Gastric cancer

Carcinoma of the stomach has been described as one of the ‘Captains of the men of death’. Examining the survival statistics from the UK it is not hard to agree with this gloomy view. Some series demonstrate overall 5-year survival statistics in the region of 5 per cent. These data obscure the fact that gastric cancer is an eminently curable disease provided that it is detected at an appropriate stage and treated adequately. Gastric cancer rarely disseminates widely before it has involved the lymph nodes and therefore there is an opportunity to cure the disease prior to dissemination. Early diagnosis is therefore the key to success with this disease. The only treatment modality able to cure the disease is resectional surgery.

Incidence

There are marked variations in the incidence of gastric cancer worldwide. In the UK it is approximately 15 per 100 000 per year, in the USA 10 per 100 000 per year and in Eastern Europe 40 per 100 000 per year. In Japan the disease is much more common with an incidence of approximately 70 per 100 000 per year, and there are small geographical areas in China where the incidence is double that in Japan. These underlying epidemiological data make it clear that this is an environmental disease. In general men are more affected by the disease than women and, as with most solid organ malignancies, the incidence increases with age.

Currently marked changes are being observed in the West in terms of both the incidence and site of gastric cancer and the population affected, changes that to date have not been observed in Japan. First, the incidence of gastric cancer is continuing to fall at about 1 per cent per year. This reduction exclusively affects carcinoma arising in the body and distal stomach. By contrast, there appears to be an increase in the incidence of carcinoma in the proximal stomach, particularly the oesophagogastric junction. Carcinoma of the distal and body of the stomach is most common in low socioeconomic groups, whereas the increase in proximal gastric cancer seems to affect principally higher socioeconomic groups. Proximal gastric cancer does not seem to be associated with H. pylori infection, in contrast to carcinoma of the body and distal stomach. 

Aetiology 

Gastric cancer is a multifactorial disease (Correa). Epidemio­logical studies point to a role for H. pylori although there is argument about how important this factor is. Certainly the EUROGAST study revealed a correlation between the incidence of gastric cancer in various populations and the prevalence of H. pylori infection, although there was a considerable scatter about the regression line indicating that other factors were also important. There is insufficient evidence at the moment to support eradication programmes in asymptomatic patients who are infected with Helicobacter with a view to reducing the population incidence of gastric cancer. However, clinical trials may subsequently change this view. As mentioned above Helicobacter seems to he principally associated with carcinoma of the body, stomach and distal stomach rather than the proximal stomach. As Helicobacter is associated with gastritis, gastric atrophy and intestinal metaplasia the association with malignancy is perhaps not surprising.

Several other risk factors have been identified as being important in the aetiology of gastric cancer. Patients with pernicious anaemia and gastric atrophy are at increased risk, as are those with gastric polyps. Patients who have had peptic ulcer surgery, particularly those who have had drainage procedures such as Billroth II or Polya gastrectomy, gastro­enterostomy or pyloroplasty are at approximately four times the average risk. There is no direct evidence to date that highly selective vagotomy is associated with an increased risk of gastric cancer. Presumably duodenogastric reflux and reflux gastritis are related to the increased risk of malignancy in these patients. Intestinal metaplasia is a risk factor. Carcinoma is associated with cigarette smoking and dust ingestion from a variety of industrial processes. Diet appears to be important, as illustrated by the often quoted example of the change in the incidence of gastric cancer as Japanese families moved to the USA. The high incidence of gastric cancer in some pockets in China is probably environmental and probably diet related. The ingestion of substances such as spirits may induce gastritis and, in the long term, cancer. Excessive salt intake, deficiency of antioxidants and exposure to N-nitroso compounds are also related. The aetiology of proximal gastric cancer remains an enigma. Genetic factors are also important but imperfectly elucidated (see below).

The molecular pathology of gastric cancer

In contrast to colorectal cancer, the molecular pathology of gastric cancer is less well worked out. However, it is likely that with time the importance of the genetic events in gastric cancer will similarly be realised. The oncogenes H-ras and c­erb B2 have both been studied. Evidence suggests that H-ras mutations occur at an early stage of gastric carcinogenesis and it is not clear that ras mutations are of importance in tumour progression. c-erb B2 encodes for a transmembrane tyrosine kinase receptor which has sequence homology with epidermal growth factor receptor. c-erb 132 is amplified and overexpressed in well-differentiated gastric carcinomas of the intestinal type and, as it is commonly seen in metastases, it may therefore be important in tumour progression.

The role of tumour supressorgenes has also been examin­ed. The APC gene that is responsible for familial polyposis is mutated in 25 per cent of moderately/well-differentiated carcinomas, and loss of heterozygosity of this region is seen in about 60 per cent of tumours. However, loss of the APC gene has not been detected in poorly differentiated gastric cancers making its role unclear. p53 is the archetypal tumour supressor gene. p53 protein is overexpressed in many trans­formed cells and this overexpression is often related to a p53 mutation, the protein product of the mutant gene being more stable. Again, the role of p53 in gastric cancer is unclear. Abnormalities in p53 have been found in intestinal meta­plasia in the stomach but not in the primary rumours except at a late stage.

Microsatellite instability is a form of genetic instability resulting from deficiencies in the mismatch repair genes. The result of this phenotype is the rapid accumulation of muta­tions within the genome (mutator phenotype), hence predis­posing to malignant transformation. Inherited mismatch repair deficiency is responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Gastric cancers are also found in families with this phenotype. Microsatellite instability is found in about 15 per cent of sporadic colorectal cancers and apparently in a similar per centage of sporadic gastric cancers.

Clinical features

The features of advanced gastric cancer are usually obvious. However, curable gastric cancer has no specific features to distinguish it symptomatically from benign dyspepsia. The key to improving the outcome of gastric cancer is early diag­nosis and, although in Japan there is a screening programme, most curable cases are picked up by the liberal use of gastroscopy in patients with dyspepsia. Present guidelines suggest gastroscopy for any new dyspepsia, however mild, in a patient over 40 years of age. The same advice applies to a patient of any age with persistent dyspepsia or any unusual feature. It is important to note that gastric antisecretory agents will improve the symptoms of gastric cancer so the disease must be excluded, preferably before therapy is started.

In advanced cancer early satiety, bloating, distension and vomiting may occur. The tumour frequently bleeds resulting in iron deficiency anaemia. Obstruction leads to dysphagia, epigastric fullness or vomiting. With pyloric involvement the presentation may be of gastric outlet obstruction, although the alkalosis is usually less pronounced or absent compared to when duodenal ulceration leads to obstruction. In recent years gastric outlet obstruction is more commonly associated with malignancy than benign disease. Nonmetastatic effects of malignancy are seen, particularly thromboplebitis (Trous­seau’s sign) and deep venous thrombosis. These feature result from the effects of the tumour on thrombotic and haemostatic mechanisms.  mass lesions but spreads widely in the gastric wall. Not surprisingly, this has a much worse prognosis. A small proportion of gastric cancers are of mixed morphology.

Gastric cancer can be divided into early gastric cancer and advanced gastric cancer. Early gastric cancer is defined as cancer limited to the mucosa and submucosa with or without lymph node involvement (Ti, any N). The classification is shown in Fig. 51.28. This can be either protruding, super­ficial or excavated in the Japanese classification (Fig. 51.29). This type of cancer is eminently curable and even early gastric cancers associated with lymph node involvement have 5-year survival rates in the region of 90 per cent (Fig. 51.29). In Japan approximately one-third of gastric cancers diag­nosed are in this stage. However, in the UK it is uncommon to detect gastric cancers at this stage. A number of reasons probably still accounts for this. First, because gastric cancer is less common in the UK dyspeptic patients are not always referred for endoscopy at an appropriate stage. Secondly, endoscopists are unfamiliar with the appearances of early gastric cancer and in all probability many such cases are missed.

Advanced gastric cancer involves the muscularis. Its macroscopic appearances have been classified by Bormann into four types (Figs 51.30 and 51.31). Types III and IV are commonly incurable.

Staging

The International Union Against Cancer (UICC) staging is shown in Table 51.5.

Spread of carcinoma of the stomach

No better example of the various modes by which carcinoma spreads can be given than the case of stomach cancer. It is important to note that this distant spread is unusual before the disease spreads locally and distant metastases are uncommon in the absence of lymph node metastases. The intestinal and diffuse types of gastric cancer spread differently. The diffuse type spreads via the submucosal and subserosal lymphatic plexus and it penetrates the gastric wall at an early stage.

Direct spread

The tumour penetrates the muscularis, serosa and ultimately adjacent organs such as the pancreas, colon and liver.

Lymphatic spread

This is both by permeation and emboli to the affected tiers (see below) of nodes. This may be extensive, the tumour even appearing in the supraclavicular nodes (Trosier’s sign). Unlike malignancies such as breast cancer, nodal involvement does not imply systemic dissemination.

Blood-borne metastases

This occurs first to the liver and subsequently to other organs including lung and bone. This is uncommon in the absence of extensive nodal disease.

Trans peritoneal spread

This is a common mode of spread once the tumour has reached the serosa of the stomach and indicates incurability. Tumours can manifest anywhere in the peritoneal cavity and commonly give rise to ascites. Advanced peritoneal disease may be palpated either abdominally or rectally as a tumour ‘shelf’. The ovaries may sometimes may be the sole site of transcoelomic spread (Krukenberg’s tumours). Tumour may spread via the abdominal cavity to the umbilicus (Sister Joseph’s nodule).

Lymphatic drainage of the stomach

Understanding the lymphatic drainage of the stomach is the key to comprehending the radical surgery of gastric cancer. The lymphatics of the antrum drain into the right gastric lymph node superiorly, and right gastroepiploic and subpyloric lymph nodes inferiorly. The lymphatics of the pylorus drain into the right gastric suprapyloric nodes superiorly and the subpyloric lymph nodes situated around the gastroduodenal artery inferiorly. The efferent lymphatics from suprapyloric lymph nodes converge on the para aortic nodes around the coeliac axis, while the efferent lymphatics from the subpyloric lymph nodes pass up to the main superior mesenteric lymph nodes situated around the origin of the superior mesenteric artery. The lymphatic vessels related to the cardiac orifice of the stomach communicate freely with those of the oesophagus.

Whether or not there is histological evidence of regional lymph node involvement affects the prognosis of operable cases of carcinoma of the stomach. Retrograde (downward) spread may occur if the upper lymphatics are blocked. In Japan the lymph node dissection is highly advanced and the Japanese Research Society for Gastric Cancer has assigned a number to each lymph node station to aid the pathological staging (Fig. 51.32). Many centres in the West now perform surgery that involves a radical lymphadenectomy, but in others both the staging and surgery are inadequate.

Operability

It is important that patients with incurable disease are not subjected to radical surgery that cannot help them. Un­equivocal evidence of incurability is haematogenous metastases, involvement of the distant peritoneum, N4 nodal disease and disease beyond the N4 nodes, and fixation to structures that cannot be removed. It is important to note that involvement of another organ per se does not imply incurability provided that it can be removed. Controversies with respect to operability include N3 nodal involvement and involvement of the adjacent peritoneum. Curative resection should be considered on the remaining patients.

Total gastrectomy

This is best performed through a long upper midline incision. The stomach is removed en bloc including the tissues of the entire greater omentum and lesser omentum (Fig. 51.33). In commencing the operation the transverse colon is completely separated from the greater omentum. The dissection may then be commenced either proximally or, more usually, distally. The subpyloric nodes are dissected and the first part of the duodenum is divided, usually with a surgical stapler. The hepatic nodes are dissected down to clear the hepatic artery; this dissection also includes the suprapyloric nodes. The right gastric artery is taken on the hepatic artery. The lymph node dissection is continued to the origin of the left gastric artery which is divided flush with its origin. The dissection is continued along the splenic artery taking all of the nodes at the superior aspect of the pancreas and in the splenic hilum. Separation of the stomach from the spleen, if this organ is not going to he removed, is carried out and this then allows access to the nodal tissues around the upper stomach and oesophagogastric junction. The oesophagus can then be divided at an appropriate point using a combination of stay sutures and a soft noncrushing clamp, usually of the right-angled variety. It is important that the resection margins are well clear of the tumour. Involvement of either proximal or distal resection margin carries an appalling prognosis and if in doubt frozen section should be performed. There is some controversy regarding the management of the spleen and distal pancreas in this procedure and this is discussed below.

Gastrointestinal continuity is reconstituted by means of a Roux loop. Other methods of reconstruction should be discouraged because of poor functional results. The Roux loop should be at least 50 cm long to avoid bile reflux oesophagitis. The simplest means of effecting the oesophagojejunostomy is to place a purse string in the cut end of the oesophagus and, using a circular stapler introduced through the blind end of the Roux loop, staple the end of the oesophagus on to the side of the Roux loop. The blind open end of the Roux loop may then be closed either with sutures or, alternatively, with a linear stapler. The anastomosis can also he fashioned end to end. The Roux loop may placed in either an anticolic or retrocolic position. The jejunojejostomy is undertaken at a convenient point in the usual fashion (end to side, Fig. 51.34).

There remains some controversy about the extent of the lymphadenectomy required for the optimal treatment of curable gastric cancer. In Japan a D2 gastrectomy (removal of the second tier of nodes) at least is performed on all operable gastric cancer and some centres are practising more radical surgery (D3 and even D4 resections). Certainly, the results of surgical treatment stage for stage in Japan are much better than commonly reported in the West, and the Japanese contention is that the difference is principally related to the staging and the quality of the surgery. It is observed that the build of the average Japanese patient favours the performance of more radical procedures compared with the average patient in the West. However, radical lymphadenectomies above D2 have not been subjected to any randomised controlled trials. In the UK and Europe randomised trials have been set up to compare Dl and D2 gastrectomy but the results are difficult to interpret. One of the problems relates to standardisation of the operation. Overall, it seems that the oncological outcome may be better following a D2 gastrectomy but this operation is associated with higher levels of morbidity and perioperative mortality. It is clear that most of this morbidity and mortality relates to the removal of the spleen with or without the distal pancreas. The traditional radical gastrectomy removes the spleen and distal pancreas en bloc with the stomach and, although this is indeed an adequate means of performing clearance of the lymph nodes around the splenic artery, there seems now little doubt that adding this substantially increases the complication rate. The Japanese D2 gastrectomy will commonly preserve spleen and pancreas.

The differentiation between a Dl and a D2 operation depends upon the tiers of nodes removed. Different tiers need to be removed depending on the positions of primary tumour and this is outlined in Table 51.6. In general, a DI resection involves the removal of the perigastric nodes and a D2 resection involves the clearance of the major arterial trunks.

Subtotal gastrectomy

For tumours distally placed in the stomach it appears unnecessary to remove the whole stomach. The operation, however, is very similar to that of a total gastrectomy except that the proximal stomach is preserved, the blood supply being derived from the short gastric arteries. Following the resection the simplest form of reconstruction is to close the stomach from the lesser curve near the oesophagogastric junction with either sutures or staples and then perform an anastomosis of the greater curve to the jejunum. Although this can be performed as in a Billroth II/Polya-type gastrectomy, this reconstruction results in quite marked enterogastric reflux and bile reflux oesophagitis, and the preferred reconstruction is to perform the reconstruction using a Roux loop. 

Palliative surgery

In patients suffering from significant symptoms of either obstruction or bleeding, palliative resection is appropriate. A palliative gastrectomy need not be radical and it is sufficient to remove the tumour and reconstruct the gastrointestinal tract. Sometimes it is impossible to resect an obstructing tumour in the distal stomach and other palliative procedures need to be considered, although the prognosis in such patients, even in the short term, is poor. A high gastroenterostomy is a bad operation that very frequently does not allow the stomach to empty adequately but may produce the additional problem of bile reflux. A Roux loop with a wide anastomosis between the stomach and jejunum may be a better option, although even this may not allow the stomach to empty particularly well. Gastric exclusion and oesophagojejunostomy is practised by some surgeons. For inoperable tumours situated in the cardia either palliative intubation, stenting or another form recanalisation can be used (Chapter50).

Postoperative complications of gastrectomy

Radical gastrectomy is complex major surgery and predict­ably there is a large number of potential complications of the operation. Leakage of the oesophagojejunostomy should be uncommon in experienced hands. When it occurs it can often be managed conservatively as the Roux-en-Y reconstruction means that it is mainly saliva and ingested food that leaks. Some patients may establish a fistula from the wound or drain site and others may need radiological or surgically placed drains. It is unclear whether a nasoenteric tube should be used routinely. Many surgeons use such tubes routinely but this is not supported by any evidence base. It is common practice to perform a water-soluble contrast swallow at 5—7 days after the operation to determine whether the anastomosis is intact, and finding a small radiological leak is not uncommon. It is unusual to detect a major leak in the absence of clinical signs.

As with any gastrectomy, leakage from the duodenal stump can occur. This is usually due to a degree of distal obstruction and care must be taken when performing the Roux-en-Y anastomosis that there is no kinking. Paraduodenal collections can be drained radiologically which will often convert the collection into an external fistula. Biliary peritonitis requires a laparotomy and peritoneal toilet, and in this circumstance it is best to leave a Foley catheter in the duodenum to establish a controlled duodenal fistula. If it is established that there is no distal obstruction, or any such obstruction is dealt with, then with time the fistula will close.

The presence of septic collections along with a very radical vascular dissection may lead to catastropic secondary haemorrhage from the exposed or divided blood vessels. This situation may be very difficult to manage whether reoperation or interventional radiology is employed. 

Long-term complications of surgery 

It is surprising that, considering the radical nature of the total gastrectomy, many patients, particularly the younger ones, have a good functional results. Most patients, however, will have a reduced capacity particularly in the short term. They need to be given detailed nutritional advice, the substance of which is to eat small meals and often while the jejunum or small gastric remnant adapts. There is, in fact, very little functional difference between patients who have a total and subtotal gastrectomy. Various attempts have been made to try and improve the short-term functional results by a forming a jejunal pouch and attaching this to the oesophagus. Most surgeons do not perform this as in the long term there seems little functional advantage. It is surprising that these patients only infrequently suffer from the complications of gastric surgery such as dumping and diarrhoea. Nutritional deficiencies may occur and the patient should be monitored with this in view. The loss of the parietal mass leads to vitamin B12 deficiency and replacement should be given routinely. 

Outlook after surgical treatment

The outlook after surgical treatment varies considerably between the West and Japan. In Japan approximately 75 per cent of patients will have a curative resection and of these the overall 5-year survival rate will be in the region of 50—70 per cent. By contrast, in the West most series show that only 25—50 per cent of patients undergoing surgery will have a curative operation and the 5-year survival rate in such patients is only about 25—3 0 per cent, although in some series it approaches Japanese levels. These figures need some qualification to explain the differences in outcome between patients with gastric cancer in the West and in Japan. The allegation by some authors, not surprisingly all in the West, that gastric cancer is a somewhat different disease in Japan and that such differences explain the better outcome has no basis in evidence. Indeed, all of the studies in which the molecular pathology of gastric cancer has been studied suggest quite the reverse. A combination of differences in staging and a higher standard of surgery in Japan probably accounts for the differences. Staging is clearly crucial when survival figures are being compared. The more thorough the staging the higher the stage is likely to be and therefore stage for stage the outcome seems better in patients who are adequately staged pathologically. This phenomenon is termed ‘stage migration. Studies in the UK have shown that the lymph node yield after gastrectomy is minute in comparison to Japan. The pathologist will have considerable difficulty orientating a fixed specimen and finding lymph node groups, and therefore the optimal approach is for the surgeon to dissect the nodes from the specimen and send them separately to the pathologist, a practice commonly followed in Japan. Only in this way can an accurate staging be achieved. 

Other treatment modalities

Because of the failure of radical surgery to cure advanced gastric cancer there has been an interest in the use of radio­therapy and chemotherapy.

Radiotherapy 

The routine use of radiotherapy has not been supported by clinical trials. There is a number of radiosensitive tissues in the region of the gastric bed which limit the dose that can be given; this may partly explain the disappointing results. Radiotherapy has a role in the palliative treatment of painful bony metastases. 

Chemotherapy

Gastric cancer may respond well to combination cytotoxic chemotherapy, and interest now focuses on the utility of such treatment in improving outcome. In treating advanced gastric cancer there is a number of well-investigated regimes but the best results are currently obtained using a combination of epirubacin, cisplatinurn and 5-FU (5-fluorouracil) (ECF) by continuous infusion. A significant proportion of patients will respond to this regimen and, although studies comparing best supportive care with chemotherapy are not abundant, there is a consensus that improvement in survival of several months at least can be achieved by treatment. However, combination chemotherapy of this type is quite intensive and such benefits have to be set against the morbidity associated with chemotherapy. Systemic adjuvant chemotherapy has been investigated in a number of trials and has proved disappointing.

However, many patients in these studies have not actually completed the course of chemotherapy and the total dose given was rather low compared with the regimens used for advanced disease. Good results have been obtained in Japan from the use of mitomycin C-impregnated charcoal given by the intraperitoneal route. The rationale for this is that this is taken up by the peritoneal lymphatics and may target the principal site of recurrence, which is the gastric bed. This treatment has not been widely used in the West. There is current interest in neoadjuvant chemotherapy given with a view to down-staging gastric cancer prior to surgical resection. Whether treatment of this type is effective awaits the results of randomised trials.

Pattern of relapse following surgical treatment

As might be expected, the most common site of relapse following radical gastrectomy is the gastric bed and represents inadequate extirpation of the primary tumour. Widespread nodal intraperitoneal rnetastases, distant nodal rnetastases and liver metastases are all common. Dissemination to the lung and bones usually only occurs after liver metastases are already established.