Elsevier

The Lancet

Volume 374, Issue 9688, 8–14 August 2009, Pages 477-490
The Lancet

Seminar
Gastric cancer

https://doi.org/10.1016/S0140-6736(09)60617-6Get rights and content

Summary

Gastric cancer is the second most frequent cause of cancer death worldwide, although much geographical variation in incidence exists. Prevention and personalised treatment are regarded as the best options to reduce gastric cancer mortality rates. Prevention strategies should be based on specific risk profiles, including Helicobacter pylori genotype, host gene polymorphisms, presence of precursor lesions, and environmental factors. Although adequate surgery remains the cornerstone of gastric cancer treatment, this single modality treatment seems to have reached its maximum achievable effect for local control and survival. Minimally invasive techniques can be used for treatment of early gastric cancers. Achievement of locoregional control for advanced disease remains very difficult. Extended resections that are standard practice in some Asian countries have not been shown to be as effective in other developed countries. We present an update of the incidence, causes, pathology, and treatment of gastric cancer, consisting of surgery, new strategies with neoadjuvant and adjuvant chemotherapy or radiotherapy, or both, novel treatment strategies using gene signatures, and the effect of caseload on patient outcomes.

Introduction

Gastric cancer is a very common disease worldwide and the second most frequent cause of cancer death, affecting about one million people per year.1 The ratio of men to women is about 2:1. Large differences in incidence exist between continents. The highest incidence—up to 69 cases per 100 000 people per year—is in men in northeast Asia (Japan, Korea, and China).2 Intermediate incidences occur in Europe and South America; North America, Africa, south Asia, and Oceania (including Australia and New Zealand) are low-incidence regions, with rates of 4–10 cases per 100 000 people.

Explanations for these differences in incidence have been sought. High intake of various traditional salt-preserved foods and salt, and low consumption of fresh fruit and vegetables are associated with a raised risk of gastric cancer.3, 4 Further in support of this idea is the finding that gastric cancer incidence in migrants from low-incidence countries increases from a low rate in first-generation migrants to the high incidence of their host country in the second generation.5 Additionally, Helicobacter pylori is a major risk factor for development of gastric cancer.6 However, not all populations with high rates of H pylori infection, such as Africa and south Asia, have a raised incidence of gastric cancer. Differences in H pylori cagA and vacA genotypes might explain these geographical variations.2 Smoking is another important environmental risk factor for gastric cancer.7

Primary prevention strategies to reduce gastric cancer include improvement of sanitation, high intake of fresh fruits and vegetables, safe food-preservation methods, and avoidance of smoking. Although frequency of distal gastric cancer has declined, incidence of proximal gastric cancer has risen. Unlike distal gastric cancer, development of proximal gastric cancer is mainly related to gastro-oesophageal reflux and obesity.8

Countries with high incidences of gastric cancer have screening programmes for groups at high risk, but clinical evidence is insufficient to recommend endoscopic screening worldwide.1 Of 880 000 people diagnosed with gastric cancer in 2000, about 650 000 (74%) died of the disease. In Japan, survival is good (52%), in part attributable to early detection in screening programmes, whereas survival in the USA, Europe, and China generally is only 20–25%.9 Survival in patients with resectable gastric cancer is better than for those with unresectable disease, but even in the resectable group more than half of patients in developed countries (excluding Japan) die.

Improved imaging techniques enable patients to be staged more adequately than previously. Minimally invasive techniques such as endoscopic resections, sentinel node, and laparoscopy have been developed and can be used for early stages of disease. For advanced gastric cancer, achievement of locoregional control remains a substantial difficulty. In the Gunderson re-operative series,10 54% of patients had locoregional recurrence only. To improve results, the extension of surgery has been studied widely. Use of neoadjuvant and adjuvant treatment to further improve results continues to be investigated. A biological approach might lead to further individualised treatment options.

Section snippets

Aetiology

Hereditary diffuse gastric cancer accounts for about 1–3% of gastric cancer cases. In roughly 30% of familial gastric cancers, a germline mutation in one allele of the E-cadherin gene (CDH1) is identified.11 Inactivation of the second allele happens either by mutation or hypermethylation.12 Additional genomic changes eventually lead to early onset of diffuse gastric cancer. Estimated life-time risk of gastric cancer in carriers of a CDH1 mutation is 67% in men and 83% in women. In families with

Histopathology and molecular pathology

The intestinal-type gastric carcinoma has well defined ductal structures or cords, surrounded by a desmoplastic stroma reaction containing different amounts of a mixed inflammatory infiltration. Tumour cells are large, and nuclei are polymorphic and anisochromatic, and have a coarse chromatin pattern. Mitotic figures are easily detected. Intestinal-type carcinomas are usually well to moderately well differentiated. By contrast, diffuse-type adenocarcinomas have solitary or small groups of

Prevention and early detection

H pylori eradication and surveillance of precursor lesions for early detection have long been thought the best approaches to reduce gastric cancer mortality. However, follow-up studies investigating the effect of H pylori eradication have shown contradictory results for reversibility of precursor lesions and reduction of gastric cancer rate. Although eradication has a prophylactic effect on gastric cancer in experimental studies, the effect in people remains controversial. A meta-analysis58 of

Diagnosis and imaging

No typical signs suggestive of gastric cancer exist. In advanced disease, pain in the epigastric region, anaemia, aversion to meat, weight loss, obstruction, bleeding, and perforation might arise. Diagnosis should be made with a gastroscopic biopsy sample and histology specified by WHO criteria. Initial staging consists of clinical examination, including Virchow's lymph nodes and digital rectal examination, blood counts, and liver and renal function tests. The currently known tumour markers are

Surgical treatment

Early gastric cancer is defined as a tumour of the stomach confined to the mucosa or submucosa, irrespective of lymph-node metastases. For some of these tumours, risk of lymph-node metastasis is thought to be very low. For patients with a well to moderately well differentiated tumour of less than 2 cm in size with no submucosal invasion or lymph-angio invasion, local excision by endoscopic mucosal resection has been the preferred treatment in Japan for the past 15 years.74

A systematic review75

Caseload

The Maruyama index of unresected disease is based on a study of 3843 patients.105 From each patient, the involvement of all separate lymph-node regions (figure 3) was registered. Based on seven input variables (age, sex, Borrmann type, tumour size, tumour location, tumour position, and histology) the likelihood for nodal involvement for each regional lymph-node station can be calculated. The Maruyama index can be calculated with the Maruyama computer program.105 This index is defined as the sum

Radiotherapy

The optimum effect of surgery alone on local control and survival seems to have been reached—at least in developed countries. Therefore, preoperative and postoperative strategies with chemotherapy or radiotherapy, or both, have been and are presently being assessed. Radiotherapy is used as palliative treatment for uncontrolled gastric bleeding and unresectable tumours. In these cases, radiotherapy did not improve survival, but locoregional control rates of 70% were reported.118 Importantly,

Targeted therapy

Chemotherapy is useful in advanced gastric cancer,157 but overall survival does not exceed 1 year in phase III studies. Good biomarkers of chemotherapy response might improve quality of life of non-responders, reduce time until surgery in non-responders, and reduce costs. Additionally, optimum treatment can be achieved for patients. Several tumour markers are thought to be predictive of therapy response in gastric cancer (eg, microsatellite instability, chromosomal instability, and

Conclusion

Reduction of gastric cancer mortality can be achieved by implementation of prevention programmes and personalised treatment. Effective prevention strategies should be based on specific risk profiles, including H pylori genotype, host gene polymorphisms, and environmental factors. Treatment and the extent of resection is still decided on the basis of the disease stage identified with conventional techniques. For improvement of locoregional control, new strategies with neoadjuvant and adjuvant

Search strategy and selection criteria

We searched the Cochrane Library, Medline, and Embase for publications from January 1, 2000, to August 31, 2008. We used the search terms “gastric cancer” or “stomach cancer” in combination with the terms “review”, “randomised”, and “clinical trial”. We largely selected publications in the past 5 years, but did not exclude commonly referenced older publications. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant.

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