Stomach cancer

Abstract

Introduction

Stomach cancer is usually an adenocarcinoma arising in the stomach, and includes tumours arising at or just below the gastro-oesophageal junction (type II and III junctional tumours). The annual incidence varies among countries and by sex, with about 80 cases a year per 100,000 in Japanese men, 30/100,000 in Japanese women, 18/100,000 in British men, and 10/100,000 in British women.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of radical versus conservative surgical resection? What are the effects of adjuvant chemotherapy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: adjuvant chemoradiotherapy, adjuvant chemotherapy, lymphadenectomy (radical, conservative), removal of adjacent organs, and subtotal gastrectomy for resectable distal tumours.

Key Points

Stomach cancer is usually an adenocarcinoma arising in the stomach and includes tumours arising at or just below the gastro-oesophageal junction (type II and III junctional tumours). Only non-metastatic stomach cancers are considered in this review.

• The incidence varies among countries and by gender, with about 80 cases a year per 100,000 in Japanese men, 30/100,000 in Japanese women, 18/100,000 in British men, and 10/100,000 in British women.

With regard to surgical resection, subtotal gastrectomy seems as effective as total gastrectomy.

• In practice, surgeons sometimes recommend total gastrectomy "de principe" in people with poorly differentiated "diffuse" cancer, to prevent infiltration of microscopic tumour deposits into the proximal resection margin.

Removal of adjacent organs (spleen and distal pancreas) is associated with increased morbidity and mortality compared with gastrectomy alone.

• Current consensus is that adjacent organs should only be removed to ensure complete tumour removal, or when required because of trauma during surgery.

We found insufficient evidence to judge the effectiveness of radical lymphadenectomy compared with conservative lymphadenectomy.

Adjuvant chemoradiotherapy seems to improve survival compared with surgery alone in people with resectable stomach adenocarcinoma.

Adjuvant chemotherapy might also be effective compared with surgery alone, although the evidence is inconsistent.

About this condition

Definition

Stomach cancer is usually an adenocarcinoma arising in the stomach, and includes tumours arising at or just below the gastro-oesophageal junction (type II and III junctional tumours). Tumours are staged according to degree of invasion and spread (see table 1 ). Only non-metastatic stomach cancers are considered in this review.

Table 1.

Staging of stomach cancer (see text).

Stage	Description
T1	Involvement of mucosa ± submucosa
T2	Involvement of muscularis propria
T3	Involvement of serosa but no spread to adjacent organs
T4	Involvement of adjacent organs
N0	No lymph node involvement
N1	Local (perigastric) nodes involved
N2	Regional nodes involved
N3	More distant intra-abdominal nodes involved
M0	No metastases
M1	Metastases

Incidence/ Prevalence

The incidence of stomach cancer varies among countries and by sex (incidence per 100,000 population a year in Japanese men is about 80, Japanese women 30, British men 18, British women 10, white American men 11, and white American women 7). Incidence has declined dramatically in North America, Australia, and New Zealand since 1930, but the decline in Europe has been slower. In the USA, stomach cancer remains relatively common among particular ethnic groups, especially Japanese-Americans, and some Hispanic groups. The incidence of cancer of the proximal stomach and gastro-oesophageal junction is rising rapidly in many European populations and in North America. The reasons for this are poorly understood.

Aetiology/ Risk factors

Distal stomach cancer is strongly associated with lifelong infection with Helicobacter pylori and poor dietary intake of antioxidant vitamins (A, C, and E). In Western Europe and North America, distal stomach cancer is associated with relative socioeconomic deprivation. Proximal stomach cancer is strongly associated with smoking (OR about 4), and is probably associated with gastro-oesophageal reflux, obesity, high fat intake, and medium to high socioeconomic status.

Prognosis

Invasive stomach cancer (stages T2-T4) is fatal without surgery. Mean survival without treatment is less than 6 months from diagnosis. Intramucosal or submucosal cancer (stage T1) may progress slowly to invasive cancer over several years. In the USA, over 50% of people recently diagnosed with stomach cancer have regional lymph node metastasis or involvement of adjacent organs. The prognosis after macroscopically and microscopically complete resection (R0) is related strongly to disease stage, particularly penetration of the serosa (stage T3) and lymph node involvement. Five-year survival rates range from over 90% in intramucosal cancer to about 20% in people with stage T3N2 disease (see table 1 ). In Japan, the 5-year survival rate for people with advanced disease is reported to be about 50%, but the explanation for the difference remains unclear. Comparisons between Japanese and Western practice are confounded by factors such as age, fitness, and disease stage, as well as by tumour location, because many Western series include gastro-oesophageal junction adenocarcinoma, which is associated with a much lower survival rate after surgery.

Aims of intervention

To prevent progression; extend survival; and relieve symptoms, with minimal adverse effects.

Outcomes

Survival; quality of life; adverse effects of treatment.

Methods

BMJ Clinical Evidence search and appraisal August 2007. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE clinical guidelines. The author also performed hand searches of conference proceedings and consultations with experts to identify relevant studies in August 2004. Abstracts of the studies retrieved were assessed independently by two information specialists using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 people, of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. In many instances, we have separated trials and results from different geographical areas, because of differences in baseline risk and demographics and possible differences in responses to treatments. However, the meanings of terms to describe such populations, such as "Western" and "Asian" were not clearly defined in many identified studies. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table.

GRADE evaluation of interventions for stomach cancer

Important outcomes	Mortality, adverse effects
Number of studies (participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of radical versus conservative surgical resection in people with stomach cancer?
2, 2 reports (817)	Mortality	Subtotal v total gastrectomy	4	−2	0	0	0	Low	Quality points deducted for blinding flaws and incomplete reporting of results
2 (1111)	Mortality	Radical v conservative lymphadenectomy	4	0	0	−2	0	Low	Directness points deducted for differences in surgeon expertise and because results were affected when different surgical techniques were employed
2 (403)	Mortality	Total gastrectomy plus splenectomy v total gastrectomy	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
What are the effects of adjuvant chemotherapy in people with stomach cancer?
1 (556)	Mortality	Adjuvant chemoradiotherapy v surgery alone	4	0	0	−1	0	Moderate	Directness point deducted for lack of standardised surgical techniques
27 (at least 1330 people)	Mortality	Adjuvant chemotherapy v surgery alone	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results

Type of evidence: 4 = RCT; 2 = Observational Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio

Glossary

Adjuvant chemotherapy

Treatment with cytotoxic drugs given in addition to surgery in an attempt to achieve cure.

Conservative lymphadenectomy (D1)

Removal of perigastric lymph nodes — lymph nodes that lie adjacent to the stomach.

Disease stage

Surgical and microscopic assessment of the primary tumour. Microscopic spread to distant sites can be detected only by radical surgery, creating a potential bias.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Radical lymphadenectomy (D2)

Removal of regional lymph nodes — lymph nodes that lie along the blood vessels that supply the stomach.

Stage migration bias

Apparent increase in stage-specific survival without influencing overall survival caused by recategorisation of the stage after removal of diseased lymph nodes.

Subtotal distal gastrectomy

Removal of the lower part (usually two thirds or four fifths) of the stomach.

Total gastrectomy

Removal of the whole stomach.

Total gastrectomy “de principe”

Total gastrectomy where it is not technically necessary (i.e. for a distal cancer which could be removed using a partial gastrectomy).

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