Oesophageal Cancer

Oesophageal adenocarcinoma (OA) is now the most common type of oesophageal cancer in USA and Europe, with gastro-oesophageal reflux disease (acid reflux)(GORD) and obesity, the main risk factors. Barrett’s oesophagus, seems to be the recognised precursor lesion, and can be detected by high quality endoscopic. Early detection can lead to treatment of precancerous lesions and surveillance for the development of neoplastic progression in high risk groups. Squamous –Cell Carcinoma remains the predominant oesophageal cancer in Asia, Africa, and South America and among African Americans in North America. Alcohol and tobacco use seem to be the main risk factors, and oesophageal squamous dysplasia is the precursor lesion. The 5-year survival rate for patients with oesophageal cancer has improved during the past decade, and long-term survival is increasingly possible for patients with early or locally advanced disease.

Epidemiology;
Oesophageal cancer has two main subtypes — SCC and OA. SCC accounts for about 90% of cases of oesophageal cancer worldwide. However, the incidence of and mortality rates associated with OA have risen dramatically in North America and Europe and is now more prevalent that Squamous disease. Oesophageal carcinoma increases in incidence with age, peaking in the seventh and eighth decades of life. Adenocarcinoma is three to four times more common in men, whereas the sex distribution is more equal for SCC. In the USA, 18,000 new cases of oesophageal cancer and more than 15,000 deaths from oesophageal cancer were expected in 2014. Over the past three decades, the rates of SCC have declined, while those of OA have been progressively increasing

Environmental risk factors; Population-based case–control and cohort studies suggest that reflux, cigarette smoking, and obesity are the main risk factors for oesophageal cancer. The absolute risk of OA developing in a person 50 years of age or older is approximately 0.04% per year. However, about 40% of patients who develop oesophageal cancer do not report reflux symptoms.
The risk of OA is about twice as high among current smokers, but smoking seems a more significant risk factor for SCC. Population-based studies have not shown an association between alcohol consumption and OA, whereas SCC is three to five times as likely among people who consume alcohol (three or more drinks daily), and the risk increases synergistically with tobacco smoking. High intake of red meat, fats, and processed foods is associated with an increased risk of both types of oesophageal cancer, whereas high intake of fibre is associated with a lower risk.
It has been suggested that the increasing incidence of OA is related to the increasing prevalence of reflux disease alone, obesity plus reflux, and with the declining prevalence of Helicobacter pylori infection. Obesity is associated with a risk of OA that is increased by a factor of 2.4 to 2.8. Populations in which H. pylori infection is prevalent seem to have a reduced risk of OA. A meta-analysis of 15 observational studies showed that the risk of adenocarcinoma decreased by 41% among persons with H. pylori infection. H. pylori infection, which leads to gastritis, may reduce acid production by causing gastric atrophy, leading to a reduction in the exposure of the oesophageal epithelium to acid, thereby reducing the risk of Barrett’s and adenocarcinoma. Treatment and eradication of H. pylori in infected patients neither causes nor exacerbates GORD in most cases. Overall, no consistent association between H. pylori and SCC has been shown.
OA has been reported in association with alendronate use.18 However, subsequent population-based studies and meta-analyses examining the association between bisphosphonate use and OA yielded conflicting results. Oncogenic human papillomaviruses may increase the risk of SCC, but the evidence is inconclusive. In addition, SCC is up to 10 times as likely to develop in patients with achalasia, an oesophageal motility disorder, as it is in persons without achalasia.

Genetic factors
Familial clustering in Barrett’s and adenocarcinoma has been observed. Genome-wide, combined linkage-association analysis, germline mutations were identified in one of three candidate genes. Identifying these genes and other biomarkers may enable identification of high risk individuals. In addition non-endoscopic cell collection device called the Cytosponge, promises to make screening for Barrett’s and oesophageal cancer easier and cheaper. This immunocytological approach will allow screening of patients at risk for oesophageal cancer (adenocarcinoma, and in time squamous cell cancer), on a large scale and in a cost-effective way.

Endoscopic screening and Barrett’s
In Barrett’s, which is considered the precursor of OA, specialised intestinal columnar epithelium replaces the normal squamous epithelium. Large cohort studies suggest that the annual cancer risk for patients with non-dysplastic Barrett’s is 0.12 to 0.40%. Dysplasia within Barrett’s lesions signals a marked increase in cancer risk — the annual risk is approximately 1% for patients with low-grade dysplasia and more than 5% for patients with high-grade dysplasia. However, 80 to 90% of cases of OA are diagnosed in patients without known Barrett’s. Endoscopic screening detects of Barrett’s in 6 to 12% of patients with prolonged GORD symptoms, most frequently white men older than 50 years of age. Endoscopic surveillance every 3 years is recommended for patients with known non-dysplastic Barrett’s. Despite the absence of direct evidence from randomised trials, most studies have shown that when adenocarcinoma is detected in an individual during a surveillance procedure the lesion is more likely to be early-stage cancer, receive curative therapy, and survive longer than symptomatic patients in whom adenocarcinoma is detected.
Radiofrequency ablation of Barrett’s lesions with low-grade or high-grade dysplasia results in resolution of oesophageal metaplasia in up to 77% of cases and resolution of dysplasia in 86% of cases. Long-term follow-up has demonstrated the durability of such effects, but ongoing surveillance after radiofrequency ablation is essential because of the risk of recurrence, which tends to be mostly non-dysplastic and endoscopically manageable.55 Current guidelines do not support the use of endoscopic ablation for non-dysplastic Barrett’s; however, there maybe an argument to consider all high-risk patients with long-segment Barrett’s, severe GORD, or a family history of Barrett’s or adenocarcinoma to be considered for ablative procedures.
The precursor lesion for SCC is oesophageal squamous dysplasia; patients with mild, moderate, or severe dysplasia have a risk of SCC that is increased by a factor of 3, 10, or 30, respectively. Endoscopic screening or non-endoscopic use of balloon brush cytological testing has been performed in some regions in China and may have merit; these techniques are also recommended for patients with achalasia or those with a history of lye ingestion resulting in stricture, although there are no evidence-based guidelines for the treatment of these patients.

Prevention
Proton-Pump Inhibitors;
Several observational, clinic-based cohort studies have shown a significant association between treatment with proton-pump inhibitors and a decreased risk of high-grade dysplasia and adenocarcinoma in patients with Barrett’s. However there are some limitation to these studies including possible selection bias and limited adjustment for possible confounding factors. Several retrospective cohort studies have shown no reduction in the risk of OA among patients with GORD or Barrett’s after anti-reflux surgery.
Aspirin and NSAIDs
Observational studies show a 40 to 50% reduction in the risk of OA and SCC with aspirin or non-steroidal anti-inflammatory drug (NSAID) treatment. One randomised trial of celecoxib did not show a reduction in cancer risk among patients with Barrett’s and low-grade or high-grade dysplasia. Another randomised trial showed that celecoxib did not affect the progression of oesophageal squamous dysplasia As a consequence of this conflicting data, large trials examining the effects of proton-pump inhibitors and aspirin on clinical outcomes in Barrett’s are ongoing.
Statins
A meta-analysis of 13 studies demonstrated a 28% reduction in the risk of OA in those taking a statin when compared with nonusers, and a 41% reduction in the risk of OA among patients with Barrett’s. However, there was considerable inconsistency in these studies and no clear associations with dose, duration, or statin type.

Clinical presentation of Oesophageal Cancer
The clinical presentation is similar between OA and SCC, despite differences in demographic and risk factors. The endoscopic appearance is also similar, although the majority of adenocarcinoma lesions are in the distal oesophagus, whereas SCC is more common in the upper to middle oesophagus. Common clinical presentations include progressive dysphagia, weight loss, and heartburn unresponsive to medical treatment, as well as with symptoms and signs of anaemia; An increasing number of essentially asymptomatic cases are being discovered as part of screening and surveillance endoscopy. Less common symptoms include hoarseness, cough, and pneumonia related to laryngeal nerve paralysis or invasion of the tracheobronchial tree. There is also an increased risk of synchronous and metachronous SCC in patients with head and neck SCC.

Management
An outline of the management of oesophageal carcinoma is shown in table 1
Management Approach
Staging Endoscopy with or without mucosal resection, CT TAP EUS and PET
Treatment
Mucosal tumours (stage 0/1)
All tumours except T1b Endoscopic mucosal resection (EMR) or oesophagectomy with lymphadenectomy
T1b tumours Oesophagectomy with lymphadenectomy
Localised tumours (stage 11a or 11B) Oesophagectomy preceded by neo-adjuvant chemoradiotherapy
Advanced tumours (stage111 or 1V) Endoscopic palliation with self expanding metallic stent with or without brachytherapy
Advanced or recurrent tumours 2-3 drug combination therapy (if medically fit)

The management principles are generally similar for the two histologic types of oesophageal carcinoma, except for differences in the choice of chemotherapy or surgery. Adenocarcinoma involving the gastro esophageal junction is generally considered part of the continuum of OA.
Staging
The prognosis and treatment for patients with oesophageal carcinoma depends on accurate and reliable assessment of the depth of invasion and status with respect to lymph-node involvement. Over the last decade the use of endoscopic ultrasonography (EUS) and positron-emission tomography (PET) has improved staging; adding fine-needle aspiration to endoscopic ultrasonography improves the sensitivity of lymph-node staging. EUS is particularly helpful for staging in patients with no obvious regional or distant spread seen on imaging of the chest and abdomen; in such cases, endoscopic mucosal resection offers improved staging as well as an opportunity for cure. PET scanning identifies occult distant metastases, which are most common in the supraclavicular and retroperitoneal lymph nodes, and leads to establishment of a more advanced stage in 10 to 20% of cases.
Mucosal Tumours
Endoscopic mucosal resection (EMR) with or without ablation has been a major advance in treating Barrett’s with high-grade dysplasia or adenocarcinoma that is limited to the epithelial portion of the mucosa (category T1a), particularly for small tumours (<2 cm in diameter) that are asymptomatic and non-circumferential. This approach is usually followed by endoscopic ablation of the remaining Barrett’s lesions.

The risk of lymph-node metastasis (and need for surgery) is correlated with the depth of tumour invasion; the risk is close to zero among patients with Barrett’s who have high-grade dysplasia and is only 1 to 2% among patients with stage I tumours. There are no data from randomised trials comparing endoscopic therapies with surgical approaches, but observational studies suggest that cure and survival rates associated with endoscopic treatments are equivalent to the rates with surgical resection, without the potential mortality/morbidity. Endoscopic therapy should be considered as first-line therapy for patients with stage 0 or I OA who do not have contraindications or major coexisting conditions. For patients with T1b tumours that have penetrated into the submucosa, the risk of lymph-node spread is as high as 20%, and radical oesophagectomy may be the preferred method of treatment, although some treatment centres have expanded the indications for endoscopic therapy to include low-risk submucosal tumours.
Locally Advanced Tumours
Locally advanced tumours, defined as category T3N1, are best treated with oesophagectomy. Although cure through definitive chemoradiotherapy alone has been reported, especially in patients with SCC, this approach is not supported by evidence from randomised, controlled trials and should be restricted to patients who are unfit for oesophagectomy. Unfortunately, oesophagectomy alone is associated with a high rate of recurrence and low 5-year survival rates (5 to 34%). The main advance in treating patients who undergo oesophagectomy has been the adoption of neo-adjuvant treatment. Randomised, controlled trials have shown a survival benefit with neo-adjuvant chemoradiotherapy or chemotherapy, as compared with oesophagectomy alone, in both types of oesophageal carcinoma. Surgical outcomes appear to be better in high-volume centres and with experienced surgeons, a benefit apparently related to the incidence and management of postoperative complications.

Advanced Tumours
Obstructive symptoms related to unresectable disease can be palliated with endoscopic oesophageal stenting or high-dose intraluminal brachytherapy. Endoscopic placement of self-expanding metal stents has become the standard palliative option for dysphagia. Randomised, controlled trials have shown higher symptomatic relief, as well as less need for re-intervention due to complications, with self-expanding metal stents than with loco-regional treatment. The addition of high-dose brachytherapy to stenting may lead to a modest improvement in survival. Other options such as endoscopic dilation or ablation, placement of plastic stents, bypass surgery, or chemoradiotherapy, are not recommended because of their low efficacy and high rates of complications. Palliative chemotherapy is also commonly used to treat patients with unresectable, metastatic, or recurrent disease.

Prognosis
The overall 5-year survival rate for patients with OA in the United States is approximately 17%, which is slightly higher than rates for patients with SCC. There has been a progressive improvement in overall survival and a marked improvement in progression-free survival among patients who undergo surgical resection. Although access to diagnostic tests has improved most tumours are found when regional metastasis (in 30% of cases) or distant metastasis (in 40% of cases) has already occurred, at which point the 5-year survival rate declines from 39% in cases of localized disease to 4% in cases with distant metastasis.

Conclusions
The main risk factors for OA are acid reflux, obesity, and cigarette smoking; H. pylori infection is associated with a reduced risk. Cigarette smoking and alcohol consumption are the main risk factors for SCC. Gastroscopy in symptomatic patients will allow for the identification of Barrett’s, which should lead to appropriate surveillance of Barrett’s for the detection of dysplasia and early-stage OA. Endoscopic ablative therapy is effective for the treatment of dysplasia and may have an important role in the treatment of intra-mucosal adenocarcinoma. Identification of certain genes might provide insights into the underlying pathogenesis of oesophageal cancer and may have translational implications for biomarker identification and development of novel therapies