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ORIGINAL ARTICLE
Year : 2013  |  Volume : 1  |  Issue : 1  |  Page : 19-27

Advances in oesophageal cancer


Department of Surgery, University of Adelaide and Royal Adelaide Hospital, Adelaide, South Australia

Date of Web Publication17-Apr-2013

Correspondence Address:
Peter Devitt
Department of Surgery, University of Adelaide and Royal Adelaide Hospital, Adelaide
South Australia
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DOI: 10.4103/1658-600X.110670

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  Abstract 

Adenocarcinoma (AC) of the oesophagus is an important disease in western communities in terms of its unprecedented recent increase in incidence and its relatively poor outcomes despite today's variety of treatment options. The increasing incidence of this deadly disease is probably related to the changing lifestyle patterns within affluent societies, in terms of diet and sedentary practices, obesity and the prevalence of gastro-oesophageal reflux disease. Barrett's oesophagus has been identified as a major risk factor and surveillance strategies for at-risk groups are being proposed, together with endoscopic management strategies for those with high-grade dysplasia or early and localised AC. It is recognised that the disease is better treated in high-volume centres under the guidance of a multidisciplinary team. Increasing availability and accuracy of sophisticated staging tools such as endoscopic ultrasound, endoscopic mucosal resection and positron-emission tomography (PET) have helped define treatment strategies. Endoscopic tools can identify patients who might be suitable for some form of local ablative therapy and PET scanning will often pick up metastatic disease missed with other imaging investigations. Refinement of the pathological staging system has also helped define treatment modalities. Although surgery may still be seen as the mainstay of treatment, its use is now more in context with adjuvant therapies. With the unwavering epidemic of obesity, it is likely that AC of the oesophagus is going to remain an important disease confronting healthcare and this paper deals with some of the current issues.

Keywords: Adenocarcinoma, oesophageal cancer, squamous cell carcinoma


How to cite this article:
Knight B, Devitt P. Advances in oesophageal cancer. J Health Spec 2013;1:19-27

How to cite this URL:
Knight B, Devitt P. Advances in oesophageal cancer. J Health Spec [serial online] 2013 [cited 2020 Jan 17];1:19-27. Available from: http://www.thejhs.org/text.asp?2013/1/1/19/110670


  Introduction Top


Changes in the incidence of carcinoma of the oesophagus and new strategies in its management have had a major impact on healthcare delivery for this important gastrointestinal tract cancer. For reasons that are not absolutely clear, incidence of the disease has increased out of proportion to that of many other cancers, particularly in white males. [1] There have been a number of important recent changes in the approaches to its management in terms of screening, staging and treatment. This paper covers some of the current issues and developments.


  Epidemiology Top


Cancer incidence

Oesophageal cancer comprises mostly two histological subtypes, adenocarcinoma (AC) and squamous cell carcinoma (SCC), the latter mostly a disease of the developing world and lower socioeconomic class. It is the eighth most common cancer in the world (estimated 480,000 new cases per year), with SCC predominating. It is the sixth most common cause of cancer death. [2],[3]

Over the last three decades there has been a dramatic increase in the incidence of oesophageal cancer. Whereas the rate of SCC is declining (reported incidence decreasing from 17.9 per 100,000 in 1973 to 8.9 per 100,000), AC has now become a relatively common cancer in many Western communities. [4],[5] In these regions there has been a 600% increase in the incidence of oesophageal AC since the 1970s - a far greater rate than for any other solid tumour. [6] The reasons for this rapid increase are not absolutely clear, but are probably related to diet, obesity, gastro-oesophageal reflux and smoking. [7] Recent population-based studies suggest that obesity, per se, is an independent risk factor for AC of the oesophagus. [7],[8]

Tumour location

Over the last 50 years, the pattern and distribution of oesophageal and gastric cancers have changed with migration towards the oesophago-gastric junction (OGJ). Gastric cancers have migrated proximally and oesophageal cancers distally. The most marked change has been in Western males in whom the incidence of AC of the OGJ has increased from 1-2 per 100,000 to 8-12 per 100,000 over the last 35 years. [9]


  Risk Factors Top


Obesity

The mechanism defining the link between obesity and oesophageal AC would appear to be an increased incidence of gastro-oesophageal reflux disease in the overweight population. However, the association between the two appears to be independent of symptomatic reflux and obesity might have a separate role as a risk factor. [7],[8] On the other hand, it is possible that asymptomatic reflux occurs more frequently in obese individuals. [10] From the obesity perspective, there may be other possible mechanisms, including changes at the molecular level, such as upregulation of leptin, a hormone known to stimulate cell growth in oesophageal AC, and an increase in the prevalence of Barrett's oesophagus in the obese. [11],[12]

Gastro-oesophageal reflux disease

Gastro-oesophageal reflux disease predisposes towards the development of Barrett's oesophagus and it is postulated that Barrett's oesophagus is a pre-cursor of many - if not all - cases of AC of the oesophagus. Epidemiological studies suggest that gastro-oesophageal reflux and Barrett's metaplasia occur more frequently among the affluent and overweight, and while these conditions have shown a five-fold increase in incidence in the Western countries in the last 30 years, they are now becoming more common in Asian countries, the latter probably being a reflection of their "westernisation" in terms of diet and lifestyle. [13]

Obesity contributes to hiatus hernia formation and encourages gastro-oesophageal reflux. Reflux promotes a metaplastic change in the lower oesophagus and thus the risk of malignant change.

Barrett's oesophagus - screening and surveillance

Barrett's oesophagus is defined as replacement of the normal squamous epithelium with columnar lining and intestinal metaplasia. Barrett's is not common in Chinese and Asian communities, where most oesophageal cancers are SCC. [14] This observation again lends support to the hypothesis that Barrett's oesophagus is an important aetiological factor in the development of AC.

For a disease that has shown such a sharp increase in incidence, it might appear logical to identify and screen at-risk populations. Screening the population as a whole is unlikely to be cost-effective, but it might be feasible to target those at higher risk. If it is accepted that Barrett's oesophagus is a sequelae of chronic reflux, then it might make sense to screen these patients. The risk profile for Barrett's parallels that for AC and includes higher socioeconomic status, obesity and smoking. [15] There may be an inverse relationship between the presence of  Helicobacter pylori Scientific Name Search rett's with high-grade dysplasia, suggesting that the relative achlorhydria of chronic H. pylori infestation may be exerting a protective effect in patients with gastro-oesophageal reflux. [16]

One problem with this proposition to screen at-risk patients is how best to identify them. The prevalence of Barrett's oesophagus is less than 2% of the adult Caucasian population, and almost half of the patients who develop AC of the oesophagus do not present a history of any prior heartburn. [17] A random sampling of an otherwise healthy population found a prevalence of Barrett's oesophagus of 1.6% in individuals with symptoms of gastro-oesophageal reflux and a very similar (1.2%) prevalence in asymptomatic individuals. [18]

While a patient with Barrett's oesophagus has a 20-fold increased risk of developing AC of the oesophagus, the absolute risk for such a patient is less than 1 per 1,000 person years. [19] Confounding the issue even further is the observation that endoscopic screening has not improved the outcome for oesophageal AC. [20],[21] A smaller high-risk group needs to be identified for a screening program to be viable and this may come in the form of novel biomarkers. [22]

Provided there is no dysplasia, the risk of a malignant change is probably no greater than for any patient without Barrett's epithelium. [23] Current guidelines suggest that these patients only require endoscopic surveillance every 3-5 years. [24]

Barrett's can be subdivided into long- (>3 cm) and short-segment (<3 cm), with the suggestion that there is a lower incidence of cancer in the latter. [25] However evidence is conflicting and any difference might represent observer error on what is short-segment Barrett's and what is gastric epithelium in a small hiatus hernia. The risk of submucosal disease and with it, lymph node involvement, appears to increase with the length of an endoscopically visible tumour, particularly if nodularity or ulceration is present. [26]

High-grade dysplasia and early oesophageal cancer

The importance of this disease in medical practice is that among all malignancies, AC of the oesophagus is the one that appears to be increasing in incidence at the greatest rate and has a relatively poor prognosis with an average 5-year survival of 15-30%. [27],[28],[29] However, if the disease can be detected at an early stage, the prospects of survival are good. [30]

There is considerable inter-observer error in the distinction between high-grade dysplasia and intra-mucosal carcinoma, and it is suggested that such biopsies be assessed by at least two experienced gastrointestinal pathologists. [19] The presence of visible lumps or nodules increases the likelihood that the lesion is more advanced and endoscopic mucosal resection often leads to an upgrading of the final diagnosis with a consequent change in management. [31]

Morphologically, Barrett's can be divided into long- or short-segment disease, with the former having a greater risk of malignant change. A population-based study from Sweden suggested a prevalence of Barrett's oesophagus of about 2% in the adult population. [18]

Treatment of high-grade dysplasia and early AC of the oesophagus is controversial. The risks of treating invasive disease or early disease with possible lymph node spread have to be balanced against the morbidity (and mortality) of oesophagectomy. Oesophagectomy is associated with an operative mortality rate of 2% and this must be taken into account when counselling patients with intra-mucosal carcinoma, where unexpected lymph node involvement will be found in 1-2% of patients undergoing resection. [32] However, endoscopic mucosal resection/surgical dissection, argon beam plasma coagulation and radiofrequency ablation are all effective strategies. [33]


  Assessment and Staging Top


Multidisciplinary team (MDT) and specialist centres

Ideally, all cases of oesophageal cancer should be discussed by a local or regional oesophago-gastric MDT meeting, and this practice is now the standard of care. Clinical policy is generally agreed through a local cancer network. MDT members will comprise representatives of all disciplines likely to be involved in the management, with input from medical gastroenterologists, histopathologists, radiologists, oncologists, specialist cancer nurses, dieticians and palliative care physicians. Patients managed by an MDT are more likely to have appropriate and timely treatment, better trial recruitment and cancer outcomes. [34] High-volume centres (>10 cases per year) are associated with better 30-day mortality and morbidity, greater lymph node harvest and 3-year disease-free survival. [35],[36],[37],[38],[39]

Staging investigations

Accurate staging will help determine which patients might be best treated by some form of local ablative therapy (radiofrequency ablation or endoscopic mucosal resection), who might be suitable for a more radical approach and who would be better treated on a palliative basis.

Upper gastrointestinal endoscopy with biopsy and computerised tomography (CT) of chest, abdomen and pelvis remain mandatory staging investigations. Positron-emission tomography (PET) and endoscopic ultrasound (EUS) have been valued additions to the staging algorithm over the last decade.

Positron-emission tomography

PET assesses the physiological functions (and to a lesser degree anatomical details) of tumour cells by utilising radiolabelled 18 F-fluorodeoxyglucose and conventional CT imaging. [40] Approximately 90-95% of primary oesophageal cancers are PET-avid. [41],[42] This is in contrast to gastric cancers, which are approximately 60% PET-avid. [43]

The major benefit of PET-CT is in the detection of distant metastasis with a reported sensitivity and specificity of 67% and 97%. [44] Its role in detecting regional lymph nodes is less clear and results have been disappointing probably because of the close proximity of nodal disease to the primary tumour. A recent article evaluating 200 patients has shown that PET altered patient management in 17% of the patients. [45]

A novel role of PET is assessing tumour response to adjuvant treatment. Trials have shown that an observed response to neo-adjuvant chemo-radiotherapy on PET- CT was strongly associated with a better prognosis. [46],[47] A systematic review assessing different modalities in assessing tumour response to neo-adjuvant treatment has also shown that PET is significantly better than CT at predicting tumour response and was associated with a better 5-year survival. [48] PET may be used to assess patients who are not responding to neo-adjuvant treatment, and whose treatment should be cut short and go straight to surgery to avoid the ongoing toxic effects of an ineffectual treatment.

Endoscopic ultrasound

EUS utilises a small ultrasonic transducer (either radial or linear) on the tip of an endoscope. Its primary role is accurately staging the depth of local tumour involvement (T-stage), the length of tumour and the presence of nodal (N-stage) metastasis. [49] With respect to loco-regional disease, EUS is superior to PET and CT, and is as effective as PET and better than CT in assessing the response to neo-adjuvant therapy. [48],[49],[50],[51],[52]

EUS has a key role in its ability to differentiate between T1a, T1b and T2 lesions. [53] If suspicious, tissue can be obtained from loco-regional lymph nodes for cytological analysis, thereby increasing the accuracy of this staging investigation. [54] Limitations of EUS include its inability to negotiate tightly stenotic tumours and its operator dependency. [55],[56]

Endoscopic mucosal resection has allowed detailed histological analysis of early lesions and better staging accuracy than EUS, and may supersede its role. [57],[58],[59] Accurate T-staging is critical as the incidence of lymph node involvement rises from less than 2% with T1a lesions to about 20% with T1b lesions. [60]

Pathological Staging

The seventh edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual was published in 2009 and is universally used for staging oesophageal cancer. [61] One of the main goals of the revision was to dismantle the ambiguity surrounding OGJ cancers. OGJ cancers, including those arising within 5 cm of the proximal stomach and crossing the OGJ, are staged as oesophageal cancers. Those not crossing the OGJ are classified as gastric cancers. T1 tumours have also been subdivided into T1a (tumour invading the lamina propria or submucosa) and T1b (tumour invading submucosa). The importance of this is that T1a tumours have a 2% chance of lymph mode metastasis compared with T1b in which lymph node metastasis of 25% has been seen. [62] Node status has also been reclassified: N0 (no nodes), N1 (1-2 nodes), N2 (3-6 nodes) and N3 (>7 nodes).

Sentinal Lymph Nodes and Micrometastasis

The sentinel lymph node is the first lymph node receiving lymphatic drainage from a tumour and should in theory be the first site of metastatic tumour spread. The sentinel lymph node concept is well established in breast cancer and malignant melanoma, but is less well defined in oesophageal carcinoma due to the variation in lymphatic drainage patterns of oesophageal cancers.

According to the current AJCC TNM classification, it appears that prognosis is more closely related to the number of lymph nodes involved rather than their site or tumour depth. [63] Methodologies are now being developed to apply the sentinel node principle to oesophageal cancer. [64] In a report from the UK examining 1667 lymph nodes, the sentinel lymph node was identified in all 57 patients with lower oesophageal cancer. In this report, the sensitivity of the sentinel lymph node in determining lymph node metastasis was 96%. [65]

Using techniques similar to that of sentinel node biopsy in breast cancer, such nodes can also be identified by both methylene blue dye and radioscintigraphy. [66] Preliminary studies have shown that sentinel nodes can be identified in vivo and ex vivo in patients with oesophageal cancer undergoing resection with conservative lymphadenectomy. There are conflicting views on the efficacy of these techniques, with a false-negative rate of 15% reported using the patent blue and trans-hiatal oesophagectomy, but a sensitivity of 90% with the radiolabelled technique. [66],[67] If such nodes can be identified with certainty and subsequently biopsied, it might be possible to avoid resection for early-stage disease - and perhaps even T2 disease. Such decisions are likely to be influenced by the degree of accuracy of lymph node staging, with the recognition that the traditional single-slice sectioning of nodes may lead to under-staging and serial sectioning of targeting sentinel nodes may be more appropriate. [68],[69]

Management of Oesophageal Cancer

Management options will be determined by the mode of presentation, the stage of the tumour and the general state of health of the patient. With increased sophistication in staging, availability of new treatments, use of MDTs in decision-making and the recognition that better outcomes can be expected from high-volume centres, the management of oesophageal cancer is very different to what it was two or three decades ago. [34],[35],[36],[39]

Recognition of T1a and T1b disease is of crucial importance in terms of determining treatment and likely outcome due to the increase incidence of lymph node involvement in T1b disease. Where there is a significant chance of lymph node involvement, some form of neo-adjuvant therapy might be appropriate, patients with true T1a disease could go straight to surgery. Thus an accurate histological diagnosis is essential and endoscopic mucosal resection has an important role in assessing the stage of disease, providing sufficient tissue for thorough pathological assessment and determination of the depth of tumour invasion. [26]


  Neo-Adjuvant Treatment Top


Chemo-radiotherapy

The proposed advantages of neo-adjuvant therapy are tumour down-staging, increased resection rates with clear microscopic tumour margins, and early targeting of distant and local micro-metastasis prior to surgery.

For the last 20 years, concomitant chemo-radiotherapy (CRT) has been the gold standard in the USA and Australia. [70],[71],[72] Walsh et al., [72] showed improved median survival from 11-16 months with the addition of neo-adjuvant CRT and this forms the backbone of the treatment protocols in the USA, central Europe and Australia.

It is accepted that CRT offers significant survival advantage over surgery alone, but it is still disputed if it is superior to chemotherapy alone particularly with respect to AC. van Hagen et al., [73] recently published an RCT comparing CRT and surgery vs. surgery alone in a mixture of SCC and AC. Pathological complete response rate was 29% and with a significantly better 5-year survival in the CRT arm (hazards ratio 0.65). Criticism has been that significance was only due to the inclusion of SCC, which comprised 25% of all the cases. It did however conclusively show that surgery can be performed safely after CRT with no increase in morbidity or mortality. These findings have also been replicated in a meta-analysis. [74]

Chemotherapy

The major trials comparing chemotherapy and surgery vs. surgery alone have been conducted in the USA and UK. [75],[76],[77],[78] A more recent randomised trial from Europe also showed that addition of neo-adjuvant chemotherapy increased 5-year disease-free survival from 21-34% for gastric and lower oesophageal AC. The Medical Research Council (MRC) MAGIC trial compared neo-adjuvant chemotherapy and surgery vs. surgery alone for gastric cancer and included lower oesophageal AC. Five-year survival favoured chemotherapy (36% vs. 23%) and as a consequence changed practice in the UK. [79] A French study (ACCORD-07) confirmed these findings but results have not yet been fully published. [80]

The most influential study in Europe showed a 5-year survival benefit in favour of neo-adjuvant chemotherapy (23% vs. 17%) with a relative risk reduction in death of 26%. [77],[78] This has been supported by an updated Cochrane review of 11 randomised, controlled trials and as such is the standard of care in the UK. [81]

The MRC 0E05 trial compares the standard 0E02 regime (cisplatin and 5-fluorouracil) with four cycles of epirubicin, cisplatin and capecitabine (ECX) chemotherapy based on the positive results from the MRC MAGIC trial. Early results are expected next year.

Biological therapies

Detailed discussion regarding modern biological therapies is not within the scope of this article. However, the most promising work so far appears to be with epidermal growth factor receptor and vascular endothelial growth factor, although most evidence is from phase-II trials. [82],[83],[84],[85],[86],[87],[88] The ToGA trial is a randomised phase-III trial investigating trastuzamab (a monoclonal antibody against human epidermal growth factor receptor) for treating HER-2-positive advanced or metastatic gastric and gastro-oesophageal reflux disease. It showed improved median survival of 13.8 vs. 11.1 months (hazards ratio 0.74) and is now utilized widely in Europe. [89]

Assessing tumour response

The key to neo-adjuvant therapy is assessing the "responders". Up to 29% of patients receiving CRT can achieve a pathological complete response. The need for surgery following pathological complete response remains uncertain. Bedenne et al., [90] randomly assigned "responders" following CRT to receive further CRT or surgery. Mortality was greater in the surgery arm and survival data were the same for both groups as was QOL data.

Identifying tumour response, especially pCR, remains elusive. PET-CT has been investigated for this purpose and results have been conflicting. PET has been shown to be effective in assessing tumour response to neo-adjuvant chemotherapy treatment. [47] The group showed that metabolic responders achieved a 58% histological response and this translated to a better 5-year survival. They also showed that stopping treatment in the non-responders and proceeding to early surgery had no undue consequence. The authors advocated that PET may be used to develop a response-guided algorithm for neo-adjuvant treatment. Similar results have not been achieved with CRT. Possible explanations for this are the local inflammatory response to the radiotherapy increasing 18 F-fluorodeoxyglucose uptake.

Surgery

The mortality and morbidity rates for oesophageal cancer surgery have decreased over the last two decades due to better preoperative staging, peri-operative care, patient selection and surgical techniques. Mortality for oesophagectomy is reported at approximately 5% with 5-year survival of approximately 30-35% across all pathological subgroups. [74],[91],[92]

Lymph node resection

Debate continues regarding lymph node clearance. Some surgeons believe that nodal disease is a surrogate marker of metastatic burden and therefore radical nodal dissection confers no benefit to patients. Others believe that some patients can be cured with radical dissection even in the presence of nodal burden. [93],[94] Improved 5-year survival has been linked to the total number of nodes resected. [95] Clearly the key is to identify those patients with a low nodal burden who stand the best chance of cure with radical surgery.

Minimally invasive oesophagectomy

Minimally invasive oesophagectomy comprises an abdominal laparoscopic approach and thoracoscopic oesophageal mobilisation with intra-thoracic anastomosis or neck anastomosis. The technique is well described and appears to have comparable short-term outcomes to conventional oesophagectomy but perhaps with fewer pulmonary complications and less operative blood loss. [96],[97],[98],[99],[100],[101],[102]


  Future Strategies Top


Oesophageal cancer is a changing disease and is now primarily a disease of a westernised society, with obesity and gastro-oesophageal reflux disease being the most important aetiological factors.

Future approaches to improving cancer survival must include primary prevention and reducing exposure to aetiological risk factors. Detection of high-grade dysplasia and early oesophageal cancer is also of paramount importance in achieving improved disease-free survival. Effective strategies to treat and potentially cure early oesophageal cancer now exist and these include endoscopic mucosal resection/surgical dissection, argon beam plasma coagulation and radiofrequency ablation.

For surveillance programs to be effective we need the ability to target the truly "high-risk" groups and this may be achieved through new genetic and novel biomarkers. For example, detection of abnormal cell DNA content within Barrett's mucosa has been shown to be a predictive marker of disease progression. Technical and financial barriers currently prevent its mainstream use, but it is likely to become routine in the future.

Recurrent disease following treatment with curative intent remains commonplace and effective second-line therapies are desperately needed. This is likely to come from ongoing clinical trials in the form of second-line chemotherapeutic agents and new biological therapies.

 
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