterminate liver lesions detected on CT.
- Bronchoscopy
Tumours at or above the level of the carina may invade the tracheobronchial tree, and this can be assessed with bronchoscopy and biopsy if indicated. In experienced hands, EUS alone may be sufficiently accurate to exclude airway invasion, but if there is uncertainly a bronchoscopy should be performed. This may be supplemented with endobronchial ultrasound in combination, if appropriate, with guided aspiration for cytology of mediastinal nodes.
Table: TNM staging specifically referring to depth of invasionin T staging
Table: Aspect of staging
The clinical staging of esophageal cancer is assessed with the widely accepted TNM system developed by the American Joint Committee on Cancer (AJCC). Pretreatment staging of esophageal cancer will directly affect overall treatment options available to each patient and their prognosis, so accurate staging is essential.
T staging of esophageal cancer focuses on identifying the depth of invasion of the primary tumor. A critical aspect of T staging focuses on establishing if the primary tumor has invaded the surrounding mediastinal structures, given that these patients would no longer be considered surgical candidates. Table Table11 describes the TNM system, specifically referring to depth of invasion in T staging[28]. This aspect of staging is essential in determining stage-specific protocols for treatment (Table (Table22[28]). For example, for T3 or T4 tumors the oncology team will use preoperative chemotherapy or combination radiation and chemotherapy in order to render the primary tumor resectable by surgical excision. In contrast, T1 or T2 tumors are treated primarily with surgical resection[29]. Given the importance of T Staging in treatment options and overall prognosis, many modalities have been utilized to accurately establish T Stage. These options include computer tomography (CT), endoscopic ultrasound (EUS) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET scan)[30].
T stage
When assessing the esophagus by CT, a basic starting point to consider is the esophageal wall thickness. A wall thickness greater than 5mm is considered abnormally thick[31] given that the distended wall of the esophagus is usually less than 3 mm[32]. Esophageal wall thickness asymmetry is a classic but nonspecific CT finding of esophageal cancer and esophageal wall thickness symmetry should always be considered when evaluating the esophagus by CT. CT has been shown to be less accurate when compared to other assessment modalities such as EUS[33]. CT assessment of the esophagus is also unable to accurately differentiate between T1, T2 and T3 stages of the primary tumor invasion. This information is essential in order to guide stage-specific protocols of treatment. The most useful aspect of CT imaging in determination of T status is evaluating if the primary tumor invades into adjacent structures. Obliteration of the fat planes between the primary tumor and the adjacent structures on CT would establish the primary tumor as a T4 stage cancer. The sensitivity and specificity of CT to detect mediastinal invasion ranges between 85%-100%[34,35]. It should be noted that while obliteration of the fat planes between the primary esophageal tumor and adjacent structures is usually reliable in the establishment of a T4 stage tumor, it can occur in patients with prior radiation therapy or cachectic patients.
EUS is now considered the most accurate imagining modality available to establish T staging of esophageal cancer. In comparison to CT, EUS is more accurate to differentiate between T1, T2 and T3 tumors[36]. In comparing the two imaging modalities, EUS was able to determine the preoperative T stage 76%-89% in comparison to 49%-59% when CT imaging was utilized[37-39]. This differentiation is essential in guiding stage-specific treatment protocols and the overall prognosis. Overall in a study conducted by Rösch[40], EUS was able to correctly stage esophageal cancer 84% of the time, and the accuracy improved as the T stage of the primary tumor increased. Accuracy ranged from 75%-82% for the T1 disease state to 88%-100% for the T4 disease state[41]. EUS is a useful tool in assessing the extent of disease as well as response to chemotherapy, when the dimensions of the tumor are analyzed as the primary variable. However, EUS is unreliable for staging esophageal cancer after neoadjuvant chemoradiation[42]. Other potential limitations of EUS do exist. With any form of ultrasound the accuracy of the study is operator dependent. Also, in cases of esophageal cancer where the esophageal lumen has been narrowed by strictures or stenosis, it may not be possible to pass the endoscope through to visualize the entire tumor[30].
N stage
In esophageal cancer, N Staging can be defined by the involvement (N1) or absence of involvement (N0) of periesophageal lymph nodes. Sensitivity and specificity of CT scans to detect periesophageal lymph node involvement depends on the size of the lymph nodes. Most studies, used the common size criteria of 1 cm to define a lymph node as enlarged. Sensitivity was reported as 30%-60% while specificity was 60%-80%[43]. An obvious limitation of CT imaging in the ability to detect nodal involvement, comes from the possibility that a normal sized lymph node may contain metastatic foci without an obvious increase in the size of the lymph node. Also, an enlarged lymph node does not necessarily mean metastasis, given that benign enlargement and inflammation may occur[43]. Accuracy to detect N stage by CT imaging was reported as 46%-58%[39].
EUS has been shown to be more accurate in determining nodal involvement in esophageal cancer, with an accuracy of 72%-80%[44]. Accuracy has increased greatly with the use of EUS in combination with United States guided fine-needle aspiration to evaluate for lymph node metastasis.
FDG-PET has also been utilized in determining nodal involvement in esophageal cancer. Assessment of local and regional lymph nodes for uptake of FDG is difficult to determine given the intense uptake of FDG by the primary esophageal tumor. However, PET is quite useful in detecting distant metastasis, including metastasis to the abdomen and cervical lymph nodes. Sensitivities were reported as high as 90% in distant lymph node metastasis[45].
M stage
Esophageal cancer is notoriously aggressive and invasive in nature. In fact 20%-30% of patients with esophageal cancer will have distant metastasis at time of initial diagnosis[27]. The presence or absence of distant metastasis will be essential in guiding treatment options and in determining operability. Common sites of distant metastasis include liver, lung and bones[30].
In the classification system of metastasis set forth by the AJCC, distant metastasis can be subdivided into M1a and M1b. Each of these classifications is crucial in determining possible treatment options. M1a includes metastasis to celiac and cervical lymph node groups. This classification is associated with a better prognosis compared to M1b. Patients classified as M1a often times complete a course of neoadjuvant therapy followed by surgical resection. Patients with M1b include those with distant site metastasis. This classification usually carries a worse prognosis given that surgical resection with curative intent is not indicated in these cases[46].
CT is the most commonly used imaging modality to rule out distant metastasis in patients with esophageal cancer. The most common areas of distant metastasis can be quickly assessed using contrast-enhanced CT. Sensitivity for spiral CT to detect masses ≥ 1 cm has been reported as high as 90%[47].
EUS is limited in its ability to assess for distant metastasis. In general, CT or FDG-PET is preferred over endoscopic United States for M staging of esophageal cancer.
FDG PET most distinct role in esophageal cancer staging is in the detection of distant metastasis. In comparison to CT, PET has been shown to be more accurate in detecting distant metastasis[48]. One study showed that PET was able to detect distant metastasis 15% of the time in patients that were believed to only have primary esophageal cancer by other imaging modalities[49]. If present, distant metastasis places the patient in M1b category and surgery with curative intent is no longer recommended. Accurate M staging is imperative in guiding treatment options.
Esophageal cancer is staged according to the widely accepted TNM system. Staging plays an integral part in guiding stage specific treatment protocols and has a great impact on overall survival. Common imaging modalities used in staging include computed tomography, endoscopic ultrasound and positron emission tomography scans.
(Europe)
Since therapeutic strategy is based on clinical staging, all efforts should be made to assess the optimal pre-therapeutic tumour stage.
Staging should include clinical examination, blood count, liver-, pulmonary- and renal function tests, endoscopy (including upper-aerodigestive tract endoscopy in case of tumours at or above the tracheal bifurcation), and a computed tomography (CT) scan of chest and abdomen. In candidates for surgical resection endoscopic ultrasound and positron emission tomography (PET)-CT should be added in order to evaluate the T- and N-category of the tumour. Nevertheless, the accuracy of clinical N-staging does not exceed 80%.
Moreover, PET (or PET-CT) may be helpful in identifying otherwise undetected distant metastases [II, B].
In locally advanced (T3/T4) ACs of the oesophago-gastric junction (OGJ) infiltrating the anatomic cardia, laparoscopy can be added to rule out peritoneal metastases which are found in about 15% of patients [III, B]. With this procedure, the sensitivity for detecting peritoneal metastases was 70% compared with about 15% with ultrasound or CT scan.
For selection of local treatments, tumours should be ascribed to the cervical or intrathoracic oesophagus or to the OGJ [IV, C].
The stage is to be given according to the American Joint Cancer Committee (AJCC)/Union for International Cancer Control (UICC) TNM system with corresponding stage grouping (7th edition) (Table 1) [3]. Of note, lymph node metastases in the region of the coeliac trunk and in para-oesophageal nodes in the neck are now defined as regional metastases.
Staging table
Management/treatment[edit]
(UK/Ireland)
"Treatment recommendations should be undertaken in the context of a UGI MDT taking into account patient co-morbidities, nutritional status, patient preferences and staging information. Recommendations made by the MDT should be discussed with patients within the context of a shared decision-making consultation."
Current treatment options include multimodality therapy mainstays of current treatment include surgery, radiation and chemotherapy. (sic)
"Both types (AC & SCC) are successfully managed by mucosal ablation strategies if patients present with early- stage lesions, whereas chemoradiation treatment offers limited but slowly improving success in patients presenting with late-stage lesions."
— WHO World Cancer Report
Principles of treatment[edit]
(Europe)
Upfront interdisciplinary planning of the treatment is mandatory. The main factors for selecting primary therapy are tumour stage and location, histological type and the medical condition, as well as considerations from patients. Independent prognostic factors for long-term survival comprise N/T category and grading for AC as well as N/T category and localisation for SCC [4].
Surgery alone is regarded as standard treatment only in carefully selected operable patients with localised SCC (T1-2 N0-3 M0) [II, B].
Transthoracic oesophagectomy with two-field lymph node dissection and a gastric tube anastomosed in the left neck (supra-bifurcal tumours) or in the upper thorax is recommended [5] for intrathoracic SCC [III, B]. Minimally invasive techniques have been introduced to reduce post-operative complication rates and recovery times. Debates continue as to whether these challenging techniques decrease morbidity and whether the oncological outcome is compromised. Part of this answer is given in a recent randomised trial [6], showing a threefold decrease in post-operative pulmonary infection rate after totally mini-invasive oesophagectomy compared with open transthoracic surgery. Open surgery remains the standard of care. No standard surgical treatment can be identified for carcinomas of the cervical oesophagus.
The extent of surgery in ACs is still a matter of debate. One randomised study showed a non-significant improvement in long-term survival for extended transthoracic compared with transhiatal resection [7], but this benefit appears to be restricted to patients with AC of the lower oesophagus (type I according to Siewert classification) [8].
Preoperative or post-operative radiation alone (without chemotherapy) does not add any survival benefit to surgery alone [9]. This treatment is not recommended for curative intent in localised tumours [I, A].
Evidence for clinical benefit from preoperative chemotherapy exists for all types of oesophageal cancer, though it is stronger for AC. Patients with AC of the lower oesophagus/OGJ should be managed with pre- and post-operative chemotherapy (or chemoradiation)[10–12] [I, B].
A couple of meta-analyses and two recent phase III trials [13–16] suggested that preoperative chemoradiation confers a survival benefit [I, B], and it appears that patients benefit with increased tumour down-staging from preoperative chemoradiation [III, B]. Of note, post-operative mortality may be increased.
Data on adjuvant chemo(radio)therapy is limited, except for lower oesophageal/OGJ AC after limited surgery (lymph node dissection D1 and less). Therefore, adjuvant therapy is not recommended.
Selected unfit patients with localised tumours not considered for surgery can be treated with (also) curative intent with combined chemoradiation [16–18]. Otherwise, principles of palliative therapy are recommended for these patients (see treatment of metastatic disease).
Pre-treatment assessment[edit]
(UK/Ireland)
The aim of preoperative co-morbidity assessment is to provide the opportunity of optimising the patient’s physiological status to undergo potentially curative treatment (including surgery or definitive chemoradiotherapy). There are a number of established risk predictors, but there is a lack of consensus on the selection criteria for patients undergoing gastric and oesophageal resection or radical chemoradiotherapy or radiotherapy alone.
- Exercise testing
Poor exercise tolerance correlates with an increased risk of perioperative complications which are independent of age and other patient characteristics. Although exercise capacity is a subjective estimation it can be a useful measure of functional cardiorespiratory reserve. Any patient who remains asymptomatic after climbing several flights of stairs, walking up a steep hill, running a short distance, cycling, swimming or performing heavy physical activity should tolerate UGI surgery. However, it is important to appreciate that an apparent ability to perform these activities does not exclude cardiorespiratory disease and, indeed, this is a major criticism of exercise testing performed in the absence of cardiopulmonary monitoring. Malnourished patients will also exhibit a reduced exercise tolerance. The true value of preoperative exercise testing currently remains debatable. In the absence of accepted evidence-based data, and the lack of an agreed protocol, exercise testing for UGI cancer surgery patients remains an area worthy of consideration and evaluation but should not be used as a sole criterion for denying someone an operation.
Stair climbing
Patients with poor exercise tolerance, defined as an inability to climb two flights of stairs without stopping, have more co-morbidity, higher ASA (American Society of Anesthesiologists) scores and postoperative complications. Although this test is a subjective assessment, there is some evidence that where this is not possible there is an almost 90% chance of developing postoperative cardiorespiratory complications. Desaturation during exercises equivalent to climbing three flights of stairs, suggesting an inability to meet the increased metabolic demands of exercise, appears to have some predictive power as regards postoperative complications in patients undergoing lung reduction surgery. Exercise-induced hypotension, possibly indicating ventricular impairment secondary to coronary artery disease, is an ominous sign and must be further investigated.Cardiopulmonary exercise (CPX) testing
CPX testing is a dynamic non-invasive objective test that evaluates the ability of the cardiorespiratory system to adapt to a sudden increase in oxygen demand. The ramped exercise test is performed on a cycle ergometer with ECG monitoring and analysis of expired carbon dioxide and oxygen consumption, the latter being directly related to oxygen delivery and a linear function of cardiac output when exercising. A 24% incidence of previously undetected and ‘silent’ ischaemic heart disease has been reported during CPX testing. With increasing exercise, oxygen consumption will eventually exceed oxygen delivery. Aerobic metabolism becomes inadequate to meet the metabolic demands, and blood lactate rises, reflecting supplementary anaerobic metabolism. The value for oxygen consumption at this point is known as the anaerobic threshold (AT), expressed as ml/kg/min. A greater mortality has been reported in patients with an AT <11 ml/kg/min undergoing major abdominal surgery, the risk being compounded by the presence of ischaemic heart disease.Advocates of CPX testing claim the results can be used to stratify operative risk, identify those who will most benefit from presurgery optimisation and facilitate anaesthetic and post-operative care. It may be particularly useful in those patients in the intermediate risk group of the ACC/AHA (American College of Cardiology/American Heart Association) preoperative cardiac evaluation guidelines. A valued reliable preoperative assessment of risk is crucial in this group, but can be fraught with difficulties. In a study of 91 patients who had undergone transthoracic oesophagectomy, maximum oxygen uptake during exercise correlated well with postoperative cardiopulmonary complications. The authors concluded that transthoracic oesophagectomy can safely be performed on patients with a maximum oxygen uptake of at least 800 ml/min/m. This conclusion has been disputed in a recent study of 78 consecutive patients who had CPX testing prior to oesophagectomy, where CPX testing was found to be only of limited value in predicting postoperative cardiopulmonary morbidity. Limitations of CPX testing can occur in patients with reduced lower limb function related to osteoarthritis or limb dysfunction.
Shuttle walk test
A simpler and more viable alternative to CPX testing is incremental and progressive shuttle walk testing (SWT). SWT endurance appears to correlate well with oxygen utilisation seen in CPX. In a study of 51 patients undergoing oesophageal resection, preoperative SWT was a sensitive indicator of 30 day operative mortality. Although the causes of death or complications were not recorded, no patient who walked >350 m on SWT died. The authors suggest that the inability to maintain adequate oxygen delivery, as reflected by an exercise tolerance of <350 m at SWT, may impair wound healing and increase anastomotic failure. Patients with musculoskeletal disease and morbid obesity may be unable to complete any form of dynamic exercise testing. In such circumstances, upper limb ergometry, pharmacologically induced myocardial stress testing monitored by thallium imaging or ECHO cardiography may be an alternative. Meticulous history taking, clinical examination, baseline investigations and exercise testing will help identify those patients who need further non-invasive or invasive investigation such as echocardiography, myocardial stress testing, imaging and angiography. Only after thorough assessment can the appropriateness of the planned anaesthesia and surgery be determined.
- Nutritional status
Preoperative malnutrition is associated with higher rates of morbidity, including infection, delayed wound healing and pulmonary complications (including adult respiratory distress syndrome with associated increased mortality). Malnutrition is common and may be related to dysphagia, disease cachexia or neoadjuvant chemotherapy. Assessment of nutritional status at presentation and before surgery is therefore recommended. Malnutrition is defined as:
- A BMI of <18.5 kg/m2
- Unintentional weight loss >10% within the last 3—6 months
- A BMI <20 kg/m2 and unintentional weight loss >5% within the last 3—6 months.
Additional biochemical measures can contribute to the assessment of nutritional status, although serum albumin which reflects an acute phase response is not a reliable marker of malnutrition.
Management of locoregional disease (M0) - limited disease (Tis-T2 N0 or N1-3)[edit]
(Europe)
Surgery is the treatment of choice in early cancer (Tis-T1a N0). Endoscopic resection is a treatment option for selected patients as similar cure rates in specialised centres have been reported [19] [II, B].
For localised disease without suspected lymph node involvement (T1-2 N0M0), surgery is regarded as a standard treatment [II, B]. However, long-term survival does not exceed 25% if regional lymph nodes are involved (pN1-3). Therefore, preoperative treatment can also be justified.
For localised disease with suspected lymph node involvement (T1-2N1-3M0), preoperative therapy is recommended in patients with AC.
Meta-analyses showed a small but significant benefit for preoperative chemotherapy [12, 13], but they included very limited numbers of patients with localised tumours (e.g. tumour category T1-2).
A couple of meta-analyses in unselected patient groups revealed a significant benefit for preoperative chemoradiation. The extent of this benefit was smaller for patients with T2 tumours [20]. A French phase III trial (FFCD 9901) predominantly in localised SCC did not show increased survival with preoperative chemoradiation.
Studies with post-operative chemotherapy in oesophageal SCC have been carried out in Asian patients only. In a randomised Japanese trial, adjuvant chemotherapy was inferior to the identical neoadjuvant therapy. This treatment is not recommended.
Data with adjuvant chemotherapy in oesophageal AC may be extrapolated from studies and meta-analyses in gastric cancer. Therefore, the recommendations of the gastric cancer guideline may be followed.
For patients unable or unwilling to undergo surgery, combined chemoradiation is superior to radiotherapy alone [21] [I, A]. Four courses of cisplatin/5-fluorouracil (5-FU) combined with radiation doses of 50.4 Gy in fractions of 1.8 Gy are regarded as standard treatment of definitive radiotherapy in the United States. Increased radiation doses up to 60 Gy in fractions of 1.8–2.0 Gy are recommended in parts of Europe and Japan for definitive chemoradiotherapy. This is due to an obvious dose–response correlation of radiotherapy in oesophageal cancer and the positive experience with these radiation doses in prospective multi-centre trials [16, 17] (Figure 1). locally advanced disease (T3-T4 N0-3 M0)
Surgery alone is not a standard treatment in these stages since a complete (R0) tumour resection is not possible in about 30% (pT3) to 50% (pT4). Furthermore, even after complete tumour resection, long-term survival rarely exceeds 20%. Therefore, preoperative treatment is clearly indicated in operable patients.
Squamous cell carcinoma[edit]
(Europe)
A couple of meta-analyses and two recent phase III trials [12–15] demonstrate that patients with locally advanced disease benefit from preoperative chemotherapy or, most likely to a greater extent, from preoperative chemoradiation, with higher rates of complete tumour resection and better local tumour control and survival [I, A]. It is suggested, however, that preoperative chemoradiation will also increase post-operative mortality rates. In cases of response to neoadjuvant chemo(radio)therapy (40–50 Gy), further continuation of chemoradiation resulted in equivalent overall survival compared with surgery, albeit that the non-operative strategy was associated with higher local tumour recurrence [16, 17]. Therefore, chemoradiotherapy with planned surgery or definitive chemoradiotherapy with close surveillance, and salvage surgery for local tumour persistence or local tumour progression, may be considered as a definitive treatment of selected patients with locally advanced disease [22] [I, B]. Experienced multidisciplinary teamwork is warranted for this treatment approach and post-operative mortality will increase with the dose of radiotherapy applied.
Definitive chemoradiotherapy is recommended for cervically localised tumours [III, B].
For patients unable or unwilling to undergo surgery, treatment recommendations from the ‘limited disease’ section may be adapted.
Adenocarcinoma[edit]
(Europe)
Perioperative chemotherapy with cisplatin and 5-FU should be considered standard in locally advanced AC of OGJ [10–12] [I, A]. Preoperative chemoradiotherapy is preferred in oesophageal AC for selected patients, since meta-analyses and a recent phase III trial [12, 15] revealed a significant survival benefit for AC. This benefit was particularly seen in high-risk patients, e.g. those with locally more advanced stages. The preference for chemoradiotherapy is also supported by the results of a phase III study which compared chemoradiotherapy to chemotherapy before surgery [23]. Chemotherapy with cisplatin/5-FU combined with 41.4–50.4 Gy in fractions of 1.8–2.0 Gy has long been standard treatment, but two recent randomised trials showed a favourable toxicity profile for (bi)weekly combinations of oxaliplatin/5-FU or carboplatin/paclitaxel with radiotherapy [15, 24]. Even after complete tumour response to preoperative chemo(radio)therapy operable patients with AC should proceed to surgery [IV, C] (Figure 2).
Management of metastatic disease (M1)[edit]
(Europe) Patients with metastatic oesophageal cancer can be considered for different options of palliative treatment depending on the clinical situation. Single-dose brachytherapy may be a preferred option even after percutaneous radio(chemo)therapy, since it provides better long-term relief of dysphagia with fewer complications than metal stent placement [25] [I, B].
Chemotherapy is indicated for palliative treatment in selected patients [III, B], particularly for patients with AC who have a good performance status. Newer regimens based on oxaliplatin/fluoropyrimidine combinations are an alternative to the ‘classical’ cisplatin/5-FU schedule [26]. Infusional 5-FU may be replaced by capecitabine if swallowing of tablets is not compromised. As in gastric cancer, taxanes are recommended in first-line combinations or as monotherapy in second-line therapy also in AC of OGJ.
In SCC, the value of palliative chemotherapy is less proven. Cisplatin-based combinations showed increased response rates but no survival gain compared with monotherapy. Overall, results with palliative chemotherapy are inferior to those in AC. Therefore, best supportive care or palliative monotherapy has also to be considered.
Personalised medicine
Randomised data with biologically targeted medical therapies are limited in oesophageal carcinoma. For treating patients with HER2-positive tumours, the recommendations of the gastric cancer guideline should be followed. response evaluationResponse is routinely evaluated by evaluation of tumour related symptoms, endoscopy, and CT scan. In case of local tumour progression of (still) locoregional manifestations, the potential benefit of a surgical intervention must be discussed by a multi-disciplinary board. If distant metastases may be detected, the recommendations for metastastic disease should be followed.
Biopsies may be taken after neoadjuvant intended chemo-radiotherapy in case a patient has increased operative risks, and surgery may be omitted if a complete tumour remission will be documented. However, this is not a standard procedure. Additionally, tumour response to chemotherapy may be predicted early by fluor-18-fluorodeoxyglucose(FDG)-PET(-CT) in oesophago-gastric AC [27] [III, C]. However, at the present time, this will not change the therapeutic strategy.
follow-up and long-term implications
Except for those patients who may be potential candidates for an early ‘salvage surgery’ after (failing) endoscopic resection or definitive chemoradiation, there is no evidence that regular follow-up after initial therapy may have impact on the outcome. Follow-up visits should be concentrated on symptoms, nutrition and psycho-social support [IV, D].
Illustration: Algorithm for the treatment of limited disease. CT, chemotherapy; RT, radiotherapy; Cis, cisplatin; Carbo, carboplatin; FU, fluorouracil; E, epirubicin; D, docetaxel; R0, complete resection; R1-2, incomplete resection; #, fit means medically operable according to local standards of the treating centre (excluding patients with poor performance status, respiratory insufficiency, portal hypertension, renal insufficiency, recent myocardial infarction and advanced peripheral arterial disease).
Illustration: Algorithm for the treatment of locally advanced disease. CT, chemotherapy; RT, radiotherapy; Cis, cisplatin; Carbo, carboplatin; FU, fluorouracil; E, epirubicin; D, docetaxel; R0, complete resection; R1-2, incomplete resection; #, fit means medically operable according to local standards of the treating centre (excluding patients with poor performance status, respiratory insufficiency, portal hypertension, renal insufficiency, recent myocardial infarction and advanced peripheral arterial disease).
Table: Levels of evidence and grades of recommendation (adapted with permission from the Infectious Diseases Society of America-United States Public Health Service Grading Systems)
Endoscopic therapy[edit]
(UK/Ireland)
Endoscopic therapy has become an integral part of the multidisciplinary management of oesophageal and gastric cancer. The UK NICE guidance recommends that such procedures need to be carefully audited in high volume tertiary referral centres with access to an oesophageal and gastric cancer surgeon, should be performed by appropriately trained staff, and patient care must be managed through an MDT.
EMR and ESD, PDT, mucosal ablation using lasers (photo-thermal), electrocoagulation, APC and radiofrequency ablation (RFA) (thermal) have all been employed to remove dysplasia and early cancer. Most techniques are now being used in combination to eradicate local disease and address any field change abnormality. It is important to emphasise that patients must have reversal of the underlying abnormality with reflux control and H pylori eradication and have repeat endoscopic surveillance to detect metachronous or recurrent tumours.
- Pathology
The pathology of early cancer of the oesophagus varies with histological subtype. In one review, Stein and colleagues reported that submucosal in filtration was more frequent in T1 squamous cancers (80.5%) than in T1 adenocarcinomas (55.4%). The risk of lymph node involvement is also greater in squamous cell carcinoma. An analysis of 1690 lesions has reported the risk of lymph node metastases with early oesophageal squamous carcinomas as being 19% for lesions invading the muscularis mucosa and 44% for lesions invading deeper than the superficial one-third of the submucosa. In contrast, the risk of nodal disease in adenocarcinoma limited to the muscularis mucosa is negligible. In submucosal in filtration of adenocarcinoma the risk of lymph node spread reflects the depth of invasion. Once penetration into the superficial third (sm1) has occurred, the risk is 0 —8% and once through into sm2 and sm3 it rises to at least 26%.
- Endoscopic resection
Data from the from the Surveillance Epidemiology and End Results (SEER) database of the National Cancer Institute (USA) examined patients with stage 0 (Tis N0 M0) and stage 1 (T1 N0 M0) early adenocarcinoma of the oesophagus. This demonstrated no significant difference in survival of patients treated with endoscopic therapy compared with those having a radical surgical resection.
Endoscopic resection is indicated for early cancer (T1mN0), moderately and well differentiated cancers and mucosal dysplasia. There are now consistent reports indicating a 5 year disease free survival (DFS) of 95% and a low morbidity rate. Similarly, early mucosal Barrett’s cancer and dysplasia can be safely eradicated. The use of a single and purely localised therapy can result in the development of metachronous cancer in up to 30% of patients. The risk of recurrence can be reduced to 16% by ablation of the remaining Barrett’s epithelium with PDT, with a complete long-term control of 96% at a median of 5 years follow-up. Similarly eradication of the Barrett’s segment with RFA improves local control particularly for flat areas of dysplasia and reduces the risk of malignant degeneration.
Comparative studies (non-randomised and retrospective) of surgery and endoscopic ablation therapy for dysplasia and early cancer are misleading because of selection bias. Patients selected for endotherapy are older with earlier tumours and small segments of Barrett’s oesophagus. Overall survival (OS) and cancer-related mortality seem to be very similar (>90%), with significantly fewer complications associated with endo-therapy. Circumferential EMR is associated with stricture formation but can be used to destroy the field change in Barrett’s oesophagus and eradication of mucosal cancer. Well-designed and conducted RCTs comparing the effectiveness and cost-effectiveness of endoscopic therapy with surgical resection are urgently required.
- Photodynamic therapy
Treatment of early cancer and high grade dysplasia in Barrett’s oesophagus, squamous cell dysplasia/cancer and adenocarcinoma of the oesophagus with PDT has resulted in prolonged survival which is comparable with surgery. There are large case series of PDT for the treatment of Tis, T1 early and some T2 squamous cell and adenocarcinoma, with a complete response reported of 40—93% with follow-up of 4—47 months. The main complications have been skin photosensitivity and stricture formation, with perforation occurring in 4—34% of patients.
In a randomised trial using PDT to eradicate high grade dysplasia, patients (208) were randomised 2:1 to endoscopic PDT with omeprazole or received omeprazole (control) only. There was a significant difference (p <0.0001) for PDT (106/138¼ 77%) compared with control (27/70¼ 39%) in complete ablation of high grade dysplasia. The occurrence of adenocarcinoma in the photodynamic group was significantly lower (p <0.006). The response remains robust at 5 year follow-up. PDT is the most cost-effective solution for the management of high grade dysplasia in Barrett’s oesophagus when compared with surveillance and radical surgery.
- Thermal ablation
Laser, APC, electrocoagulation, cryotherapy, RFA
These methods are used to eradicate field change in Barrett’s oesophagus, destroy any occult synchronous cancers and prevent the development of metachronous lesions after EMR of all macroscopic lesions. The optimal method of ablation has been much debated.Since APC is in widespread use, many single device and comparative studies have compared this with other methods. Current evidence shows that complete eradication rates vary from 38% to 99%. It is important to have profound acid suppression. Complications of haemorrhage, perforation and stricture do occur (10%). An RCT comparing APC against endoscopic surveillance following antireflux surgery demonstrated significant reversal of Barrett’s (follow-up 12 months) following APC.
Randomised studies have compared APC with PDT. The results vary, with no significant difference between ALA (5-aminolaevulinic acid)-PDT and APC, and others finding APC simpler and more effective. Photofrin PDT was more effective than APC in eradicating, dysplasia although not significantly so (12 months follow-up). The complication rate was similar but PDT was more costly. Multipolar electro-coagulation requires fewer treatment sessions than APC, with an ablation rate of 88% compared with 81% (APC). None of these trials was able to assess progression to cancer.
RFA has proved an effective method for eradication of preneoplastic Barrett’s epithelium. Recent randomised data compared RFA with sham treatment, and have demonstrated the short-term effectiveness of RFA. Eradication of dysplasia and prevention of progression to cancer in patients with dysplastic Barrett’s oesophagus was achieved using RFA. At 12 months high grade dysplasia was eradicated in 81%, with only 2.4% progressing to cancer (RFA) compared with 19.0% eradication and a 19.0% progression to cancer (sham treatment). Strictures developed in 6%, bleeding in 1%, and 2% of patients needed admission to hospital for pain. Long-term follow-up and further research to establish the role of this intervention are still needed. The optimal management of high grade dysplasia in Barrett’s is currently being assessed by an international consensus task force (Barrett’s Dysplasia and CAncer Task force; BAD CAT) and is due to report at the end of 2011.
Surgery[edit]
(UK/Ireland)
- All patients should have antithrombotic (grade A, 1b) and antibiotic prophylaxis (grade C) instituted at an appropriate time in relation to surgery and postoperative recovery
- Oesophageal and gastric cancer surgery should be performed by surgeons who work in a specialist MDT in a designated cancer centre with outcomes audited regularly
- Surgeons should perform at least 20 oesophageal and gastric resections annually either individually or operating with another consultant both of whom are core members of the MDT. The individual surgeon and team outcomes should be audited against national benchmarked standards.
(UK/Ireland)
There is a strong relationship between lower hospital mortality and increasing surgeon and institutional patient volumes. Large volume units consistently report hospital mortalities well below 10%. In the National Oesophago-Gastric Cancer Audit during October 2007—September 2008, 1109 and 747 patients underwent curative resection for oesophageal and gastric cancer, respectively. The hospital mortality was 5.0% (95% CI 3.8% to 6.4%) for oesophagectomy and 6.7% (95% CI 5.0% to 8.7%) for gastrectomy. The proportion of patients undergoing radical curative resection has fallen. In 1998 overall resection rates were 28% (oesophageal 14%, oesophago-gastric junctional 33% and gastric 31%) decreasing to 20% in 2005 (oesophageal 10%, oesophago-gastric junctional 24% and gastric 23%). These changes are likely to reflect service reconfiguration following implementation of IOG and better staging and MDT working.
The benefit of surgeon and surgical team volume is less well defined. However, surgeon competence does seem to plateau with increasing experience. A prospective audit of the learning curve for D2 gastrectomy reported that such a plateau was reached after 15—25 procedures. A number of factors have influenced surgeon experience including reduction in resection rates, centralisation with a trend towards team working, and reduced working hours in the context of providing a comprehensive UGI surgical service. It would seem therefore that an individual surgeon should be undertaking a minimum of 20 oesophageal and gastric resections annually, either individually or in conjunction with a consultant colleague. The National Oesophago-Gastric Cancer Audit has clearly shown the standards that have been reached, and an individual’s practice should be audited against these benchmarked standards. AUGIS has recommended that an ideal oesophago-gastric unit should consist of 4—6 surgeons each carrying out a minimum of 15—20
resections per year serving a population of 1—2 million.
- Perioperative optimisation
(UK/Ireland)
Appropriately directed perioperative care is associated with an improved surgical outcome in those with recognised risk predictors. Establishing that current treatment for co-existing cardiorespiratory disease is optimal is essential prior to any additional interventions directed towards optimising preoperative status.
β-Blockade
There has been much interest in adrenergic β-blockade prior to major surgery as a means of improving ischaemic ventricular dysfunction. Current ACC/AHA guidelines suggest that β-blockers should be considered in all patients with an identifiable cardiac risk as defined by the presence of more than one clinical risk factor. For the treatment to be efficacious, patients should be optimally β-blocked in the weeks preceding elective surgery and continued throughout the immediate postoperative period. Although no particular β-blocker has been identified as preferable, long-acting β-blockers initiated before surgery were thought to be superior to shorter acting drugs.The protective mechanism of β-blockers is unclear, the control of heart rate being only part of the explanation. In contrast, recent critical expert re-evaluation of perioperative β-blockade has questioned the validity of some of the evidence that β-blockers are indeed cardioprotective. Adverse effects can be associated with β-bockade, especially the non-selective β-blockers. Vagal responses to surgery and anaesthesia can be exacerbated by concomitant β-blockade, and responses to sympathomimetic inotropes may be altered.
Statins
There is growing interest in statins as a pre-emptive intervention treatment in the preoperative period in patients with ischaemic heart disease or hypercholesterolaemia. A meta-analysis of postoperative outcome following cardiac, vascular and non-cardiac surgery demonstrated a significant reduction in early postoperative mortality in patients taking long-term statins. An alternative review, however, felt that the evidence for the routine perioperative use of statins to reduce cardiovascular risk was currently lacking. To date no specific studies evaluating perioperative statin treatment and postoperative outcome following gastric or oesophageal surgery have been reported. Current ACC/AHA guidelines on perioperative cardiovascular care recommend that patients should continue statin treatment throughout the operative period. Until further prospective studies can clarify the true value of statins in the perioperative period, their continuation is at the discretion of the attending clinician.Goal-directed haemodynamic preoptimisation
The normal physiological response to surgery is to increase oxygen delivery by an increase in cardiac output. Shoemaker and colleagues showed that patients who incurred an oxygen debt as a consequence of limited cardiorespiratory reserve incurred more postoperative morbidity and mortality. Non-survivors tended to have the greatest and most persistent oxygen debt. Goal-directed optimisation aims to attain predetermined target physiological parameters that are known to correlate with a favourable outcome. With the aid of invasive monitoring, using crystalloid, colloid, blood, inotropes and oxygen, heart rate, stroke volume, haemoglobin and oxygen saturation can be manipulated. Following a period of preoptimisation, a reduction in mortality and length of hospital stay was reported, with preoperative fluid loading considered the most important factor. A positive effect on surgical outcome after oesophagectomy has been demonstrated with judicious fluid administration. When fluid loading alone fails to attain the predetermined physiological targets, inotropes such as dopexamine, dobutamine and epinephrine have been used. However, they can alter regional blood flow, cause tissue hypoxia and increase myocardial oxygen demand, provoking ischaemia. An adequate cardiac output is not necessarily synonymous with good regional or anastomotic blood flow. Goal-directed preoptimisation may be beneficial in appropriately selected high risk patients. It has been advocated that only those patients undergoing surgery for which mortality exceeds 20% and those identified as high risk during risk stratification should be considered.Nutritional support
Patients who are identified as malnourished prior to surgery should be considered for preoperative nutritional support for 10—14 days. Liquid nutritional products containing immuno-nutrients, namely arginine, omega-3 fatty acids and nucleotides, have been used in preoperative and postoperative patients undergoing surgery for UGI malignancies. Some, but not all, RCTs have demonstrated a reduction in postoperative infective complications in both malnourished and normally nourished patients when used for 5—7 days preoperatively. Studies in malnourished patients included use of both preoperative and postoperative immunonutrition and it may be that this group of patients require immunonutrition both preoperatively and postoperatively to gain benefit. Its use may also reduce length of hospital stay. Postoperative feeding via the jejunal route is routine in some centres, and this may improve nutritional status, although evidence to show improved clinical outcomes compared with standard care is currently lacking. It is recommended that nutritional support should be provided for all patients who are malnourished or at risk of malnutrition and have an inadequate oral intake defined as having eaten little or nothing for >5 days and/or likely to eat little or nothing for the next 5 days or longer. Preferably this should be given via the gastrointestinal tract if it is functioning and adequate access can be obtained.Thromboembolic disease
Venous thromboembolism (VTE) is a not infrequent co-morbidity in patients with oesophageal or gastric cancer. This is not only because of the higher risk of VTE for patients with malignancy but also because VTE is associated with some chemotherapy regimens. All patients considered for surgery should be offered VTE prophylaxis according to NICE guidance. Patients who have recently sustained a VTE should be considered for placement of temporary caval filters prior to radical surgery.
(UK/Ireland)
- Neoadjuvant, perioperative (neoadjuvant and adjuvant) and adjuvant therapy
(UK/Ireland)
Historically, the majority of trials and meta-analyses evaluating combined modality treatment regimens in the treatment of oesophageal cancer have included squamous cell, adeno- and undifferentiated carcinomas, and tumours located in the proximal, mid and lower oesophagus as well as oesophago-gastric junctional tumours. These recommendations describe the current rationale for treatment strategies based on the main histological subtypes and tumour location.
Preoperative radiotherapy
A meta-analysis of preoperative radiotherapy for patients with resectable oesophageal carcinoma (any histological subtype) demonstrated that there was a 3—4% absolute improvement in OS (HR 0.89; 95% CI 0.78 to 1.01; p=0.062). Preoperative radiotherapy is therefore not recommended for potentially resectable oesophageal squamous cell or adenocarcinoma.
Preoperative chemoradiation
Preoperative chemoradiation followed by surgery is superior to surgery alone, as demonstrated in a meta-analysis of 10 RCTs comparing the two strategies. The HR for all-cause mortality was 0.81 (95% CI 0.70 to 0.93; p=0.002), corresponding to a 13% absolute difference in survival at 2 years. A significant benefit favouring preoperative chemoradiation over surgery alone was observed in oesophageal cancer of both squamous cell carcinoma and adenocarcinoma histological subtypes. There have been two further phase III trials comparing chemoradiation with surgery alone in patients with resectable oesophageal or oesophago-gastric junctional cancer. In the Dutch trial, paclitaxel and carboplatin were given with radiotherapy. The median survival for the combined therapy group was 49 months compared with 26 months for the surgery-alone arm. The majority of patients (74%) had distal oesophageal tumours and ~12% had oesophago-gastric junctional tumours. In the subgroup analysis, the beneficial effect was more pronounced in patients with squamous cell carcinoma (HR 0.34; 95% CI 0.17 to 0.65) compared with adenocarcinoma (HR 0.82; 95% CI 0.58 to 1.16). In the FFCD 9901 trial, patients were randomised to combination 5-FU/cisplatin and radiotherapy. The trial included 195 patients with localised stage I and II oesophageal squamous cell carcinoma (70%) and adenocarcinoma (29%). It was stopped early as there was no advantage to the combination regimen. In addition the operative mortality was significantly greater at 7.3% in those treated with chemoradiotherapy. The authors concluded that triple modality therapy was not indicated for such early stage oesophageal cancers.
Preoperative chemoradiation alone and preoperative chemotherapy have not been directly compared in the context of a phase III RCT. A phase III RCT has been conducted comparing preoperative chemotherapy with preoperative chemotherapy and chemoradiation in locally advanced lower oesophageal and gastric cardia adenocarcinoma. This study closed early due to poor accrual. A trend towards improved survival in the chemotherapy plus chemoradiation arm was reported; however, this was associated with higher perioperative morbidity.
There is a lack of assessment of HRQL in the RCTs comparing preoperative chemoradiation followed by surgery with surgery alone. Prospective series evaluating HRQL during chemoradiation and surgery show a deterioration of HRQL during preoperative treatment that recovers before surgery. After oesophagectomy there is a dramatic reduction in all aspects of HRQL, but no evidence that undergoing preoperative chemoradiation delays postoperative recovery of HRQL.
Definitive chemoradiation
Chemoradiation results in superior disease control and survival outcomes compared with radiation alone, but is associated with greater toxicity as seen in a review of 19 RCTs. There are few trials directly comparing definitive chemoradiation with surgery alone. A Chinese study of 80 patients with squamous cell carcinoma randomised to surgery or chemoradiation failed to show superiority of either strategy in terms of early DFS or OS. This trial was powered to show superiority of one treatment over another, but failed to report what magnitude of difference was considered superior. There is also a small Swedish study of 91 patients with either squamous cell carcinoma or adenocarcinoma of the oesophagus (50/50) that did not find any differences in treatment outcomes and equivalent survival.
Adding surgery to chemoradiation for squamous cell carcinoma can improve local control rates compared with chemoradiation alone, but combined-modality therapy has not been shown to improve survival. A European study of 172 patients with squamous cell carcinoma randomised to induction chemotherapy followed by chemoradiotherapy (40 Gy) and surgery, or induction chemotherapy followed by chemoradiotherapy (at least 65 Gy) reported equivalent OS, but better local progression-free survival in the surgery arm. The addition of surgery also significantly increased treatment-related morbidity (12.8% vs 3.5%; p=0.03). A second European study, the French FFCD 9102 trial, recruited 444 patients with potentially resectable oesophageal cancer of predominantly squamous cell carcinoma subtype (90%). After induction chemoradiation, responding patients were randomised to further chemoradiation or surgery. Median OS was 19.3 months for patients randomised to further chemoradiation and 17.7 months for those randomised to surgery. Again toxicity was higher with combined-modality therapy. The study met its primary end point of non-inferiority for 2 year survival (p=0.03). Both the European studies were equivalence studies powered to determine whether the two treatments could be considered equivalent in terms of survival at 2 years. Equivalence was defined as a difference of <10% and 15%. It is questionable for a cancer with such a low survival rate that such differences would be deemed clinically important. The French trial included an observer-assessed measure of HRQL. Participants randomised to surgery reported worse HRQL 3 months after treatment, but similar scores in both arms were reported at 2 years. In this trial the HRQL assessment was performed by a non-blinded observer, introducing the possibility of bias. One non-randomised prospective series comparing HRQL between patients selected for definitive chemoradiation versus chemoradiation and surgery showed a similar pattern. In the first few months after treatment, HRQL was more severely comprised following a surgical than a non-surgical approach, but at 1 year scores were similar in both groups.
In localised squamous cell carcinoma of the oesophagus, although definitive chemoradiation is a current recommended standard of care, there is a lack of evidence to support either a surgical or a non-surgical approach. The recent UK National Audit shows that the disease is treated by both approaches. Surgery should be considered in those treated with chemoradiation who at the end of treatment have histologically confirmed residual disease. A feasibility RCT is being set up to examine whether it is possible to effectively recruit into a trial comparing these treatment options. Ongoing clinical trials, such as SCOPE-1, are evaluating the additional effect of biological agents to treatment regimens, but trials with both clinical and HRQL outcomes comparing chemoradiation with combination treatments including surgery are still needed. For patients with localised oesophageal adenocarcinoma deemed unsuitable for surgery, definitive chemoradiation is a valid treatment option, with consideration given to participation in relevant clinical trials.
Guidelines for the management of oesophageal and gastric cancer (2011)
Esophageal resection[edit]
(UK/Ireland)
- There is no evidence favouring one method of oesophageal resection over another (grade A), and evidence for minimal access techniques is limited (grade C)
- The operative strategy should ensure that adequate longitudinal and radial resection margins are achieved with lymphadenectomy appropriate to the histological tumour type and its location (grade B)
Surgery can be a definitive treatment for Tis, T1 and some T2 carcinoma of the esophagus. There is some debate on whether neoadjuvant chemoradiotherapy or surgery be performed first on T2 esophageal cancer because staging difficulties[59]. There are different surgical techniques for esophagectomy but the main two are transhiatal esophagectomy (THE) and transthoracic esophagectomy. THE does not include a thoracotomy and instead the stomach is mobilized from the surrounding omentum and blood vessels through a midline supraumbilical incision during the abdominal phase[56]. The esophagus is removed from a small cervical incision usually on the left side of the neck during the cervical phase. The transthoracic esophagectomy uses the Ivor Lewis method, the McKeown Modification (3 hole approach), or the left transthoracic approach. Surgeons choose the method based on tumor location and size. The McKeown modification is performed more for middle and upper esophageal cancer while tumors in the lower third of the esophagus are best approached using the left transthoracic approach[56]. The abdominal phase of the transthoracic esophagectomy is identical to the THE and the thoracic phase is accomplished with a posterolateral thoracotomy in the fifth intercostals space. The McKeown modification also includes a cervical phase where the proximal esophagus can be anastomosed to the stomach conduit[60]."
Another critical component of esophagectomy is the lymph node dissection. There is debate about which surgical approach is appropriate based upon access, adequacy of the lymph node retrieval, and the lymph node dissection[54]. Each surgical technique have different lymph node retrieval rates based on the surgical exposure of open, laparoscopic or laparoscopic assisted surgery. Laparoscopic surgery offers less blood loss and more patient comfort but not as many lymph nodes can be retrieved compared to the open approach. Placement of a thorascopic port has been shown to provide more exposure into the chest cavity allowing for a more thorough dissection. One study looked at the difference between open and laparoscopic THE without a thorascopic port and found that while the open procedure yielded more lymph nodes this did not affect the patient’s overall prognosis[61]."
The differences between transthoracic and THE have been extensively debated. A meta-analysis of 52 studies was performed in 2011 comparing the 5 years survival, postoperative morbidity and mortality between transthoracic and transhiatal esophagectomy. The analysis showed that transhiatal method is associated with reduced operating time, length of stay in hospital, postoperative respiratory complications, and decreased early mortality. The transthoracic method is associated with fewer anastomosis leaks, anastomotic strictures, and vocal cord paralysis. There was no significant difference between transhiatal and transthoracic method in 5-year survival rates[62]. These findings agree with two previous meta-analysis conducted in 1999 and 2001[63-64]. This data suggest that the outcome of the esophagectomy does not depend on the surgical method chosen but more on the surgeon’s and hospital’s experience in dealing with these complex oncological cases[65]."
Another treatment option for high grade dysplasia is esophageal mucosal resection (EMR) or esophageal mucosal dissection. EMR dissects the esophageal submucosa to better evaluate and stage early carcinoma[66]. It has been suggested the EMR be performed on lesions with a diameter ≤ 2 cm and only occurs in less than one third of the esophageal wall circumference. EMR is used in conjuction with radiofrequency ablation therapy and cryotherapy ablation to eradicate BE[67]. In one trial, EMR with radiofrequency ablation eradicated 90% of dysplasia and metaplasia in patients[68]."
One study investigated the hemodynamic changes during surgery between patients who underwent a transthoracic vs THE and their post-operative changes. It was found that there was no statistical significance between transthoracic and THE in their intraoperative hemodynamic changes. However more vasopressors were used during surgery in patients with transthoracic esophagectomy due to increased hemodynamic liability[69]."
- Oesophageal surgery
Guidelines for the management of oesophageal and gastric cancer (2011)
Chemotherapy and radiotherapy[edit]
(UK/Ireland)
- SCC
- There is no evidence to support the use of preoperative radiotherapy in oesophageal squamous cell carcinoma.
- Chemoradiation is the definitive treatment of choice for localised squamous cell carcinoma of the proximal oesophagus.
- Localised squamous cell carcinoma of the middle or lower third of the oesophagus may be treated with chemoradiotherapy alone or chemoradiotherapy plus surgery (grade A; Ib).
- There is no evidence to support routine use of adjuvant chemotherapy in oesophageal squamous cell carcinoma
- Oesophageal adenocarcinoma (including type I, II and III oesophago-gastric junctional adenocarcinoma)
- Preoperative chemoradiation improves long-term survival over surgery alone
- There is no evidence to support the use of preoperative radiotherapy in oesophageal adenocarcinoma
- Preoperative chemotherapy with cisplatin and 5-fluorouracil (5-FU) improves long-term survival over surgery alone.
- Perioperative chemotherapy (combined preoperative and postoperative) conveys a survival benefit and is the preferred option for type II and III oesophago-gastric junctional adenocarcinoma
"Chemotherapy and radiotherapy are other critical modalities of treatment along with surgery and are used either in a neoadjuvant or adjuvant setting. A patient will receive neoadjuvant chemoradiotherapy for either a T3 or N1 stage disease. According to the 2013 National Comprehensive Cancer Network guidelines of esophageal cancer, the triple therapy drug regimen include paclitaxel/carboplatin, cisplatin/fluoropyrimidine, and oxaliplatin/fluorouracil. The recommended dose of radiation is 41.4-50.4 Gy[70]. However, one study proposes using chemotherapy alone to treat patients with locally advanced esophageal cancer. Their results showed less toxicities and no difference in their five-year survival rate[71].
"An article from Cancer Control found that in the United States, neoadjuvant chemoradiotherapy followed by esophagectomy for resectable esophageal cancer, had a better survival rate than those patients treated with surgery alone[72]. A meta-analysis comparing neoadjuvant chemotherapy with surgery vs surgery alone showed a survival increase for those patients who underwent neoadjuvant chemotherapy vs surgery alone[73].
"A Japanese study found that patients < 60 years of age with a hemoglobin ≥ 13 g/dL who underwent pre-operative chemoradiotherapy, survived longer than those patients who did not undergo treatment. Albumin ≥ 3.5 g/dL was also associated with prolonged survival[74]. Another study recommends that patients with esophageal cancer who are non-resectable or who refuse surgery can still be treated with definitive chemoradiotherapy due to a 2-year survival rate of 40-55[75]. Another Japanese study found that patients undergoing triple chemotherapy and esophagectomy without the prognostic factors of five or more positive lymph nodes, metastasis to the cervical, mediastinal and abdominal lymph nodes, stage III or IV disease, or intramural metastasis had better recurrence free survival than patients with esophageal cancer and one of the unfavorable prognostic factors[76]."
Targeted therapy[edit]
Palliative treatment[edit]
(UK/Ireland)
Palliative treatment should be planned by the MDT taking into account performance status and patient preference, with early direct involvement of the palliative care team and the clinical nurse specialist.
- Palliative external beam radiotherapy can relieve dysphagia with few side effects, but the benefit is slow to achieve
(grade B).
- Palliative brachytherapy improves symptom control and health-related quality of life (HRQL) where survival is expected to be longer than 3 months (grade A; Ib).
- Palliative chemotherapy provides symptom relief and improves HRQL in inoperable or metastatic oesophageal cancer (grade A; Ib).
- Palliative combination chemotherapy improves survival compared with best supportive care in oesophageal squamous cell carcinoma, adenocarcinoma and undifferentiated carcinoma (grade A; Ib).
- Trastuzumab in combination with cisplatin/fluoropyrimidine should be considered for patients with HER2-positive
oesophago-gastric junctional adenocarcinoma as there is an improvement in disease-free survival (DFS) and overall survival (OS) (grade A; Ib).
- Oesophageal intubation with a self-expanding stent is the treatment of choice for firm stenosing tumours (capable of retaining an endoprosthesis),
- 2 cm from the cricopharyngeus, where rapid relief of dysphagia in a one-stage procedure is desirable, particularly for patients with a poor prognosis (grade B).
- Antireflux stents confer no added benefit above standard metal stents (grade A; Ib).
- Covered expandable metal stents are the treatment of choice for malignant tracheo-oesophageal fistulation or following oesophageal perforation sustained during dilatation of a malignant stricture (grade B).
- Laser treatment is effective for relief of dysphagia in exophytic tumours of the oesophagus and gastric cardia, and in treating tumour overgrowth following intubation (grade A; Ib).
- For patients whose dysphagia is palliated using laser therapy, the effect can be prolonged substantially by using adjunctive external beam radiotherapy or brachytherapy (grade A; Ib).
- Photodynamic therapy (PDT) is experimental and its use is not currently recommended (grade B).
- Argon plasma coagulation (APC) may be useful in treating overgrowth above and below stents and in reducing haemorrhage from inoperable tumours (grade C).
- There is no indication for local ethanol injection for symptom palliation (grade B).
First-line palliative chemotherapy for oesophageal, oesophago-gastric junctional and gastric cancer[edit]
The benefits of palliative chemotherapy over Best Supportive Care (BSC) in the treatment of advanced gastric cancer have been demonstrated in four RCTs. For patients considered suitable for systemic treatment, palliative chemotherapy improves median survival from 3 to 4 months with BSC alone to 7 to 10 months. Patients with advanced oesophageal cancer appear to derive the same benefits from systemic chemotherapy as those with gastric or oesophago-gastric junctional tumours, and those of good performance status should be offered combination chemotherapy. Several multicentre studies conducted in the UK that have defined the current standards of care in the treatment of advanced gastric or oesophago-gastric cancer have included patients with oesophageal tumours of squamous cell, adenocarcinoma and undifferentiated carcinoma histological subtypes. Many chemotherapy agents have efficacy in the treatment of advanced gastric cancer, and it is recognised that combination therapy is superior to single-agent therapy. There is, however, no international consensus regarding which combination chemo- therapy regimen should be used first line. Until recently, combination therapy with ECF has been the preferred regimen in the UK. In an RCT ECF was shown to have superior response rates (45% vs 21%, p=0.0002), median OS (8.9 vs 5.7 months, p=0.0009) and 2-year survival (13.5% vs 5.4%, p=0.03) over FAMTX (5-FU, adriamycin and metho-trexate). When compared with MCF (mitomycin C, cisplatin and infused 5-FU) in the treatment of oesophageal, oesophago-gastric junctional and gastric carcinomas, ECF had similar response rates and survival, but was preferable according to HRQL measures. Cisplatin combined with infused 5-FU (CF) is another commonly used regimen. Although ECF and CF have not been directly compared in a phase III randomised trial, a meta-analysis has demonstrated that three-drug regimens containing anthracyclines, cisplatin and 5-FU are superior to two-drug regimens containing either cisplatin/5-FU or anthracyclines/5-FU in terms of OS. The REAL-2 trial is the largest RCT evaluating first-line chemotherapy regimens for advanced oesophago-gastric cancer.
In a 2 3 2 factorial design, 1002 patients were randomised to ECF, ECX, EOF (epirubicin, oxaliplatin and infused 5-FU) or EOX (epirubicin, oxaliplatin and capecitabine). The study met its primary end points demonstrating non-inferiority in OS for capecitabine compared with infused 5-FU (HR for death, 0.86; 95% CI 0.80 to 0.99) and for oxaliplatin compared with cisplatin (HR for death, 0.92; 95% CI 0.80 to 1.10). There was no significant difference in HRQL between the four arms. EOX resulted in longer OS than ECF (HR for death 0.80; 95% CI 0.66 to 0.97; p=0.02). The combination of EOX is therefore at least as efficacious as ECF, with the additional advantages of a more convenient mode of administration (no requirement for hydration or central venous catheter insertion) and an acceptable toxicity profile. Further trials indicate that it is reasonable to substitute capecitabine for infused 5-FU, and oxaliplatin for cisplatin, in the treatment of advanced oesophagogastric cancer. In July 2010, the NICE appraisal of capecitabine determined that use of capecitabine in combination with plat- inum chemotherapy represented a cost-saving to the NHS over infused 5-FU. The V325 study is a randomised phase III trial comparing docetaxel in combination with cisplatin and infused 5-FU (DCF) with the doublet CF. A statistically significant improvement in OS (9.2 vs 8.6 months; p=0.020) was observed; however, this was at the cost of significantly more toxicity, including febrile neutropenia. In a phase II Swiss trial comparing DCF with ECF, DCF resulted in a much higher rate of complicated neutropenia (41% vs 18%). Docetaxel-containing regimens are not currently approved in the UK for this indication. Patients with adequate performance status with inoperable oesophago-gastric cancer should be considered for combination chemotherapy with EOX or ECX.
(UK/Ireland) Guidelines for the management of oesophageal and gastric cancer (2011)
First-line palliative targeted agents in combination with chemotherapy[edit]
For patients with advanced HER-2-positive oesophago-gastric junctional or gastric cancer, the addition of trastuzumab to a cisplatin and fluoropyrimidine (5-FU or capecitabine) chemotherapy doublet resulted in a statistically significant improvement in response rate (47.3% vs 34.5%; p=0.0017), progression-free survival (6.7 vs 5.5 months; p=0.0002) and median OS (13.8 vs 11.1 months; p=0.0048). Tumours were considered HER-2 positive if the immunohistochemistry score was 3+ or if fluorescent in situ hybridisation (FISH) was positive for HER-2 overexpression. Trastuzumab is now licensed in the UK for patients with previously untreated metastatic HER-2-positive (defined as IHC 3+) gastric or oesophago-gastric junctional adenocarcinoma. This regimen is a valid first-line treatment option for HER-2-positive advanced gastric and oesophago-gastric junctional cancers. How this regimen compares with chemotherapy-only triplet regimens is unknown. The use of other targeted agents, including cetuximab, panitumumab and bevacizumab, in combination with chemotherapy should remain restricted to the context of clinical trials.
(UK/Ireland) Guidelines for the management of oesophageal and gastric cancer (2011)
Second-line palliative chemotherapy for oesophago-gastric junctional and gastric cancer[edit]
The standard treatment option for patients with advanced gastric or gastro-oesophageal junction tumours is uncertain, and wherever possible it is recommended that patients are enrolled into a RCT. Data from phase II trials have demonstrated activity in the second-line setting for the following agents/combination regimes: irinotecan in combination with cisplatin or fluoropyrimidines, FOLFOX (folinic acid, 5-FU, oxaliplatin), docetaxel monotherapy, docetaxel in combination with oxaliplatin, and paclitaxel alone or in combination with platinum agents.
(UK/Ireland) Guidelines for the management of oesophageal and gastric cancer (2011)
Chemotherapy to downstage initially inoperable locally advanced disease for surgery[edit]
There is anecdotal evidence that in selected cases, palliative chemotherapy may result in sufficient downstaging of initially. inoperable locally advanced disease to allow surgical resection. For instance, in the randomised trial comparing ECF with FAMTX in patients with locally advanced disease, 12 out of 43 patients treated with ECF (nine complete resections) and five out of 51 patients treated with FAMTX (four complete resections) proceeded to surgery. Of these 17 patients, nine survived for ≥2 years from randomisation. There have not been any randomised controlled studies to compare the addition of surgery to palliative chemotherapy with palliative chemotherapy alone. Such studies may become possible and worthwhile if minimal access surgery can be achieved with reduced complications and better recovery of HRQL than standard open surgery.
(UK/Ireland) Guidelines for the management of oesophageal and gastric cancer (2011)
Palliative radiotherapy for oesophageal cancer[edit]
Dysphagia and pain are common symptoms associated with unresectable oesophageal cancer. External beam radiotherapy is a local palliative measure that can improve symptoms and is
associated with minimal toxicity, but relief from dysphagia is often slow in onset compared with stent insertion. Differences in outcome in terms of HRQL, dysphagia-free
survival and OS between different 'locoregional' palliative treatments, particularly in the era of more effective chemotherapy, requires further investigation.
(UK/Ireland) Guidelines for the management of oesophageal and gastric cancer (2011)
Endoscopic methods[edit]
- Oesophageal intubation
Oesophageal intubation is an effective means of relieving dysphagia in a single procedure, and stents are now widely used. A Health Technology Assessment (HTA)-sponsored pragmatic RCT of the cost-effectiveness of palliative treatments for patients with inoperable oesophageal cancer studied different types of oesophageal tubes and compared these with non-stent alternatives. This study confirmed the observations made previously that although the older rigid plastic tubes (Atkinson and Celestin) were cheap, they were also associated with a worse quality of swallowing and increased late morbidity. Small (18 mm) diameter self-expanding metal stents (SEMS) were as effective as large (24 mm) stents but induced less pain.
Two-thirds of patients treated with a metal stent can eat solids initially, and there appears to be little difference between the effectiveness of different types of metal stents, although one small RCT suggested that covered metal stents are more effective than non-covered stents as they are complicated by less tumour ingrowth. In the HTA trial, dysphagia was actually worse in 10% of patients 6 weeks after stent insertion. In addition, although initial hospital stay was brief, the total number of inpatient days was in the order of 2—3 weeks, with a median survival of 4 months. There was no difference in cost or effectiveness between SEMS and non-SEMS treatments. It was concluded that an RCT of 18 mm SEMS versus non-stent treatments with survival and HRQL end points would be helpful, as would an audit of palliative patient admissions to determine the reasons and need for inpatient hospital care.
Patients can suffer acid reflux after stent insertion. A series of antireflux stents have been developed to overcome this. Several small RCTs have been performed, but results are inconclusive. Another new development has been the introduction of plastic (Polyflex) stents. A number of small RCTs have shown that these seem to be more difficult to place and have a higher risk of late complications, particularly migration, than metal stents. In addition, some aspects of HRQL were poorer with plastic stents.
Early complications after stent insertion are unusual and, in all RCTs, procedural mortality was acceptable at ≤2%. Late complications are, however, common and occur in up to 25% of patients. These include recurrent dysphagia due to tumour overgrowth for covered or ingrowth for uncovered stents, bolus obstruction and stent migration. In one retrospective study, membrane degradation of covered stents occurred in 8% of cases, leading to tumour ingrowth or reopening of a tracheo-oesophageal fistula which had initially been successfully covered by a stent.
The combination of radiotherapy and stents can be complicated. In patients who have had a stent placed before palliative external radiotherapy it is important to realise that stents appear to increase the radiotherapy dose delivered to the oesophageal mucosa.
Patients who have been previously treated with radiotherapy who later have stents inserted are at increased risk of complications. These may include increased risk of chest pain or severe complications such as fever, bleeding, perforation and fistula formation, which rose in one study from 3% to 23%. In another study, these findings were not confirmed. Other small studies suggest that these complications are relevant only in patients with T4 disease.
(UK/Ireland) Guidelines for the management of oesophageal and gastric cancer (2011)
- Oesophageal dilatation
As increasing numbers of patients are now treated with palliative radiotherapy, postradiotherapy strictures are increasingly common. Dilatation for these can be effective in ~80% of treatment sessions, with fewer complications than stent insertion.
- Brachytherapy and stents
The SIREC multicentre RCT of 12 Gy brachytherapy versus stent insertion included 209 patients in The Netherlands with inoperable oesophageal cancer. The primary outcome was relief of dysphagia during follow-up, and secondary outcomes were complications, treatment for persistent or recurrent dysphagia, HRQL and cost. Analysis was by intention to treat. Dysphagia improved more rapidly after stent placement (n=108) than after brachytherapy (n=101), but long-term relief of dysphagia was better after brachytherapy. Stent placement had more complications than brachytherapy (33% vs 21%; p=0.02), which was mainly due to an increased incidence of late haemorrhage (13% vs 5%; p=0.05). Groups did not differ for persistent or recurrent dysphagia (p=0.81), or for median survival (p=0.23). Patients undergoing brachytherapy reported significantly better role, emotional, cognitive and social function than those undergoing stent placement. Total medical costs were also much the same for stent placement and brachytherapy. The authors concluded that despite slow improvement, single-dose brachytherapy gave better long-term relief of dysphagia than metal stent placement. Since brachytherapy was also associated with fewer complications than stent placement, they recommended it as the primary treatment for palliation of dysphagia from oesophageal cancer. Unsurprisingly, physical and role function and other generic aspects of HRQL deteriorated over time before death, but the decline was more pronounced in the stent group. Given the delay to onset of benefit after brachytherapy, patient data from this study and a consecutive series (n=396) were analysed to create a prognostic model to help inform which patients should be offered stents and which should receive single-dose brachytherapy. Significant prognostic factors for survival included tumour length, WHO performance score and the presence of metastases (multivariable p <0.001) together with age and gender. This model could satisfactorily separate patients with a poor, intermediate and relatively good prognosis within the SIREC trial. For the poor prognosis group, the difference in dysphagia-adjusted survival was 23 days in favour of stent placement compared with brachytherapy (77 vs 54 days, p=0.16). For the other prognostic groups, brachytherapy resulted in a better dysphagia-adjusted survival. The costs of both treatments were very similar.
In another prospective study, the palliative effect of self-expandable stent placement was compared with that of endoluminal brachytherapy regarding the effect on HRQL and specific symptoms. Sixty-five patients with advanced cancer of the oesophagus or oesophago-gastric junction were randomised to treatment with either an Ultraflex expandable stent or high dose rate endoluminal brachytherapy with three doses of 7 Gy given in 2—4 weeks. This study was small and differences in baseline HRQL scores were observed between the two groups, but results were similar to the larger SIREC trial. In a related study by the same group, stenting was considered more cost-effective than brachytherapy.
- Iatrogenic perforation and tracheo-oesophageal fistulae
Small retrospective case series have shown that covered metal stents can be used successfully to cover iatrogenic oesophageal perforation and tracheo-oesophageal fistulae with minimal procedural morbidity and almost zero mortality. A small number of patients with high oesophageal tumours involving the trachea or major bronchi may benefit from tracheal stenting. This may be combined with oesophageal stenting, but tracheal stenting should always be done first to minimise the risk of causing stridor.
- Laser therapy and stents
Various small retrospective cost-effective analyses have compared oesophageal stenting with laser therapy. The mean survival and the cost were similar. In a small prospective randomised trial comparing stents with laser followed by palliative radiotherapy, there was no difference in survival but the costs of laser and radiotherapy were higher than stents. An RCT of 65 patients compared thermal laser ablation with stents. HRQL deteriorated in the stent group but not in the laser-treated group. Patients treated by laser lived longer than patients treated by stent insertion, but the cost of laser therapy was higher.
- Novel combinations of stents with other therapies
Fifty-three patients were entered into an RCT comparing treatment response with a self-expandable oesophageal stent loaded with [125I] iodine seeds for intraluminal brachytherapy versus treatment response with a conventional self-expandable covered stent in patients with advanced oesophageal cancer. Dysphagia improved in both groups within the first month after stent placement, but was better in the irradiation—stent group than in the control group after 2 months (p<0.05). The median and mean survival times were better in the irradiation—stent group than in the control group, and the differences were significant (p<0.001). Haemorrhage occurred in a large number of patients in both groups in this study (30%).
- Photodynamic therapy
PDT using Photofrin is a relatively new technique which remains unproven. PDT was successful in relieving dysphagia for ~9 weeks in 85% of 215 patients treated in one retrospective analysis. Patients living >2 months required re-intervention to maintain palliation of malignant dysphagia, and a multimodality treatment approach was common in this study. In another study, almost half the patients required a second treatment with PDT and 10% were later stented. Given that skin photosensitivity after Photofrin administration lasts for 3 months, and mean survival is <6 months, this approach has a significant side effect profile. PDT has been suggested as a salvage treatment for local recurrence after chemoradiotherapy. Compared with using it as a primary therapy, the risk of complications for PDT after chemoradiotherapy is eight times higher.
- Argon plasma coagulation
APC has been evaluated as palliation in a few studies. A retrospective study of 31 patients described complications and tolerance. These patients underwent a median of five treatments per patient (range 1—18). Recanalisation enabling passage of the scope was achieved in 89% of treatments. The dysphagia-free interval was 25 days (range 1—175 days). Perforation was seen in three patients (10%); procedure-related mortality was 1.2%. The median hospital stay for every treatment was 2 days (range 1—27 days). APC was well tolerated, safe and effective, and is an easy and cheap technique with no further restrictions than conventional monopolar electrocoagulation. A study to prospectively evaluate a new high-power system (hp-APC) evaluated palliative treatment of oesophageal cancer as one indication. The mean number of treatment sessions required was 2.3 (range 1—5). Minor complications (pain, dysphagia, neuromuscular irritation or asymptomatic gas accumulation in the intestinal wall) were observed in 13%. Major complications (perforation or stenosis) occurred in two patients (0.9%). Because of the low number of treatment sessions required, it was suggested that hp-APC could be used as an alternative to Nd:YAG laser treatment in tumour debulking. APC also has value in haemorrhage and in recanalisation of blocked stents, particularly with proximal or distal luminal overgrowth. This modality, nevertheless, remains experimental.
- Injection therapy
In a prospective RCT comparing ethanol injection with laser therapy, both resulted in similar long-term outcomes, but patients treated with ethanol had a much higher use of analgesia, at 78% compared with 5% with laser. In the HTA study, a small number had primary treatment with ethanol. All developed complete dysphagia, leading the authors to recommend that it should not be used as primary treatment.
(UK/Ireland) Guidelines for the management of oesophageal and gastric cancer (2011)
Monitoring[edit]
- Follow-up
Regular review of patients following treatment of oesophago-gastric cancer can fulfil a number of roles including aftercare and rehabilitation following therapeutic intervention: symptom management, supportive care and surveillance. The complexity of oesophago-gastric cancer treatment frequently induces symptoms which adversely affect HRQL. Specific post-treatment side effects including dysphagia from anastomotic stricture, diarrhoea related to vagotomy and post-thoracotomy pain need appropriate management. Disorders of physiology are not uncommon and may require careful assessment and treatment by a specialist gastroenterologist. These are often insidious, and change in fat and bile salt absorption as well as bacterial overgrowth may be unrecognised by the inexperienced.
Although regular review may identify early recurrence, there is no evidence for specific investigations nor that such an approach can affect OS. Endoscopy, cross-sectional imaging and tumour markers have all been evaluated, but lack specificity or sensitivity. It is accepted that patients may gain psychological support from regular review, although few studies have formally evaluated this, and patients may feel more anxious prior to a planned hospital visit. Regular access to CNS support may obviate this effect. Evidence from The Netherlands shows that nurse follow-up after oesophagectomy is both cost-effective and provides equal if not better patient experience.
The concept of survivorship or living beyond cancer is evolving, and experience of patient-led self-referral rather than clinic review at regular intervals is developing. This requires careful discussion and explanation of potential problems with each patient, taking into account individual risk and prognosis in the context of underlying stage of disease.
Clinical nurse specialists[edit]
The number of CNSs in the UK has increased to 1800, of which 10% are UGI CNSs. However recent evidence from the NHS peer review programme show that CNS provision for UGI cancer particularly at cancer units is among the lowest for all cancer sites. The role of the nurse includes clinical education, psychological support, research and consultation. The extent of the CNS role is difficult to measure because of the multifaceted nature of the work, complexity of the patient pathway and the more specific requirement to respond to individual patient needs.
Leary and colleagues have studied the work patterns of 463 CNSs (including gastrointestinal nurses) from the UK. Data demonstrate that 68% of time is spent on clinical matters. of which 48% is physical care and 32% psychological care. Not surprisingly, 33% of the nurses' time is given to telephone advice and 34% spent in an outpatient setting. The remaining time is spent on administration (24%), research (2%) and education (3%). CNSs use 'brokering' skills, provide 'clinical rescue work', advice on symptom control and support, and negotiate care pathways, all of which are intended to prevent adverse events, particularly readmission. The impact of psychological care and tailored information given in a supportive environment improves the patients' experience and HRQL. The results from the National Oesophago-Gastric Cancer Audit provide further support from patient experience surveys: 'the CNS role is the pillar in the system'.
The MDT is central to patient care, with CNSs having an integral role; consulting with medical, surgical and allied healthcare professionals in order to provide a co-ordinated approach to care, enhancing quality of care and patients' wellbeing. Nurses also have access to important information particularly acting as the patient's advocate that may influence clinical decisions, and it is therefore essential that MDTs listen to their views.
Prognosis[edit]
"Prognosis in esophageal cancer is greatly dependent on local invasion as well as spread to regional and distant structures within the body."
"Long-term prognosis after resection is better for adenocarcinoma compared to SCC. A study by Siewert et al[24]. Of 1059 patients who underwent resection showed the overall 5-year survival rate for the adenocarcinoma group was 47% in comparison to 37% for the group with SCC."
Esophageal cancer is a serious malignancy with regards to mortality and prognosis
Despite many advances in diagnosis and treatment, the 5-year survival rate for all patients diagnosed with esophageal cancer ranges from 15% to 20%
(SCC) "The overall prognosis of oesophageal squamous cell carcinoma remains poor based on diagnosis of predominantly late-stage disease. Screening programmes to detect precursor and early-stage lesions have been implemented in some high-risk populations. Radiofrequency ablation therapy and other forms of endoscopic treatments appear promising for eradication of early lesions." (SCC) "Recently, variants in SLC39A6 were conclusively associated with survival in individuals with oesophageal squamous cell carcinoma"
— WHO World Cancer Report
" Stomach, liver, and oesophageal cancers are three of the other major cancers in men that, like lung cancer, have relatively poor survival and hence mortality rates that are close to the incidence rates (incidence and mortality of 17.4 and 12.7 per 100 000, respectively, for stomach cancer, 15.3 and 14.3 per 100 000 for liver cancer, and 9.0 and 7.7 per 100 000 for oesophageal cancer). The other major cancer in men is colorectal cancer, which has an incidence rate of 20.6 per 100 000 but a substantially lower mortality rate of 10.0 per 100 000." "Due to the high fatality rate, (EC) mortality rates are close to incidence rates, regardless of sex differences and human development levels."
— WHO World Cancer Report
Prognostic factors
Platelet count has been used to help determine the prognosis of other cancers because platelets are an integral component of the inflammation processes. Platelet count is inversely related to the cancer prognosis, as in a higher platelet count correlates to a poorer prognosis. The absolute cut off for platelet count as a prognostic factor has been debated. In one study of ESCC, platelet counts were higher in patients with large tumors. It was determined that those patients with platelet counts ≤ 205000 had a better 5-year survival rate than patients with platelets > 205000 especially when nodes were involved[54]."
Tumor length is used as a prognostic factor in ESCC but the length cutoff point in predicting survival has been contested. Researchers in China looked at tumor length in the elderly population (over 70 years old) and the cutoff point was calculated to be 4.0 cm. Patients with a tumor length of ≤ 4.0 cm had a better 5-year survival than those with a tumor length of > 4.0 cm, especially with a T3-4 grade or nodal-negative patients[55]."
Cancer causes a hypercoagulable state and this environment encourages tumors to grow and produce more pro-coagulants. D-dimers are the end product of fibrin and fibrinolysis and have been reported to be associated with tumor prognosis, tumor stage, lymph node involvement, and overall survival. One study looked at the plasma D-dimer levels in patients with esophageal cancer before and after surgery as well as patients without cancer. Their research showed that high levels of D-dimers in the pre-operative state correlated with a higher tumor stage and surgery caused more patients to have a hypercoagulable state which shortened their survival time[56]."
Nutrition is an important factor that influences patients with esophageal cancer during their perioperative period. Early enteral nutrition was noted to protect the intestinal mucosa, improved the nutritional status, and increased the immune status patients undergoing esophagectomy. Enteral nutrition protected the intestinal mucosa by maintaining the intestinal barrier against plasma endotoxins[57]. Another study looked at immunonutrition in patients with head and neck cancer and esophageal cancer undergoing chemoradiotherapy. Plasma levels of arginine, eicosapentaenoic acid, docosahexaenoic acid, and nucleotides were measured in patients undergoing chemoradiotherapy, who received either an Immune modulating Enteral Nutrition formula (IEN) or an isocaloric, isonitrogenous formula, Standard Enteral Nutrition (SEN). IEN patients had less weight loss, increased antioxidants, and maintained their functional capacities compared to those with the SEN formula[58]."
Survival rates[edit]
Recurrence rates[edit]
Epidemiology[edit]
"The epidemiological features of adenocarcinoma of the oesophagus and of the oesophago-gastric junction match those of patients with known intestinal metaplasia in the distal oesophagus, i.e. Barrett oesophagus.
— WHO World Cancer Report
Barrett esophagus incidence increases with age and is uncommon in children. It is more common in men than women and more common in whites in comparison to Asian or African American populations.
(UK/Ireland) "The past decade has also seen changes in the epidemiology of oesophageal and gastric cancer. The incidence of lower third and oesophago-gastric junctional adenocarcinomas has increased further, and these tumours form the most common oesophago-gastric tumour, probably reflecting the effect of chronic gastro-oesophageal reflux disease (GORD) and the epidemic of obesity."
(UK/Ireland)
Over the past 20 years there has been an annual increase in incidence of adenocarcinoma of the oesophago-gastric junction in the UK. Demographically the peak age group affected is between 50 and 60 years of age, and the male to female ratio varies between 2:1 and 12:1. There have been parallel increases in adenocarcinoma of the gastric cardia, which now accounts for ~50% of all gastric cancers. The age group affected and the sex incidence are similar to those of adenocarcinoma of the lower oesophagus, suggesting a similar aetiology. Despite the rise in gastric cardia tumours, the incidence of gastric cancer is declining, with rates 11% lower in 2000 compared with 1990, because of a decreased incidence in distal gastric tumours.
"Accounting for more than 400000 deaths worldwide in 2005[1]. Esophageal carcinoma is the eighth most common cancer, and the sixth most common cause of cancer related deaths worldwide with developing nations making up more than 80% of total cases and deaths[2]. Over 490000 new cases of esophageal cancer were reported in 2005. While many other types of cancer are expected to decrease in incidence over the next 10 years by 2025 the prevalence of esophageal cancer is expected to increase by 140%[1]. According to the National Cancer Institute, in the United States there will be approximately 17990 new cases and 15210 deaths in 2013[3]. ... The epidemiology of esophageal cancer in developed nations has dramatically changed over the past forty years. Forty years ago squamous cell carcinoma (SCC) was responsible for greater than 90% of the cases of esophageal carcinoma in the United States. Adenocarcinoma has now become the leading cause of esophageal cancer in the United States, representing 80% of cases[5]. In 1975 esophageal adenocarcinoma (EAC) affected four people per million, in 2001 the rate had increased to twenty-three people per million. Making it the fastest-growing cancer in United States, according to the National Cancer Institute[6]. Considerable differences of incidence of esophageal cancer exist on the basis of geographic and racial differences, which can be linked to differences in exposure to risk factors."
Worldwide SCC is the most prevalent histological type of esophageal cancer, while in certain developed nations including Australia, Finland, France, United States and United Kingdom adenocarcinoma of the esophagus predominates[7]. Esophageal cancer incidence and histological type is highly variable based upon geographic location. Incidence rates of SCC of the esophagus have been reported as high as 100 cases per 100000 annually in an area referred to as the “Asian esophageal cancer belt” and this region extends from northeast China to the Middle East[8]. In the United States the National Cancer Institute estimates close to 18000 new cases and more than 15000 deaths from esophageal cancer in 2013[3]. From 1975 to 2004, the incidence of EAC among white American males increased by more than 460% and in the same period, the incidence among white American females increased by 335%[9].
It is a growing health concern that is expected to increase in incidence over the next 10 years. Squamous cell carcinoma is the most common histological type of esophageal cancer worldwide, with a higher incidence in developing nations. With the increased prevalence of gastroesophageal reflux disease and obesity in developed nations, the incidence of esophageal adenocarcinoma has dramatically increased in the past 40 years.
"SCC is the most common type of esophageal cancer worldwide. The overall incidence increases with age, reaching a peak in the seventh decade. SCC occurs equally as often in the middle and lower esophagus, with an incidence that is three times higher in blacks in comparison to whites."
"(AC) The countries with the highest incidence of this tumour type are the United Kingdom, Australia, the Netherlands, and the USA. Relatively lower incidence rates are reported from eastern Europe and Scandinavia. In Latin America, Asia, and Africa, oesophageal adenocarcinoma remains uncommon, but it is possibly also underreported (particularly in Latin America).
— WHO World Cancer Report
"Oesophageal adenocarcinoma is characterized by a high male-to-female ratio (from 4 to 7), with a higher incidence among Caucasians and among subgroups with a high socioeconomic status [14,15]. The incidence and prevalence of oesophageal adenocarcinoma was reported as rising during the last decades of the 20th century in a number of high-resource countries [14–16]. For example, in the USA, incidence rates for adenocarcinoma have been rising markedly, whereas rates for squamous cell carcinoma are declining steadily. From 1999 to 2008, rates among White men increased substantially (1.8% per year), as among White women (2.1% per year) and Hispanic men (2.8% per year). No significant changes were observed for men or women of other racial/ethnic groups. While rates of oesophageal adenocarcinoma have been increasing among Caucasians in some populations, it is extremely difficult to quantify the rate of increase from analysis of time trends in registry data, due partly to improvements in recording and capturing histology information (decreasing numbers of tumours without histological confirmation) but also because of changes in the assignment of cancers at the gastro-oesophageal junction, from the gastric cardia (or gastric, other/non-specified) to the oesophagus.
— WHO World Cancer Report
(Europe)
The crude incidence of oesophageal cancer in the European Union (EU) is about 4.5 cases/100 000/year (43 700 cases) with considerable geographical differences within the EU ranging from 3/100 000 in Greece up to 10/100 000 in France [1]. The age adjusted mortality is about 5.4/100 000/year (20 750 deaths) in men and 1.1/100 000/year (6 950 deaths) in women, respectively. While the incidence of SCC remains stable, the incidence of AC, particularly in the lower oesophagus, is rapidly rising in Western countries [2] and it now constitutes more than half of all oesophageal cancer cases.
(EC)Less common than colon or stomach but more lethal due to late diagnosis
— WHO World Cancer Report
- Oesophageal cancer is the eighth most common cancer worldwide, with an estimated 456 000 new cases (3% of all cancers) and 0.4 million cancer deaths (5% of all cancer deaths) in 2012. About 73% of all new cases occurred in countries at low or medium levels of human development, and 49% of all new cases occurred in China.
- (EC) Incidence and mortality rates are elevated in Central and East Asia as well as in eastern Africa. Incidence rates tend to be relatively low in western Africa and in some Latin American countries.
- (EC) Incidence varies 15-fold between countries worldwide in men and almost 20-fold in women. Incidence and mortality rates are 2–4 times as high in men as in women.
"Incidence and mortality trends are variable and reflect the changing prevalence and distribution of the underlying risk factors for oesophageal cancer and its main histological subtypes (adenocarcinoma and squamous cell carcinoma)"
"An increasing tendency to classify cancers located at the gastro-oesophageal junction as adenocarcinoma (rather than gastric cardia cancer) may also have had an impact on the overall trends."
"Among men, the most common cancers and causes of cancer death are cancers of the lung, stomach, liver, colorectum, and oesophagus"
"Likewise, in sub-Saharan Africa, the average incidence rate for oesophageal cancer in men is 6 per 100 000, ranging from 25 per 100 000 in Uganda and Malawi to less than 1 per 100 000 in Guinea and Nigeria. The reason for the variation in this case is little understood, which should act as a stimulus for research [19]."
"In 2010, the largest contributors to the burden of alcohol-attributable cancer deaths were: overall, liver cancer (responsible for 23.9% of all such deaths); for women, breast cancer (responsible for 42.0% of these deaths); and for men, oesophageal cancer (responsible for 27.4% of these deaths)."
— WHO World Cancer Report
(SCC) "encountered in individuals from low-resource regions" ...
"Squamous cell carcinoma of the oesophagus is characterized by great geographical variation. Pockets of high incidence (> 50 per 100 000 people) occur in the Islamic Republic of Iran (e.g. Golestan Province; > 100 per 100 000), parts of China (e.g. Linxian, Henan Province; > 130 per 100 000), and Zimbabwe. Intermediate incidence is seen in East Africa, southern Brazil, the Caribbean, much of China, parts of Central Asia, northern India, and southern Europe; incidence is low in North America, northern Europe, and western Africa. There are some data correlating ethnicity with the risk of squamous cell carcinoma, indicating that Turkish or Mongolian people in Central Asia and African Americans in North America are more likely than other people in those regions to be diagnosed with squamous cell carcinoma." ...
— WHO World Cancer Report
(SCC) "The prevalence of oesophageal squamous dysplasia parallels rates of invasive oesophageal squamous cell carcinoma; it is typically found in 25% or more of adults older than 35 years in north central China, where the risk of this malignancy is among the highest in the world [7]."
— WHO World Cancer Report
(AC) "tend to arise in high-resource populations"
— WHO World Cancer Report
Preventive strategies[edit]
(UK/Ireland)
Primary prevention is largely dependent on population education to alter social habits. A reduction in tobacco and alcohol consumption and an increase in a diet of fresh fruit and vegetables may reduce cancer incidence. Intervention trials to prove efficacy of these dietary strategies are lacking. In addition there is an enormous public health need to prevent obesity, which may lead to a reduction in incidence of UGI cancers. The role of H pylori eradication is important, although the potential paradoxical effect on oesophageal junctional adenocarcinoma needs further evaluation. Secondary prevention strategies exploit the natural history and detection of premalignant conditions. Identification of p53 expression and aneuploidy in biopsies of Barrett’s oesophagus has been shown to predict the risk of progression. These biomarkers, however, are not validated for routine clinical use. Increasing levels of cyclo-oxygenase-2 (COX-2) in the mucosa are present in the progression of atrophic gastritis to intestinal metaplasia and gastric cancer. However, smoking, acid and H pylori are all associated with COX-2 expression. Recently it has been shown in colorectal cancer, with a similar trend in oesophageal adenocarcinoma, that the level of cytoplasmic b-catenin is directly proportional to survival (ie, low levels with poor survival and high levels with good survival). Aspirin and other non-steroidal agents inhibit COX-2 and could be chemopreventative for gastric cancer. Aspirin may have an effect in Barrett’s metaplasia and, in combination with acid suppression, may minimise progression to dysplasia. The Aspirin Esomeprazole Chemoprevention Trial (AspECT trial) has successfully completed recruitment of 2513 patients into four arms (20 mg of esomeprazole alone, 80 mg of esomeprazole alone, 20 mg of esomeprazole with low dose aspirin and 80 mg of esomeprazole with low dose aspirin) and may demonstrate whether such a strategy can have a secondary cardiac and cancer preventive effect. Currently advice about chemoprevention using aspirin cannot be given until this trial is complete in 2019. The role of surveillance is yet to be proven, and in this regard the Barrett’s Oesophagus Surveillance Study is recruiting another 2500 patients to examine the role of 2-yearly endoscopy versus symptomatic need for endoscopy to reduce oesophageal adenocarcinoma. The role of host genetic susceptibility is shortly to be reported in a genome-wide assessment study called Inherited Predisposition to Oesophageal Diseases which is part of the UK-wide ChOPIN/EAGLE translational science infrastructure.
Screening[edit]
(AC) "Screening for BE via endoscopy is controversial and challenging. Currently no definitive screening protocol has been formulated due to lack of documentation that screening effects EAC mortality. A large number of patients with BE will not have reflux symptoms therefore predicting which patients will have BE prior to endoscopy is very challenging. Despite no definitive data for universal recommendation, most gastroenterological associations consider endoscopic surveillance “reasonable” and “desirable” in patients with diagnosed BE[21]. The primary goal of surveillance is to identify dysplasia before it progresses to an invasive malignancy. Current endoscopic technique consists of four quadrant biopsies taken every 2 cm in the columnar-lined esophagus for histological evaluation. The American College of Gastroenterology has recommendation guidelines for how often surveillance should take place based upon the presence or absence of dysplasia and grade of dysplasia if present. Surveillance endoscopy is recommended every 2-3 years in patients with no dysplasia. In patients with low-grade dysplasia, surveillance is recommended every 6 mo for the first year. If the dysplasia has not progressed in the first year, yearly surveillance is applicable. In patients diagnosed with high-grade dysplasia (HGD), two alternatives have been proposed. One option is to continue intensive endoscopic surveillance every 3 mo until intramucosal cancer is detected. The other alternative is for the patient with HGD to undergo endoscopic mucosal resection[20]. Although the natural history of HGD is variable, > 30% of patients with HGD will develop EAC within 5 years[22]. Due to the high risk of cancer most patients with HGD are evaluated as if cancer is present.
(AC) "Novel endoscopic techniques for early detection and treatment of oesophageal adenocarcinoma offer promise. Ablation therapy for high-grade dysplasia (the strongest risk factor for adenocarcinoma) is probably cost-effective [24]. Ideal strategies for population-based screening in high-risk patients remain poorly established and inconsistent. "(Is this about AC or AC & SCC? It follows the above para in the source.) A recent review [25] determined that endoscopic screening is invasive, costly, and error-prone owing to sampling bias and the subjective diagnosis of dysplasia. Non-endoscopic cell sampling methods (Fig. 5.3.6) are less invasive and more cost-effective than endoscopy, but the sensitivity and specificity of cytological assessment of atypia have been disappointing. The use of biomarkers to analyse samples collected using pan-oesophageal cell collection devices may improve diagnostic accuracy."
— WHO World Cancer Report
"Screening protocols remain poorly developed for oesophageal carcinomas."
— WHO World Cancer Report
" Evidence-based programmes for population-based screening of other major cancers, such as cancers of the ovary, liver, oesophagus, lung, and prostate, have not yet been established." "Research has indicated the efficacy of mammography and faecal occult blood screening and paved the way for population-based screening programmes. Screening approaches for other tumour types, such as lung, ovarian, oesophageal, stomach, and prostate cancer, are currently being investigated in research settings..."
— WHO World Cancer Report
Cancer control in China[edit]
"In 2005, China initiated a national programme of early detection and treatment for oesophageal cancer, gastric cancer, colorectal cancer, liver cancer, nasopharyngeal cancer, and lung cancer in high-incidence areas, and in 2009, China started a national screening programme for cervical cancer and breast cancer in rural areas. In both programmes, early detection and treatment has become an effective strategy for cancer control. For example, in some local areas of China, people have had very high rates of oesophageal cancer for a long time. The early detection and treatment programme screens residents in those areas aged 40–69 years by endoscopy with iodine staining and biopsy of early lesions. Patients with early-stage neoplasia, including severe squamous dysplasia, carcinoma in situ, and intramucosal carcinoma, can receive early treatments in a timely manner.
"To accumulate experience and optimize techniques for this plan, the national programme first chose eight high-incidence areas as demonstration sites and screened about 13 000 high-risk adults each year. Now, after a step-by-step expansion, 88 high-incidence areas in 26 provinces are participating in this early detection and treatment programme for oesophageal cancer [2]. From 2006 to 2012, 412 641 adults from high-risk areas were screened by endoscopy, and 4011 patients were diagnosed with severe precancerous lesions or early-stage cancer [2]. Most of these patients received timely treatment, with great benefit to health, and an economic analysis of this programme has shown that it is cost-effective [3].
"In addition to such early detection and treatment programmes, the Chinese government promotes widespread public education about cancer prevention and treatment, and has conducted interventions to control cancer occurrence, including neonatal vaccination against hepatitis B virus, programmes promoting better nutrition, and targeted programmes to improve occupational safety.
"The China National Central Cancer Registry has also improved the national cancer registry system, and since 2008 has reported national cancer registry data annually. In 2012, there were 222 cancer registry sites, covering 200 million people nationwide."
— WHO World Cancer Report
Research[edit]
Tumor markers of esophageal cancer are an advancing area of research that could potentially lead to earlier diagnosis as well as playing a part in assessing tumor response to therapy.
Tumor markers
Serum human relaxin 2 (H2 RLN) is made in the corpus luteum of females and the prostate of males. It helps remodel various tissue components such as extracellular matrix, collagen, and matrix metalloproteinase. There is supporting evidence that RLN is a tumor growth factor and has been shown in vitro to enhance invasiveness of breast cancer cells. A study measuring RLN levels in patients with esophageal SCC (ESCC) discovered that patients with higher levels of H2 RLN had more distant metastasis, lymph node metastasis, higher clinical stage, and a shorter survival rate. This study demonstrated the possibility of using H2 RLN as a serum prognostic factor for ESCC[50]. A Japanese study, investigated the prognostic value of the tumor marker p53 in ESCC. They observed no correlation between a p53 aberration and any clinical, pathological, or epidemiology of ESCC[51]. Another study investigated the marker gene, WDR66 through genome-wide expression profiling. Other WD proteins have been used as tumor markers in other cancers, such as hepatocellular carcinoma. WDR66 has a higher concentration in ESCC tissue than healthy tissue. WDR66 was found to have a role in the growth, motility, and epithelial-mesenchymal transition of ESCC. Poor survival was noted with high levels of WDR66 in the tumor tissue[52]. In a Chinese study, the gene marker phospholipase A2 group IIA (PLA2G2A) was investigated to determine its usefulness as a prognostic factor of ESCC. PLA2G2A catalyzes multiple fatty acids, including arachidonic acid and is expressed in colorectal, pancreatic, prostate, gastric and lung cancer. Low expression of PLA2G2A in tumor tissue correlated to high-grade tumors, metastasis, increased depth of invasion, lymphatic invasion, and poorer overall survival rate[53].