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Surgery for cancer of the stomach
Introduction
There seem to be two different worlds for surgeons who confront gastric cancer. In Japan and Korea, where nearly half of the tumours are T1, ‘advanced gastric cancer’ usually means non-early tumours that are still potentially curable by radical surgery. Surgeons have developed minimally invasive techniques for T1 tumours and perform meticulous extended dissection for ‘advanced’ cancers. In the rest of the world, where patients present with much more advanced disease, the chance of cure by surgery is limited and surgeons’ best efforts are often not rewarded. Furthermore, the prevalence of a new disease called oesophageal adenocarcinoma has increased significantly in Western countries, almost overtaking distal gastric cancer, which is rapidly decreasing. Under the circumstances, surgeons in different parts of the world naturally have different strategies and standards to confront the disease. However, the ideal treatment for a patient with gastric cancer, wherever diagnosis is given, ought to be the same provided the disease is the same.
This chapter provides a Japanese perspective on surgery for gastric cancer from an international viewpoint, with the goal that surgeons in different circumstances are able to select the best available treatment to achieve a common goal.
Modes of spread and areas of potential failure after gastric cancer surgery
Gastric cancer arises in the mucosa and seldom metastasises until it penetrates the muscularis mucosae. The submucosal layer has numerous lymphatic and venous capillaries through which cancer cells spread, first to the lymph nodes and subsequently to the liver. Once the tumour penetrates the serosa, peritoneal dissemination becomes common. The depth of tumour invasion (T-category) is an important prognostic factor itself and is closely correlated to all patterns of metastasis.
A rational approach to surgery for gastric cancer requires an understanding of the modes of spread of this cancer and how it recurs after surgery. This knowledge is essential to define the aims and limitations of radical surgery.
In addition, it should be noted that the patterns of failure after gastric cancer surgery have been variously reported using similar classifications but with different definitions. An example is shown in Table 6.1 : hepatic and lymph node recurrences are categorised as distant and local failure, respectively, in the Dutch D1/D2 trial, , but as regional failure in the Intergroup 0116 study.
Table 6.1
Different definitions of patterns of failure in the Dutch and American trials on gastric cancer surgery
| Pattern of failure | Dutch D1/D2 trial , | US Intergroup 0116 |
|---|---|---|
| Local | Gastric bed, anastomosis, regional lymph nodes | Gastric bed, anastomosis, residual stomach |
| Regional | Peritoneal carcinomatosa | Liver, lymph nodes, peritoneal carcinomatosa |
| Distant | Liver, lung, ovary, and other organs | Outside the peritoneal cavity |
Metastatic pathways
Lymphatic spread
Lymphatic spread is the most common mode of dissemination in gastric cancer and lymph node metastasis is histologically proven in 10% of T1 tumours, with the rate increasing as the invasion deepens, to up to 80% of T4a tumours. ,
The lymphatic drainage system from the stomach has been well demonstrated in lymphography studies ( Fig. 6.1 ). Unlike other parts of the digestive tract, the stomach has multidimensional mesenteries that contain dense lymphatic networks. Cancer cells can flow out of the stomach through any of these routes via the nearby perigastric nodes to reach the nodes around the coeliac artery. They then enter the para-aortic nodes and finally flow into the thoracic duct and enter the systemic circulation, which can cause systemic metastasis. In particular, bone marrow carcinomatosis occurs most frequently in cases with extensive nodal disease.
The stomach has the largest number of ‘regional lymph nodes’ of any organ in the human body. After a total gastrectomy with D2 lymphadenectomy, more than 40 lymph nodes can usually be collected with careful retrieval. Of the malignant tumours listed in the Union for International Cancer Control TNM (UICC/TNM) classification, stomach cancer requires the largest number of nodes to be examined as a minimal requirement to allow a pN0 diagnosis (16 nodes) and also requires the largest number of positive nodes for the highest N category (pN3b, 16 or more positive nodes). Cancers in most other organs are staged as III or IV when a lymph node metastasis is pathologically confirmed, while pT1N1 and pT2N1 in gastric cancer are staged as IB and IIA, respectively. This suggests that lymphatic metastasis from gastric cancer may remain in the dense lymphatic filters for some time and that patients with nodal metastasis can still be cured by adequate dissection.
Peritoneal spread
Peritoneal metastasis is the most common type of failure after radical surgery for gastric cancer. Once the tumour penetrates the serosal surface (T4a), cancer cells may scatter in the peritoneal space. They can be implanted in the gastric bed or any part of the peritoneal cavity and subsequently cause intestinal obstruction or ascites. Peritoneal metastasis is much more common in diffuse-type cancers than the intestinal type and later causes peritonitis carcinomatosa, a characteristic recurrent pattern of gastric cancer that is relatively uncommon in colorectal adenocarcinomas which are mostly of the intestinal type.
Peritoneal lavage cytology is a sensitive test for this type of metastasis. Almost all patients with positive cytology subsequently develop peritoneal recurrence even after macroscopically curative surgery. Since the UICC/TNM seventh edition (TNM7), positive cytology (‘cy+’) has been included in the definition of pM1 for gastric cancer classification.
In general, surgery has no curative role in treating this mode of spread. However, in some exceptional cases where a small number of peritoneal metastases exist in the upper abdomen but peritoneal cytology is negative, complete removal of these visible nodules may bring cure.
Peritoneal metastasis is refractory to systemic chemotherapy. Intraperitoneal chemotherapy with or without hyperthermia is being vigorously tested in various centres and some promising results have been reported, but the evidence is not yet compelling.
Haematogenous spread
Liver metastasis is relatively uncommon at the time of diagnosis of gastric cancer, but is commonly seen as a part of systemic failure. In the 15-year follow-up report of the Dutch D1/D2 trial liver metastasis was found, either as the sole site or with other sites, in 102 of 319 deaths with recurrence. Liver metastasis occurs predominantly in intestinal-type tumours. Unlike in colorectal cancer, liver metastasis from gastric cancer is usually multiple and associated with other modes of spread, including peritoneal and/or extensive lymph node metastasis. Resection is rarely indicated, but with careful patient selection and R0 resection, long-term survival can be expected.
Metastasis by uncertain pathway
Lung, bone, or other distant metastases are relatively rare at the time of diagnosis and appear as part of systemic dissemination at the terminal stage. These may be regarded as haematogenous spread, but as many such cases lack liver metastasis, the initial route of spread may be the lymphatic–caval system mentioned above rather than the venous portal–caval route.
Ovarian metastasis (Krukenberg tumour) may occur especially from diffuse-type tumours, including signet-ring cell carcinoma. It is not uncommon for patients to present with ovarian tumours, and histological proof of signet-ring cells in the resected ovary leads to the diagnosis of gastric cancer. Ovarian metastasis may occur as part of peritoneal spread but, considering the absence of peritoneal disease in some cases and the usual association with lymphatic involvement, it may be considered as a special form of lymphatic spread.
Retroperitoneal spread frequently occurs in advanced diffuse-type tumours. It causes urinary tract obstruction and/or ‘frozen pelvis’ symptoms. This is usually considered as part of peritoneal dissemination, but it may occur as a purely retroperitoneal disease without visible or cytological disease within the peritoneal cavity. Direct tumour extension from the gastric body to the retroperitoneal space through the inside of the mesogastrium around the celiac artery is a possible route of spread.
Direct extension
Gastric cancer penetrating the serosa sometimes extends to the adjacent organs or structures. When the operation is potentially curative, these may be excised en bloc with the stomach. It is of note that, in a considerable proportion of apparent T4b cases, pathological assessment shows only inflammatory adhesion without direct tumour invasion.
Gastric cancer can extend intramurally to the oesophagus or duodenum, continuously or intermittently via submucosal lymph capillaries. Frozen section diagnosis is often needed for confirmation of clear margins.
Intraoperative spillage
Surgery itself can be a cause of cancer spread, especially in terms of peritoneal dissemination. A T4a tumour penetrating the gastric serosa without visible or cytological peritoneal disease sometimes recurs in the peritoneal cavity after potentially curative surgery. There are two possible explanations for this: 1) cancer cells had already been implanted but the cytology test was not sensitive enough; 2) there were no free cancer cells before surgery, but operative manipulation caused cancer cell spillage from the tumour surface.
Even serosa-negative tumours can recur in the peritoneal cavity after surgery, and these cases are usually associated with lymph node metastasis. A possible explanation for this is that during lymph node dissection lymphatic channels were broken and cancer cells in the lymph nodes spilled out. This was proven in a unique study from Korea, although it has not been confirmed whether these spilled cells can implant and grow.
Intraoperative spillages of cancer cells could be prevented by careful non-touch isolation techniques and/or the use of clips or vessel-sealing devices. However, the simplest means to prevent cancer cell implantation during surgery will be peritoneal wash with a large volume of saline before abdominal closure. A small-scale randomised study showed a significant survival benefit of extensive intraoperative peritoneal lavage (EIPL) in gastric cancer patients with positive cytology. However, the effect was not expanded in another randomised controlled trial (RCT) in which EIPL after curative resection was tested.
Summary
Of the four patterns of spread of gastric cancer (lymphatic, peritoneal, haematogenous, and direct), lymphatic metastasis occurs at the earliest stage, which can lead to other types of metastases. Surgical control of this spread at an early phase of the disease may prevent subsequent systemic failure.
The concept of radical gastric cancer surgery
Surgery plays an essential role in the curative treatment of gastric cancer. Although radical surgery has been attempted in many centres worldwide, it is Japanese surgeons who have been at the forefront of the practice of radical gastric resection and lymphadenectomy.
Gastric cancer surgery in Japan
The Japanese Classification of Gastric Carcinoma was established in 1962 and played a key role in the standardisation of surgery and pathology for gastric cancer in Japan. Detailed clinicopathological information, especially on lymph node metastasis, was prospectively collected from a large number of institutions and the optimal extent of lymphadenectomy was eagerly sought. The concept of ‘lymph node groups’ was established and the dissection of group 1 and 2 nodal stations was proposed as the standard radical surgery, which Japanese surgeons almost blindly accepted and followed.
This concept has never been tested in a randomised trial in Japan. As D2 gastrectomy is safely performed with good results in the country, Japanese surgeons think it unethical even to plan a trial in which half of the patients should undergo surgery that they consider inferior (D1).
The National Clinical Database (NCD) was launched in 2011 to collect nationwide data covering more than 95% of major surgeries in Japan. Detailed clinicopathological information including postoperative morbidity/mortality of about 50 000 gastrectomies per year has been collected, and a recent analysis of 71 307 total gastrectomies revealed hospital volume to have an impact on postoperative mortality, even in this high-incidence country.
Development of gastric cancer surgery in the West
The Japanese documentation system and excellent treatment results have influenced the Western concept of radical surgery for gastric cancer. Some surgeons visited Japanese institutions to convince themselves of the feasibility and efficacy of the technique and have successfully reproduced the results in the West. However, most non-specialist surgeons could not overcome their scepticism and were reluctant to practise this aggressive surgery on their patients. An important obstacle is the difficulty in directly comparing the results between Japan and the West due to the following two issues.
Different staging systems
The UICC and the American Joint Committee on Cancer (AJCC) unified their TNM staging system in their fourth edition in 1985. The N category in that edition was defined according to the anatomical location of the involved lymph nodes: metastasis in the perigastric nodes within 3cm of the primary tumour was staged as N1; metastasis in the other perigastric nodes and those along the named branches of the coeliac artery as N2. Although the Japanese definitions of nodal groups 1 and 2 were different, the basic concept of the two systems was similar in that the anatomical location of the involved lymph nodes determined the N category. Thus, the treatment results of tumours staged by the two different systems were able to be compared, neglecting minor differences.
In 1997 the UICC/AJCC adopted the numerical N category in the 5th edition, and the Japanese classification and the TNM classification became totally distinct systems. The Japanese results were able to be expressed using the new TNM system because the number of positive nodes in each case was also recorded, but the reverse was impossible because the anatomical data were no longer available in the West. Japanese surgeons and pathologists continued to use their system as the primary staging method, thus sticking to the surgical significance of lymph node anatomy, and they use the TNM system only when they write English papers. On the other hand, Western surgeons’ interest in lymphadenectomy may have diminished because the N category was determined regardless of the extent of lymphadenectomy.
Different disease hypotheses
A hypothesis that gastric cancer in the West may be a different disease to that in Japan prevails and prevents positive discussion to advance optimal treatment for gastric cancer patients on a global level. In the studies biologically analysing and comparing surgical specimens, evidence to support the hypothesis is scanty except for a recent study demonstrating a difference in signatures of tumour immunity that might influence clinical results. The following are the currently discussed differences.
Proximal location
It has been repeatedly highlighted that Western gastric cancers are predominantly located in the proximal stomach while Japanese tumours are found mostly in the distal stomach. This might suggest that these are different diseases. However, this needs careful consideration.
Adenocarcinoma of the lower oesophagus and the oesophagogastric junction is one of the most rapidly increasing malignant tumours in the West, especially among White males. This trend, together with the rapid decrease of distal gastric cancers, makes it plausible that Western gastric cancer arises mostly in the proximal stomach. However, lower oesophageal adenocarcinoma is a new, distinct disease with a different aetiology and contrasting patient backgrounds, and therefore should be considered separately from ‘classical’ gastric cancer. In three large-scale Western surgical trials, the Dutch D1/D2, 1 the British MRC D1/D2, and United States INT0116 studies, the proportion of proximal third tumours was 10.3%, 30.5%, and 19.5%, respectively, and was not significantly different from that in the Japanese D2/D3 study (19.1%) ( Fig. 6.2 ). This suggests that, as far as surgically targeted gastric cancers are concerned, tumour location is not largely different between the West and Japan. The apparent predominance of proximal tumours in the West may be a simple reflection of the mixture of different diseases, i.e. increasing oesophageal and decreasing gastric adenocarcinomas.
Patient factors
Western patients with gastric cancer are much more likely to be obese and more frequently have comorbidities, especially of cardiovascular diseases, than their Japanese counterparts. Although this does not mean that the disease is different, it certainly affects surgical process and outcomes. In particular, obesity hampers the completion of extended lymphadenectomy for gastric cancer, even in specialist Japanese centres. It has been shown to be an independent risk factor for postoperative morbidity.
The role of radical surgery in Western practice
Due to decreased incidence and technically demanding therapeutic requirements, gastric cancer in the West is today considered as a disease that should be treated in specialist centres. Several studies have shown relationships between the hospital/surgeon’s volume of gastric cancer treatment and operative mortality. Given the accelerated ‘proximal shift’ of the disease and the increasing surgical risks in Western patients, the trend of centralisation will further progress.
Although solid evidence of extended lymphadenectomy is yet to be established, D2 gastrectomy without splenectomy or pancreatectomy is officially recommended by the European Society of Medical Oncology. National Comprehensive Cancer Network (NCCN) guidelines for gastric cancer in the USA also recommend D2 for potentially curable gastric cancer with the condition that experienced surgeons perform it in specialist cancer centres. However, as the possible benefit of this extensive surgery could be easily offset by increased mortality, careful selection of patients is important even in specialist centres. There is an increasing move towards tailoring operations, taking not only the stage of the disease but also patient-related factors into account.
Outcomes after radical surgery for gastric cancer
The International Gastric Cancer Association (IGCA) launched a staging project and the survival data of more than 25 000 gastric cancer patients who underwent R0 gastrectomy in specialised centres around the world were collected and analysed (57 institutions in 17 countries). The eligibility criteria included: adenocarcinoma in the stomach or of Siewert type 2 or 3; gastrectomy performed between 2000 and 2004; no lost to follow-up before the fifth postoperative year; no neoadjuvant therapy; and sufficient histological data. Table 6.2 shows the stage-specific 5-year survival rates of Japanese and Western patients in this project according to the eighth UICC TNM and, in addition, those of another dataset selected from the US National Cancer Database using similar criteria. Even in this comparable setting in a project, the Japanese 5-year survival rates were better than Western ones by about 15% at all pathological stages. The additional US data show further lower survival rates in the real world, probably due to stage migration caused by insufficient nodal staging. The reasons for this are multifactorial as mentioned above, but there may be some unknown essential tumour difference between the East and West.
Table 6.2
Stage-specific 5-year survival rates after R0 gastrectomy according to the 8th edition of the TNM classification (International Gastric Cancer Association staging project and USA National Cancer Database )
| Pathological Stage | Japan | West ∗ | Whole | USA NCDB | ||||
|---|---|---|---|---|---|---|---|---|
| n | 5-year SR (%) | n | 5-year SR (%) | n | 5-year SR (%) | n | 5-year SR (%) | |
| IA | 5 394 | 93.8 | 463 | 86.0 | 10 606 | 93.6 | 1 501 | 81.0 |
| IB | 1 119 | 89.4 | 227 | 74.9 | 2 606 | 88.0 | 1 095 | 68.5 |
| IIA | 924 | 84.6 | 259 | 68.7 | 2 291 | 81.8 | 1 245 | 59.3 |
| IIB | 847 | 74.5 | 276 | 57.2 | 2 481 | 68.0 | 1 432 | 46.4 |
| IIIA | 956 | 60.3 | 376 | 42.0 | 3 044 | 54.2 | 2 310 | 30.5 |
| IIIB | 653 | 40.4 | 287 | 20.9 | 2 218 | 36.2 | 1 896 | 20.1 |
| IIIC | 389 | 21.1 | 167 | 16.2 | 1 350 | 17.9 | 1 067 | 8.3 |
SR , Survival rate.
∗ Data from 26 institutions from 9 countries in Europe and North and South America.
Summary
There are large differences between Japan and the West in incidence, staging system, tumour location, and patient factors. Consequently, the concept of radical surgery has developed separately in Japan and the West. Today in the West, gastric cancer is considered a disease to be treated by specialists, preferably with D2 lymphadenectomy without splenectomy.
Principles of radical gastric cancer surgery
Extent of gastric resection
The primary objective of gastric cancer surgery is to adequately excise the primary lesion with clear longitudinal and circumferential margins. Selection of gastrectomy depends on the tumour location and the mode of infiltration in the stomach wall. Preoperative diagnosis should focus on this and careful assessment of lateral tumour spread is indispensable.
Resection margins
Proximal resection margin is the main determinant in selecting a total or distal gastrectomy. During surgery for T2 or deeper tumours, the resection line should be determined with a sufficient margin from the palpable edge of the tumour. A 5-cm margin has traditionally been recommended. In some guidelines, 8 cm is recommended for diffuse-type tumours, but this would necessitate most tumours of the gastric body requiring a total gastrectomy or oesophagogastrectomy.
According to Japanese treatment guidelines, a 5-cm margin is recommended for tumours showing an infiltrative growth pattern with indistinct borders or diffuse-type histology, but 3 cm is usually sufficient for those showing an expansive growth pattern with grossly distinct borders, for which the histology is most frequently of the intestinal type.
For gastric cancers invading the oesophagus, a 5-cm margin is not necessarily required, but frozen section examination of the resection line is desirable to ensure an R0 resection.
In cT1 tumours, lateral mucosal extension should be preoperatively detected or excluded by stepwise biopsy, and placing clips on the negative border is helpful to accurately resect impalpable lesions.
Type of gastrectomy
Common types of gastrectomy for gastric cancer are as follows.
Total gastrectomy
This involves removal of the whole stomach including the cardia (oesophagogastric junction) and the pylorus. It is indicated for tumours arising at or invading the proximal stomach.
Distal (subtotal) gastrectomy
This involves removal of the stomach including the pylorus but preserving the cardia. Two-thirds or more of the stomach is usually removed for gastric cancer. It is indicated for middle or lower third tumours with sufficient resection margins mentioned earlier.
Proximal gastrectomy
This involves removal of the stomach including the cardia but preserving the pylorus. It is indicated for proximal tumours with or without oesophageal invasion, where more than half of the distal stomach can be preserved.
Other resections for T1 tumours
Some function-preserving gastrectomies such as pylorus-preserving gastrectomy (PPG) are applied to T1 tumours.
Total gastrectomy ‘de principe’ for distal cancers
Some European surgeons have argued that all cancers of the stomach, even those in the distal third, should be treated by total gastrectomy. This principle is based on the experience of frequent involvement of the proximal resection margin and consequent anastomotic local recurrence. Theoretically, total gastrectomy ensures more certain negative margins and sufficient lymphadenectomy. In addition, the possible occurrence of multicentric cancer in the gastric stump can be prevented. On the other hand, total gastrectomy is associated with a higher operative morbidity and mortality, increased risk of long-term nutritional problems, and impaired quality of life compared to distal gastrectomy.
Randomised trials comparing total and distal gastrectomies in distal gastric cancer have failed to show a survival benefit for total gastrectomy.
The policy of total gastrectomy ‘de principe’ should be abandoned for the following reasons:
- 1.
Provided that the rules on safe margins of resection listed above are adhered to, a positive proximal resection margin is rare. If the margins are still positive, this usually indicates an aggressive and extensive malignancy, and resection line involvement will not be a major determinant of prognosis.
- 2.
The lymph nodes that can be removed only by total gastrectomy, station numbers 2 (left cardia), 4sa (upper greater curve), 10 (splenic hilum), and 11d (distal splenic artery [SpA]), are seldom involved in distal gastric cancers. If they are involved, again this indicates an aggressive malignancy and extended surgery would not alter the survival outcome.
- 3.
The incidence of second primary cancer in the gastric stump is low. Long-term surveillance by endoscopy may detect a new lesion that can be removed by endoscopic submucosal dissection.
Lymphadenectomy
Lymph node metastasis is the most common mode of spread in gastric cancer. Histological nodal metastasis has been proven in 80% of T4a/T4b tumours, and even T1 tumours have a 10% probability of lymph node metastasis (T1a 3%, T1b 18%). , Unlike hepatic and other distant metastases, lymph node metastasis from gastric cancer can be surgically removed for potential cure provided it is confined to the regional area. The optimal extent of lymphadenectomy, however, has been controversial.
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