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K.G.M. PARK
Department of Surgery, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, AB25 2ZD
Keywords: Oesophageal cancer, gastric cancer, Barrett's oesophagus, staging, treatment, surgery
The prognosis of patients with gastric and oesophageal cancers remains poor but increased knowledge of the factors involved in carcinogenesis and a better understanding of the disease process has led to strategies to improve outcomes. These are discussed under the following headings: (1) Prevention of the disease, (2) early detection of tumours, (3) treatment selection and (4) treatment. The likely impact of developments in each of these areas is considered in relation to population-based data from the Scottish Audit of Gastro-Oesophageal Cancer (SAGOC). Although there are a number of novel developments in the management of gastric and oesophageal cancer it is only by the conduct of controlled trials that the value of these will be determined. More immediate improvements in patient care may be derived from rationalisation of existing resources to ensure that all patients benefit from early diagnosis, the appropriate selection and delivery of treatment. One model of care, which may ensure this is the development of managed clinical networks, would maintain the involvement of all units in the management and treatment of upper GI cancers to a level that is possible with the facilities available. At the same time the patients requiring more specialised treatment would benefit from established referral networks
J. R. Coll. Surg. Edin., December 2002, 716-730
The James IV lecture is given in remembrance of the Royal Charter granted by King James IV of Scotland to the Guild of Barber Surgeons of Edinburgh in 1506. The town council of Edinburgh had, the previous year, formally incorporated the Barber Surgeons of Edinburgh as a Craft Guild. This was recognised by the Seal of Cause, conferring the right of the members of this guild to practice surgery in Edinburgh and surrounding districts but at the same time imposing certain duties and obligations upon them. In particular the Seal of Cause states:
"... that no manner of person occupy or practise any points of our said craft of surgery unless he be worthy and expert in all points belonging to the said craft ...for every man ocht to know the nature and substance of everything that he works or else he is negligent".
This document can be regarded as laying the foundations of professionalism in surgery and the obligations imposed by the Seal of Cause are as relevant today as they were when they were written nearly 500 years ago. In this article I will discuss the treatment of patients with oesophageal and gastric cancer attempting to adhere to the principles established in the Seal of Cause of basing management on clinical and scientific evidence. Sadly, this is not always the case and too often accepted treatment and recommendations have been based on anecdotes or forcefully expressed opinions. I hope that this lecture will challenge some of these issues.
A number of strategies exist for improving the outcome of patients with gastric and oesophageal cancers. These will be considered under the following headings:
• Prevention of the disease - based on known risk factors.
• Early detection of tumours - based on risk factors and high risk patient groups.
• Better treatment selection - based on an understanding of the disease process.
• Better treatment - based on novel treatments and rationalisation of existing modalities.
Population-based data derived from the Scottish Audit of Gastro-Oesophageal Cancer (SAGOC) will be used to discuss the relevance, and likely impact, of developments in each of these areas to the provision of care within a whole population.1
The incidence and demographics of gastric and oesophageal cancer are changing, particularly in Western societies.2-8 This is characterised by an increased incidence of adenocarcinomas of the lower oesophagus / gastro-oesophageal junction and a paralleled decreased incidence of distal gastric cancers.3,4,7 The increasing incidence of lower oesophageal cancers is occurring at a rate of 2% per year in Scotland.4 In the USA, the incidence of these tumours is increasing faster than any other gastrointestinal cancer.6 Similar trends have been demonstrated in many European studies.2, 8-10 This clinical pattern does appear to be related to Western societies, as world-wide gastric cancer remains the second commonest cause of cancer death.7 Certain countries/regions have a particularly high incidence of gastric cancer such as Japan, South America and Portugal.7,8 Similarly, there are geographic clusters with high incidences of oesophageal cancer. In these regions, squamous cell cancers involving the middle third of the oesophagus tend to predominate, however, there is no separate ICD code for squamous and adenocarcinomas of the oesophagus and this may make some international comparisons difficult.
Although some upper gastro-intestinal (GI) cancers are due to inherited germ-line mutations, the majority of oesophageal and gastric cancers are the result of sporadic mutations, often in response to environmental insults. Environmental factors may also be responsible for increasing mucosal turnover and, hence, tumour promotion as a result of epigenetic phenomena.11 Identification of the different factors responsible for the development of gastric, oesophageal squamous cell and adenocarcinomas may provide a means of tumour prevention.
Oesophageal
A familial form of squamous cell carcinoma (SCC) of the oesophagus has been described as an autosomal dominant condition but this syndrome is very rare and although familial clustering is described for SCC most tumours are sporadic.12-15 Squamous cell carcinomas of the oesophagus are closely linked with cigarette smoking and alcohol intake.9,16-18 Other factors implicated in squamous cell carcinogenesis include a low consumption of vitamin C and beta carotene.19 It has been proposed that an increased consumption of fruits and anti-oxidants may be protective against the onset of these tumours but efforts to stop people smoking and drinking, while at the same time promoting healthier eating, continue to pose a challenge to health education programmes. It should also be noted that SCCs of the oesophagus are most common in low socioeconomic groups and any health promotion campaign needs to be appropriately targeted.20,21
In common with SCCs, few inherited germ-line mutations are associated with the development of adenocarcinoma of the oesophagus (an interesting exception may be E-cadherin/ CD1 mutations identified in familial diffuse gastric cancers [see below]). There are, however, very different risk factors involved in the development of adenocarcinomas and SCCs of the oesophagus. Adenocarcinomas are most closely linked with gastro-oesophageal reflux and obesity.22 A large Swedish case-controlled study found that longstanding severe gastrooesophageal reflux increased the odds ratio 43-fold for the development of adenocarcinoma compared with those without symptoms.22 In Scotland, approximately one third of patients with adenocarcinomas of the oesophagus have a previous history of gastro-oesophageal reflux (GOR) whereas only 12% of patients with SCC report previous GOR symptoms (Figure 1).23 It has been postulated that increased GOR may lead to increased cellular proliferation either directly or through the release of inflammatory mediators.11,24 In this regard increased expression of inducible cyclooxygenase 2 (COX 2) enzyme has been found in oesophageal adenocarcinomas; increased COX 2 activity results in the production of prostaglandin E2 which stimulates cell turnover.25,26 Case-control studies have indicated that the ingestion of aspirin, possibly as a COX 2 inhibitor, may have a protective effect against the development of oesophageal carcinomas.27,28 A key question is who to target for such treatment, i.e. the whole of a population or only those at risk due to other risk factors?
Figure 1: The incidence of a previous history of gastro-oesophageal reflux in patients with upper gastrointestinal cancers [oesophagus (Oes);oesophago-gastric junction (OG junct)]
There has been a great deal of attention paid to the role of Barrett’s oesophagus (or columnar lined oesophagus [CLO]) in oesophageal carcinogenesis and it has been suggested that a metaplasia - dysplasia - neoplasia progression, similar to the colorectal adenoma - carcinoma sequence, should form the basis of our understanding of oesophageal carcinogenesis.11,29,30 As a result, a number of techniques have been developed for ablation of Barrett’s oesophagus in the hope that these will arrest the metaplasia - dysplasia - neoplasia sequence.31-34 Unfortunately, not all of these techniques are without morbidity and the efficacy of such treatments has been challenged by the findings of dysplasic mucosal islands hidden under re-epithelialised oesophageal mucosa.31 Indeed, foci of carcinoma have been found following some ablative therapy.35 Perhaps it is appropriate to challenge the premise upon which such treatments are based, i.e. the Barrett’s oesophagus metaplasia - dysplasia - neoplasia paradigm. It is assumed that progression to a tumour is the result of successive clonal expansions with a selective growth advantage brought about by accumulations of mutations in genes that control cell proliferation and death.36 Comparison of non-dysplastic CLO to adenocarcinomas of the oesophagus does show a number of consistent genetic aberrations.37-41 Many studies, including our own, have demonstrated that there is a differential expression of oncogene products such as mutant p53, c-erb-2 and epidermal growth factor-receptor (EGF-R), associated with increased mucosal proliferation, between malignant and benign CLO (Figure 2).40 Most studies have compared tumours with adjacent-CLO and cannot be regarded as being representative of a progression through dysplasia to metaplasia and subsequently to neoplasia but are simply comparing different cells within a mosaic of cell types, one of which has progressed to cancer and the other which has not. Our own longitudinal studies have not demonstrated any differences in the expression of oncogene products in CLO of patients that subsequently progresses to adenocarcinoma and in the CLO of controls (Figure 3).41 A recent study from Seattle demonstrated that the mutations found in adenocarcinoma cells were different to those found in dysplastic CLO.42 The conclusion of this study was that clonal expansion may be more complex than was first thought - an alternative explanation may be that the dysplastic mucosa does not progress to carcinoma but that the tumour arises from a different source. It is possible that GOR predisposes to both CLO and also adenocarcinomas, both developing independently from a pluripotent stem cell stimulated by GOR. This may explain the incidence of high grade dysplasia and cancer recurring after mucosal ablation in CLO. We have demonstrated that areas of intestinal metaplasia within CLO (associated with the highest risk of adenocarcinoma) have a lower rate of protein synthesis, possibly due to lower mucus production, than areas of glandular type CLO (Figure 4).43,44 It is postulated that the lower rate of mucosal protection afforded in the areas of intestinal metaplasia allows greater exposure of the mucosa to potential carcinogens in GOR and this may lead to increased rates of adenocarcinomas in these areas. If this theory is correct treatments to prevent adenocarcinoma of the oesophagus should be directed at reducing gastro-oesophageal reflux rather than ablation of CLO. The large Swedish cohort studies would support the concept that it is GOR which is the major risk factor for the development of adenocarcinoma of the oesophagus and not CLO.22 Furthermore, there is compelling-experimental evidence that both acid and duodenogastric reflux promote cell proliferation and de-differentiation.45,46 Long-term interventional studies of treatment of GOR (both surgically and medically) are required to determine whether this is a viable means of preventing oesophageal cancers.
Figure 2: Expression of p53 and percentage expression MIB-1 in nondysplastic (NYS), dysplastic (DYS) and adenocarcinoma in patients with Barrett's oesophagus who progressed to carcinoma
Figure 3: Expression of EGF-R, p53 and percentage staining with MIB-1 in patients with CLO which progressed to adenocarcinoma(Group 1) and in age matched controls (Group 2) in whom there was no progression. Expression in the adenocarcinomas is shown for comparison
Gastric cancer
As in oesophageal cancer, the two main types of gastric cancer (diffuse and intestinal) differ in their epidemiology, aetiology and, therefore, strategies for prevention of the disease. Data from the SAGOC study and from the USA indicate a familial clustering of gastric cancers.15,23 The majority of familial gastric cancers are histologically diffuse tumours. A high proportion of these tumours have mutations in the E-cadherin gene (CDH-1) resulting in disruption of the normal E-cadherincatenin complex required to maintain intercellular adhesion.47 In most cases this is a sporadic mutation but a small proportion of patients have inherited germ-line inactivating mutations in the CDH-1 gene encoding for E-cadherin.48,49 This is an autosomal dominant trait with a high penetrance (60-80%).47-49 Although familial diffuse gastric cancers accounts for only a small proportion of gastric tumours it is important to determine the role of other germ-line mutations in patients with a weaker family history as other CDH-1 mutations with a lower penetrance may be implicated. This would of course lead to a major therapeutic dilemma. In patients with familial diffuse gastric cancer a prophylactic gastrectomy has been justified because of the aggressive nature of the tumour and the high penetrance in individuals who inherit the trait.49 In such individuals surgery would appear to be the only means of preventing the disease; however, would it be justified in germ line mutations with a lesser penetrance? It would appear that although our understanding of the disease has progressed substantially our therapeutic options have not changed significantly in over 100 years.
Figure 4: Rates of protein synthesis (Ks %/day) in cardia type and intestinal type Barret's metaplasia
Figure 5: Delays in establishing a diagnosis of oesophageal or gastric cancer after initial consultation between different health boards in Scotland (the names of the individual health boards have been removed)
In regions with a high incidence of gastric cancer it is the intestinal type of neoplasm which predominates. Also, in such regions there is frequently a high incidence of H. pylori infection. Epidemiological evidence would suggest that H. pylori infection is associated with a x3-8 times increased risk of non-cardia gastric cancer, compared with non-infected individuals.50-52 However, even in high-risk areas the majorityof patients with H. pylori infection do not develop gastric-cancer and the interaction between different strains of H.pylori and the individual may be more complex than was initially thought. Gastric atrophy and intestinal metaplasia, both regarded as pre-malignant conditions, are more likely in patients infected with CagA positive strains of H. pylori.53,54 These strains contain a genomic insertion known as the CagA pathogenicity island which incites an intense inflammatory reaction. Similarly, individual responses to H. pylori differ and as such may determine the subsequent pathophysiology of the infection. Patients with gastritis limited to the gastric antrum appear to produce excess acid and are at risk of duodenal ulceration. However, those with an extensive response in the body of the stomach develop gastric atrophy, achlorhydria and intestinal metaplasia and are at highest risk of gastric cancer. Genetic differences in cytokine responses to infection have been implicated as determinants of the pattern of disease in individuals.55
Figure 6: Operation rates in different health boards within Scotland for patients with gastric and oesophageal cancers (the names of the individual health boards have been removed)
H. pylori eradication has been demonstrated to reverse many of the findings regarded as pre-malignant in the stomachs of infected individuals, i.e. gastric atrophy and intestinal metaplasia. However, there is only indirect evidence that eradication may prevent gastric cancer.56 Other interventional studies have looked at increasing dietary anti-oxidants (including green tea and garlic) and COX2 inhibitors in at risk populations in the hope of reducing gastric cancer incidence; to-date, such studies have had mixed results and are continuing.57-59
The outcome of gastric and oesophageal cancers, in all regions, is poor - most patients presenting with advanced disease. In Scotland, two thirds of gastric and oesophageal cancer patients present at a stage when curative treatment cannot be considered and even in patients who undergo surgery the one year survival is approximately 50%.1,60-62
In contrast to these dismal figures it is known that the survival for gastric cancers limited to the mucosa and sub-mucosa of the stomach is greater than 90%. The majority of early oesophageal cancers can be cured by surgery.63,64 It has been suggested that stage-for-stage, the prognosis of patients with upper GI malignancy is similar to that of other cancers and the overall poor outlook is due to the failure to diagnose the diseaseat an early stage.63 Strategies for early tumour detection can be considered under the following headings:
• Screening programmes for asymptomatic patients
• Surveillance of at risk patients
• Early detection of symptomatic patients
Screening for upper GI cancers
Screening of asymptomatic individuals for gastric and oesophageal cancer is only justified in high incidence populations. In Japan, the high rate of gastric cancer led to the development of screening programmes based on contrast radiology followed-up with endoscopy.65 There is little doubt that such programmes have been effective in detecting gastric cancer at a far earlier stage than in non-screened populations. The incidence of gastric cancer in Japan is approximately 90/100,000 whereas in Scotland the incidence is 8/100,000.21,66 Hence, population-based screening for gastric cancer in Scotland would not be feasible.
Screening programmes have been developed in high-incidence oesophageal cancer regions and have detected large numbers of patients with severe dysplasias and early tumours. The 1995 consensus conference of the International Society of Diseases of the Esophagus (ISDE) recommended that population-based screening for carcinoma of the oesophagus be considered in high-incidence areas, i.e. >100 per 100,000 population.67 Even with the increasing incidence of oesophageal cancer in the UK the disease remains relatively uncommon (10-15 per 100,000) and mass screening cannot be justified.21 It should also be noted that neither gastric nor oesophageal cancer screening programmes have been subjected to the rigorous trials that have been conducted in breast cancer or colorectal cancer screening. Without such information it is difficult to be sure that there is a real survival benefit in the screened populations and not simply a lead time bias.
Surveillance of at risk patients
A number of factors have been identified which are associated with increased risk of upper GI malignancy, and surveillance of such high-risk groups may be justified. The 1995 consensus conference of the ISDE regarded the increased risk of SCC of the oesophagus associated with: previous SCC of the head and neck, achalasia and corrosive strictures as indications for endoscopic surveillance.67 Such recommendations are not based upon any population-based trials but the numbers of patients involved are likely to be small and, therefore, may be feasible. Unfortunately, the majority of patients with SCC in Scotland do not have a previous history of any of the above risk factors; therefore, it is only a minority of patients who could benefit from such surveillance.23
There is much debate surrounding the issue of surveillance in patients with CLO.30,68-74 Irrespective of whether the metaplasia - dysplasia - neoplasia model for the development of oesophageal adenocarcinoma is accepted there is epidemiological evidence to support the concept that CLO is associated with an increased risk of carcinoma.5,30,75 Estimates of the exact risk from retrospective studies vary from one per 75 patient years to one per 250 patient years and this may be dependant upon the definition of Barrett’s oesophagus.5,69 Namely, what length of CLO is needed for a patient to be entered into a surveillance programme? Should only those patients with certain histological sub-types of CLO be endoscoped? Accordingly, it is possible that different studies have entered different patient groups into their analysis. On a purely economic argument the incidence of cancer in CLO will determine the frequency of screening endoscopies.71 If the incidence of adenocarcinoma of the oesophagus is less than one in 200 patient years it is unlikely that endoscopic surveillance will be beneficial. 74 Although the American Association of Gastroenterology has produced guidelines for endoscopic surveillance of CLO, prospective studies have highlighted the low incidence of adenocarcinomas detected in such programmes and questioned the value of this approach.30,73 It is clear that the majority of patients with CLO do not develop cancer of the oesophagus and more accurate predictors of risk of progression are required. We have not been able to identify any oncogene products in our patients to indicate an increased risk of progression (see above). It has been proposed, however, that increased cyclin D1 may be a risk factor.76 At present the presence of dysplasia is assumed to be the best indicator of potential progression of CLO but even this is controversial and is devalued by inter-observer variation in the histological diagnosis of dysplasia.77-79 The WHO recommends that for a screening programme to be effective the following criteria must be fulfilled:80
• The natural course of the disease must be under-stood.
• There should be an asymptomatic stage of the dis-ease with can be detected and effectively treated.
• Treatment should be beneficial to the patient.
| Imaging |
Histology |
|
| CT Scan |
Positive |
Negative |
| Positive | 5 | 0 |
| Negative | 13 | 16 |
| Laparoscopic US | ||
|
Positive |
16 | 1 |
| Negative | 2 | 15 |
Table 1: Comparison of laparoscopic US and CT scanning in the assessment of intra-abdominal lymph nodes in patients with upper gastrointestinal cancer
Unfortunately, none of these criteria are met with regards to surveillance of patients with CLO. The impact of surveillance in CLO is also likely to be limited when it is realised that only one in five patients with CLO are diagnosed in life, i.e. even if there was a survival benefit in screened patients it is likely only 20% of at risk individuals would benefit.81 Data from the SAGOC indicate that only 14% of patients with adenocarcinomas were known to have CLO prior to diagnosis of their oesophageal tumour. Accordingly, a surveillance programme of patients with CLO is not likely to make any significant impact on the majority of patients with oesophageal cancer.23
The value of surveillance endoscopy in patients with severe GOR has not been established. Preliminary data has suggested that, because of the high prevelance of GOR in the community, even the presence of severe GOR would be insufficiently specific to be valuable as an indicator for endoscopic screening.82 However, a surveillance programme based on GOR symptoms (possibly allowing for BMI) would detect a higher amount of oesophageal adenocarcinomas than a programme based on CLO.
Early detection of gastro-oesophgeal cancer
One third of patients with gastric or oesophageal cancers in Scotland delay seeking medical attention for more than four months, even with significant symptoms.23 Similarly the use of potent anti-ulcer treatments may hide symptoms and delay referral for endoscopy or radiological assessment. To ensure that patients are diagnosed promptly endoscopy services need to be streamlined and available with minimal delay - even in patients with relatively innocuous sounding symptoms. The SAGOC data has indicated great variation, between regions, in the length of time it takes for an endoscopy to be performed (Figure 5). Other groups have emphasised that the number of endoscopies performed relates directly to the proportion of early gastric or oesophageal cancers diagnosed.63 Despite this, the value of “open access” endoscopy remains controversial. An alternative approach is the development of a normogram to predict the likelihood of significant pathology and, therefore, to concentrate resources in these areas.
In addition to the availability of endoscopy services a question remains as to the quality of endoscopy performed as the mucosal changes associated with many early cancers are subtle. It is clear that in Japanese centres an endoscopy takes longer than in most Western units, sedation is often deeper allowing better gastric distention and there is more frequent use of chromoendoscopy techniques.
Patients with early gastric or oesophageal tumours may be expected to be cured by appropriate treatment, whereas patients with more advanced disease will have a limited life expectancy and treatment must be aimed at providing good quality symptom relief. 83,84 Although surgical resection remains the only proven method of providing long-term survival in patients with gastro-oesophageal tumours it is only likely to be effective if a complete macro- and microscopic clearance of the tumour is possible (R0 resection).60-62 Unfortunately conventional staging techniques are limited in their sensitivity and some patients will be found, at the time of surgery, to have more advanced tumours than expected such that there is an incomplete resection.85-87 It is the ability of imaging techniques to determine whether a R0 resection is possible that is likely to make the largest impact in the management of gastro-oesophageal cancers, further refinement of preoperative staging to give more accurate anatomical staging of the disease is of doubtful clinical significance.
Improvements in the techniques of spiral computerised (CT) scanning allows for better spacial resolution, if this is combined with water distention of the stomach the accuracy of CT scanning can be improved for the assessment of the stage of primary tumours.88 An alternative to standard cross-sectional imaging techniques is the use of endoscopic ultrasonography (EUS) which provides better tumour definition and improves the accuracy of anatomical staging of oesophageal and gastric tumours, compared with conventional CT scanning.89-92 There is, however, a steep learning curve for the technique and 20-30% of oesophageal tumours will not be traversable with standard probes. Thus, although EUS may provide better anatomical staging of tumours there is little data to show that it significantly alters patient management.92,93
(A)
.gif)
(B)
Figure 7: PET images of an oesophageal tumour (A) before and (B) after chemotherapy.
A definite problem in the staging of gastric cancers is the presence of peritoneal deposits which are seldom detected with cross-sectional imaging techniques.94 Laparoscopy of the peritoneal cavity may detect such lesions and has been demonstrated to improve resection rates for gastric cancer.94 Combininglaparoscopy with high frequency ultrasonic examination of the abdomen (laparoscopic ultrasound [LUS]) has further improved the accuracy of staging gastric and oesophageal cancers.95-97 The adoption of LUS in patients with gastric and oesophageal cancers resulted in the detection of lesions precludingresection in 21% of patients and improved the resection-rate to 96% in our own series.95 A study of LUS in gastric cardia tumours found very similar results.97 Furthermore, the assessment of coeliac axis lymph nodes with LUS was found to be extremely accurate and predictive of disease-free survival (Table 1). LUS staging may allow a better selection of patients most likely to benefit from neo-adjuvant treatments.98
Positron emission tomography (PET) provides a metabolic image of tumours by determining the uptake of radiolabelled substrates into the tumour tissue. We have used the obligate glucose metabolism of gastric and oesophageal tumours and the glucose analogue fluoro-deoxyglucose to visualise upper gastro-intestinal tumours.99 Although FDG PET was able to visualise the primary tumour in all cases it was not possible to differentiate the primary from regional lymph nodes or to determine the local staging of the tumour. PET was useful in the detection of distant metastases, including ceoliac lymph nodes and was able to differentiate between benign and malignant strictures. Similar results have been reported by others.100-103
Anatomical stage may not be sufficiently sensitive to allow refinement of treatment beyond the ability to resect or not. Recently, a number of possible molecular markers have been identified which are predictive of outcome and may also predict which patients respond to chemotherapy or radiotherapy.104-108 Unfortunately, much of this work remains experimental and requires larger series to verify the significance of the early promising results.
The cornerstone of treatment for gastric and oesophageal cancers remains surgical resection but there are a number of areas of controversy regarding the optimal surgical approach, the value of adjuvant treatments and, in patients with more advanced disease the best means of providing palliation.
In patients with very early tumours of both the stomach and the oesophagus alternatives to resection have been proposed including LASER ablation, photodynamic therapy and endocopic mucosal resection (EMR).109,110 Clearly, such treatments avoid both the immediate and long-term morbidity associated with surgery but can only be recommended if they are effective in disease control. For tumours limited to the oesophageal or gastric mucosa it would appear that the incidence of lymphatic spread is minimal - accordingly mucosal techniques are likely to be effective.111,112 As tumours invade into the sub-mucosa the incidence of lymphatic spread increases and mucosal ablative techniques are unlikely to achieve clearance of the disease.111,113 Unfortunately, currently available imagingtechniques are unable to differentiate between mucosal and sub-mucosal tumours and we have adopted diagnostic endoscopic mucosal resection (EMR). In patients with endoscopic early tumours an EMR is performed and the pathologist asked to comment specifically on the depth of invasion and the lateral excision margins. If there is evidence of submucosal invasion a formal resection is performed whereas in patients with mucosal disease a policy of regular endoscopic surveillance is undertaken; this is combined with ablation of the surrounding mucosa. Care must be taken to ensure that the specimen is correctly orientated for the pathologist and that excess diathermy is avoided as this may make histological interpretation difficult. Lesions that are ulcerated pose particular problems with infiltration and may also be difficult for the pathologist to interpret. Furthermore, some reports have indicated that such lesions may metastasise early to regional lymph nodes; accordingly, we would tend not to recommend EMR in such tumours.111
Figure 8: Survival for locally advanced oesophageal tumours treated with aggressive chemotherapy that were resected or not resected after treatment.
There is great variation between clinicians dealing with gastric and oesophageal cancers in their indications for surgery and this is reflected in the variation in resection rates seen between different units.60,61 Within Scotland, the operation rate varies between 20% of patients seen within one health board to 42% of those within another (Figure 6).1 This variation may reflect surgical bias as much as differences in staging accuracy as it is clear that some surgeons will attempt surgery if a resection is possible while others will only undertake surgery if a R0 resection is possible. Accordingly, the rates of incomplete resections vary between regions.114
Perhaps the area of greatest controversy for surgeons treating gastro-oesophageal cancers is the extent of lymphadenectomy that is required to obtain tumour clearance. The arguments for and against radical lymphadenectomy are common to both oesophageal and gastric cancer. The advocates of extended lymph node dissections argue that such an approach provides better local control and allows a more accurate determination of the tumour stage and, therefore, prognosis. Whereas those opposed to this approach argue that the excess morbidity associated with a longer and more involved operation is not justified by any tangible benefit to the individual patient.
For gastric cancer meticulous mapping of lymphatic involvement by the Japanese Research Society for Gastric Cancer (JRSGC) has led to a table of probabilities of any lymph node station being involved with metastatic tumour from any primary gastric cancer.115 From this the concept of systemic lymphadenectomywas developed and has been shown in Japan to improve the outcome of patients, when compared with historical controls.116,117 However, two randomised controlled trials, in Europe, comparing systematic lymph node dissection (D2) with localised lymph node resection (D1) showed that D2 resections were associated with increased mortality and morbidity and did not improve the long-term outcome of patients.85,118 Both trials have been heavily critisised and much of the morbidity associated with the systematic lymphadenectomy was due to the distal pancreatectomy and splenectomy that was undertaken. Individual centres have demonstrated that D2 dissections can be performed with limited morbidity and, in most cases, a splenectomy and pancreatectomy can be avoided.63,119 It would appear that the major benefit of the D2 lymphadenectomy is in patients with relatively early tumours with early lymphatic invasion.120,121 A prospective audit of D2 gastrectomy identified an advantage in patients with stage II and IIIa tumours.122 Unfortunately, the majority of patients present in Western series with more advanced tumours; based on SAGOC data, less than 50% of patients who underwent a gastrectomy were likely to have benefited from a D2 lymphadenectomy (T0-T2, N0 -N1).123 In contrast, in Japan the earlier presentation of the disease may explain the observed benefits of D2 lymphadenectomy.
There has been similar debate regarding the value of lymph node dissections of the oesophagus and accordingly the optimal surgical approach. Some authorities have advocated an extensive three field nodal dissection, i.e. intra-abdominal, mediastinal and cervical for patients with SCS.124-127 The rationale being that in a proportion of these patients cervical and mediastinal recurrence will be the first site of recurrent disease. It is likely that only a minority of patients benefit from the additional neck dissection and, in Western centres, most debate surrounds the value of a trans-hiatal oesophagectomy or a trans-thoracic approach.128-130 Strictly speaking this is not the same as two field vs limited lymphadenectomy as a radical resection of the lower oesophagus is possible using a transhiatal approach. A meta-analysis of all series between 1986 and 1996 did not demonstrate any difference between the two approaches in terms of long-term survival, respiratory or cardiac complications. There was a higher incidence of anastomotic leakage with the trans-hiatal approach but the peri-operative mortality was lower with this technique. The same study calculated that a trial of over 3000 patients would be required to demonstrate any statistical difference between the two approaches.131 Local audit data did not show any difference between trans-thoracic and transhiatal oesophageactomy, in terms of peri-operative mortality or morbidity. Similarly, there was no difference between the most commonly used approaches and the incidence of resection margin involvement (most commonly radial).1 Our own approach is to be flexible and tailor the surgery according to the build of the patient and the position of the tumour. If the tumour can be mobilised under direct vision a transhiatal approach is generally possible, whereas if the tumour cannot be mobilised from the abdomen then the right chest is opened and an Ivor-Lewis oesophagectomy performed.
Combination chemotherapy has improved both the length and quality of survival of patients with advanced gastric and oesophageal tumours, when compared with best supportive treatment.132,133 This has led to the suggestion that such treatment should be used as an adjuvant to surgery. In patients with gastric cancer, there is no evidence that either adjuvant or neo-adjuvant chemotherapy is of value in patients in whom a complete surgical resection is possible.134,135 The use of either pre-operative or post-operative chemotherapy in gastric cancer cannot be justified outwith a controlled trial. The situation for oesophageal cancer patients is a little more confusing as the recent MRC neo-adjuvant trial does show a small but definite benefit for pre-operative chemotherapy in patients with operable tumours.136 In contrast, a similar trial conducted in the USA showed no difference.137 Review of the published trials of neo-adjuvant chemotherapy in operable oesophageal cancer does not show any overall benefit to treatment. However, patients who do respond to chemotherapy do have an improved survival.138,139 Current response rates to chemotherapy are in the region of 50-60%, thus, more active regimens are required.140-142 At present, a means of detecting early response to treatment is required so that responders can gain the maximal benefit from a full course of treatment and non-responders can be discontinued early.
Reports have indicated that FDG-PET may be useful in the early detection of response to chemotherapy in breast cancer.143,144 Many PET studies have relied on visual inspection of images.100-103 The activity of a tumour, however, is dependant both upon the tumour uptake of FDG and the metabolic state of the patient. To meaningfully compare a tumour before and after chemotherapy a means of quantification of the PET image, which is independent of the metabolic state of the patient is required. Accordingly, we have developed a simple means of quantification of FDG uptake, and this has allowed us to demonstrate that FDG uptake was significantly reduced in patients, with gastric and oesophageal cancers, who responded to chemotherapy (Figure 7).146 Although similar results have subsequently been demonstrated by other groups,145,146 PET cannot be regarded as being a part of standard clinical practice but it does provide much promise for a means of documenting chemotherapy responses using metabolic changes. Further research is required to determine the exact level of change in FDG uptake corresponding with a response. In addition, alternative tracers (e.g. labelled 5-FU) may provide a means of determining chemotherapy delivery to tumours or indicators of other metabolic pathways such as rates of protein synthesis using 11C methionine.
In patients with advanced localised tumours of the oesophagus a multi-modality approach may be of value. Early studies showed that chemoradiotherapy leads to a prolonged survival, compared with radiotherapy alone.148 It is not clear whether the addition of surgery to chemotherapy or chemoradiotherapy results in any additional benefits. In our own series of patients with locally advanced tumours there was a prolonged survival in patients in whom a surgical resection was possible following initial “down-staging” with chemotherapy (Figure 8).149 This was not a controlled trial but did show that further treatment was required in order to provide long-term local disease control after chemotherapy. There are four randomised controlled trials of surgery after concurrent chemoradiotherapy in patients with oesophageal cancer but comparison of the trials is hampered by lack of accurate staging of the tumours; it is likely that they did not all compare tumours of a similar stage.150-153 In the three studies that report three year survival data the results were very similar for the patients receiving multi-modal treatment (i.e. approx 33% survival).151-153 In one of these studies, similar survival was reported in the surgery alone group.152 In contrast, there was a trend towards a poorer survival in the surgery alone group reported by Urba et al (1997) and a definite reduced survival in the Walsh et al (1996) study.151-153 It is likely that these studies were undertakenin patients with more advanced tumours. Pre-operative-chemotherapy or chemoradiotherapy may have a role in patients with advanced localised oesophageal cancers but it would appear to add little to surgery in patients in whom a primary resection is possible. The average length of remission of patients treated with chemotherapy alone is of the order of six-nine months.140-141 Therefore, consolidation with surgery or radiotherapy would appear to be indicated in patients with localised disease who have a reasonable life-expectancy. For patients with gastric cancer radiotherapy is problematic and surgery may be the preferred option if there is sufficient downstaging of the primary tumour.
Unfortunately, the majority of patients with gastric and oesophageal cancers present with advanced tumours which are not amenable to “curative” treatment.1 There is no agreed or standard treatment for such patients and as discussed at the International Oesophageal Symposium in Edinburgh palliative treatment is too frequently directed towards symptoms rather than patients’ needs.83,84 For patients with oesophageal cancer palliation has focussed on the re-establishment of a lumen. For many patients the most distressing symptoms are frequently tiredness, anorexia, pain and general lassitude. These symptoms will not be improved by the insertion of an endoluminal prosthesis and should receive greater attention than at present. As discussed above, chemotherapy may improve both the length and quality of survival of many patients with advanced gastric or oesophageal malignancy but there is great variation between different centres in the use of chemotherapy. In general, palliative chemotherapy is used less frequently in the UK than in the USA.84
Greater understanding of the disease process in patients with gastric and oesophageal cancer provides many exciting possibilities for the earlier detection of tumours and more effective treatment. However, many questions remain unanswered, such as the role of new staging modalities in the treatment of upper GI tumours, the value of surveillance programmes for Barrett’s oesophagus and the role of multi-modality treatments in gastric and oesophageal cancers. It is only by carrying out well controlled trials that these important questions can be answered. Unfortunately, only 9% of eligible patients in Scotland were entered into ongoing trials of neo-adjuvant chemotherapy during the SAGOC study. Clearly all clinicians treating these diseases should endeavour to recruit patients into well designed trials.
Assuming that many of the issues of earlier detection, treatment selection and treatment can be answered, it is also important that all patients benefit from optimal treatment delivery and that this is readily available. This produces an apparent dichotomy between ensuring that all patients can potentially benefit from specialist treatments, often only available in larger units, while maintaining the readily available diagnostic, good quality treatment and support services for the majority of patients in local hospitals. Data from SAGOC indicates that an informal referral pattern already exists between hospitals i.e. although two hospitals perform 30% of all oesophageal resections in Scotland there is no difference in operation rates or survival by hospital size to which patients present.1 Further improvements in the quality of treatment for patients with gastric and oesophageal cancer can be attained by strengthening informal referral patterns, that currently exist, through ongoing audit and managed clinical networks. This would ensure that all units continue to be involved in the management of an increasingly common problem and provide treatment at a high standard up to a level that is possible with the facilities available. At the same time the patients requiring more specialised treatment would benefit from established referral networks.
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Copyright: 4 November 2002
Correspondence: Mr K.G.M. Park, Ward 33, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, AB25 2ZD, UK
Erratum
Barrett's oesophagus - are British gastroenterologists denying their patients prevention of malignant change? J.R.Coll.Surg.Edinb. 2002 47; 3: 521-522
The first paragraph should read:
Given the unequivocal evidence of an increase in the incidence of adenocarcinoma of the lower oesophagus in industrialised countries, there is a pressing need for better understanding of the conditions predisposing to this disease. In particular, we need to address the pathophysiology of gastro-oesophageal reflux disease, examine factors determining the occurrence of Barrett's oesophagus in around 1 in 20 of patients with gastro-oesophageal reflux disease (GORD) and to critically evaluate whether the current approach to preventing oesophageal adenocarcinoma is optimal.
Breast cancer in women aged 35 and under: prognosis and survival J.R.Coll.Surg.Edinb. 2002 47; 5: 693-699
The first author listed should read:
S. Jmor