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Gastric Cancer

Changing the paradigms in screening and prevention.

Gastric cancer remains the fourth commonest cancer worldwide despite a rapid decline in incidence in recent decades. The highest rates are found in Asia, Eastern Europe and South America. Singapore is a country with moderate risks for gastric cancer. It is the 7th most common cancer in males, with an Age-Standardised Incidence Rate of 10.7 per 100,000 person-years, and the 9th most common cancer in females with an ASR of 6.8.1 In certain subgroups, however, the risk can be much higher. For instance, the lifetime risk for gastric cancer in Chinese men is about one in 50.

The overall outcome of treatment for gastric cancer remains poor locally, in spite of advancements in surgery and medical oncology, as the majority of patients are diagnosed at a late stage. We do not have any established screening program to detect cases at an early stage. Existing guidelines do not recommend this for gastric cancer as there is no clear evidence that screening would result in a decrease in mortality.

In contrast, countries like Japan and Korea have some of the highest risk for gastric cancer but mortality is lower as mass screening has increased the early detection rate. Gastroscopy is the recommended screening test as it is readily available, safe and shown to be cost effective in a systematic review.

The argument to extend a modified screening strategy to a moderate-risk country like Singapore remains compelling, and our better understanding of the aetiology and pathogenesis of gastric cancer now suggests that benefits may even extrapolate to prevention and risk reduction.

 

What do we now know about gastric cancer?

what-is-about-gastric-cancer

By far the majority of gastric cancers are adenocarcinomas, but we have long recognised heterogeneous behaviours within this histological type Cancers that originate from the proximal stomach (cardia type) tend to be associated with obesity and gastroesophageal reflux, whilst those from the distal stomach (non-cardia type) are linked to Helicobacter pylori infection, smoking, intake of salty and smoked foods, and a family history of gastric cancer.

Histologically, Lauren divided gastric adenocarcinomas into the diffuse and intestinal subtypes. Diffuse gastric cancers arises from non-atrophic pangastritis and may develop into a morphological variant called linitis plastic where poorly differentiated and signet ring cells infiltrate the gastric wall, leading to a thickened and rigid stomach. Intestinal type cancers, on the other hand, are usually associated with H. pylori infection and corpus predominant gastritis with intestinal metaplasia.

Recent advances in gene profiling such as next-generation sequencing have allowed better understanding of the molecular characteristics of gastric cancer, and this is turn may have important therapeutic implications. In 2014, the Cancer Genome Atlas (a collaboration between the National Cancer Institute and the National Human Genome Research Institute in America) proposed a classification of gastric cancer into four major subtypes: Epstein Barr virus (EBV) associated tumors, microsatellite unstable tumors, genomically stable tumors, and tumors with chromosomal instability.

 

An infective aetiology for gastric cancer?

The link between EBV and gastric cancer is a newly recognised one, and reveals an intriguing subtype that disrupts the usual match between type and location. About 9% of gastric cancers may be associated to EBV, and both cardia and non-cardia cancers may be involved.

Although EBV has been long known to be a cause of Burkitt’s lymphoma and nasopharyngeal carcinoma, the exact pathway by which EBV promotes gastric cancer is still unclear. Nevertheless, this parallels the concept of an infective origin for gastric cancer by the bacterium H. pylori.

Pylori is a spiral, gram negative, microaerophilic bacterium that was discovered by Warren and Marsha in 1982. Within a decade its role in gastric carcinogenesis was identified. H. pylori is also related to formation of duodenal ulcers, but this is associated with antrum-predominant gastritis in contrast to the chronic corpus predominant and multifocal atrophic gastritis that is linked to gastric cancer. The outcome of a H. pylori infection seems to depend on the strain of bacterium and its virulence factors, as well as other host and environmental dynamics.

A stomach that is infected with H. pylori undergoes inflammation in the non-acid secreting gastric antrum. This mucosal damage progresses into the corpus, especially along the lesser curve. Cell differentiation is affected and intestinal metaplasia develops.

Based on studies in large groups of South Americans the Columbian scientist Pelayo Correa described in 1975 the development of gastric cancer as a multi-step process. This Correa cascade has now been updated in 1988 and 1992 as such: normal gastric mucosa, superficial (non atrophic) gastritis, multifocal atrophic gastritis, complete (small intestine type) intestinal metaplasia, incomplete (colonic) type intestinal metaplasia, low-grade dysplasia, high-grade dysplasia and invasive adenocarcinoma.

Gastric intestinal metaplasia (IM) is now well-accepted as a premalignant lesion and considered by many as a surrogate marker for gastric mucosal atrophy and future risk of gastric cancer. Based on follow up of Japanese patients with IM, the relative risk of progression to gastric cancer was 6.4 compared to those without lM.4This risk is also highly associated with the histologic subtype of IM.

In one Spanish study, the incidence of gastric cancer for the incomplete patterns of IM is 18.2% over 12.8 years compared to 0.96% in those with complete IM.5 From a practical point of view, however, this association is often useless as pathologists rarely report on the type of gastric lM since different subtypes can coexist and distinction is often difficult.

 

Can eradication of H. pylori prevent gastric cancer?

The effects of H. pylori eradication on the gastric mucosa have been reported in a number of randomized control trials. In one follow-up of mass eradication in a population with high incidence of H. pylori, the incidence of gastric cancer decreased by 25% during the study. Other data also suggests a protective role for H. pylori eradication but this effect seems to be limited to those without precancerous lesions. A critical point may therefore exist in the Correa cascade where histological changes are no longer reversible, but the exact step in this sequence where this happens is still debatable currently strongly recommends.

The Asia Pacific consensus population screening and treatment for H. pylori in high-risk regions based on the cost effectiveness of chemo-prophylaxis of gastric cancer compared to treatment when this is detected at a symptomatic and advanced stage. Furthermore, it would be possible to extrapolate this benefit to a country like Singapore which has a moderate risk for gastric cancer but where endoscopy is safe, widely available and not expensive. Gastroscopy can be easily piggybacked onto the routine colonoscopy that is already advocated for the screening and prevention colorectal cancers in the general population above the age of 50. For younger individuals, non-invasive H. pylori testing, such as the urea breath test, can be used in a test-and-treat or test-and-endoscope strategy.

Post-treatment verification of eradication by non-invasive testing is recommended, as high failure rates from increasing bacterial resistance are an obstacle to a successful screening and prevention program. The usual standard triple therapy that includes a proton pump inhibitor, clarithromycin and amoxicillin or metronidazole now has eradication rates of only about 70%. The majority of these failures are due to antibiotic resistance to metronidazole or clarithromycin, and other agents, such as levofloxacin, have been used in second-line treatments. Various strategies have also been proposed as salvage therapy in those who repeatedly fail to respond, including sequential therapy, culture based therapy and adjuvant administration of probiotics, statins an pronase.

 

What can we do for those with pre-malignant gastric lesions?

For individuals found to be positive for H. pylori by non-invasive testing, an index gastroscopy may be offered to look for pre-malignant lesions. This is especially so for Chinese males and those with a family history of gastric cancer. Gastric IM has been used as a break point in the carcinogenesis sequence, and detection of this can be improved with mage-enhanced endoscopic techniques such as narrow-band imaging and high definition magnifying endoscopy. Endoscopic mapping and multiple targeted biopsies should be obtained. Serum pepsinogen (PG) levels can also be done as this is a useful marker of atrophic gastritis.

Patients found to have extensive gastric IM, and those with extensive atrophy, defined as a serum PGI level of less than 70 ug/L and a PGI/PGIl ratio of less than 3, should be offered surveillance gastroscopy with a screening interval of between 1 and 3 years. The rationale for this that those who do develop dysplasia or gastric cancer eventually can be cured by endoscopic resection without the need for surgery if early detection is possible.

 

Conclusion

Although gastric cancer is still a deadly disease if detected at a symptomatic and advanced stage, a changing paradigm is emerging based on our clearer understanding of gastric carcinogenesis. Screening and surveillance strategies for cancer and pre-malignant lesions will help move diagnosis to an earlier and curable stage. Screening and eradication of H. pylori may help to reduce overall incidence of gastric cancer.

Newer modalities of screening are also gaining interest, including the use serology for H. pylori and serum PG. Future targets may also come in the realm of prevention of the infective causes of gastric cancer, through the development of potential vaccination against EBV and H. pylori.

 

References:

1. Singapore Cancer Registry Interim Annual Report. Trends in Cancer incidence in Singapore 2010-2014.

2. Dan YY SoJB Yeoh KG: Endoscopic screening for gastric cancer Clin GastroenterolHepatol. 2006. 4:709-716.

3. Sokic Milutinovic A.Alempijevic A. Milosavijevic Role of Helicobacter pylori infection ingastric carcinogenesis: Current knowledge and future directions. World J Gastroenterol 2015 November 7.21(41) 11654-11672.

4. Uemuta N.0kamoto S. Yamamoto S. etal, Helicobacter pylori infection and the development of gastric cancer NEngl J Med 2001 34511) 784-783.

5. Gonzlez CA, Pardo ML, Liso JM, et al. Gastric cancer occurrence in preneoplastic lesions a long term follow-up in a high risk area in Spain, Int J Cancer 2010127(11) 2654-2660

6. Lee YC, Chen TH, Chiu HM, et al, The benefit of mass eradication of Helicobacter pylori infection: a community-based study of gastric cancer prevention. Gut2013 62:676.682.

7. Fock KM, Katelaris P Sugano K. etal Second Asia-Pacific Consensus Guidelines for Helicobacter pylori infection. JGastroenterol Hepato/2009, 24: 1587-1600.

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Gastric Cancer Screening & Prevention
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Gastric Cancer Prevention
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    Patient Information

    Gastric Cancer

    Gastric (stomach) cancer can often remain asymptomatic for a long time, especially in the early stages. As such, it usually presents late. The usual symptoms are pain and discomfort in the upper abdomen. It can also cause early satiety (fullness after a small meal), vomiting, loss of weight and loss of appetite. Occasionally it presents as an emergency with severe pain from perforation or bleeding (vomiting of blood or passage of black stools due to altered blood).

    Gastric cancer is the 3rd most common cancer in males and 5th most common cancer in females in Singapore. In spite of this, there is no strong evidence to suggest that routine screening of gastric is useful if you are asymptomatic. If, however, you have recent onset of “gastric pain” or any of the symptoms mentioned above, and have not been investigated before, you should see your family doctor to see if a gastroscopy is recommended. This is a simple test in which a thin, flexible telescope is inserted through the mouth and into the stomach for a complete visualization of the cause of your symptoms.

    Gastroscopy is very safe and takes less than 10 minutes of an outpatient procedure. No preparation is required other than fasting for 6 hours. You will be given an anaesthetic to numb the throat. You will be awake but if you find this uncomfortable you may choose to have sedation for the procedure.

    Biopsies will be taken during the gastroscopy to confirm the cancer. This biopsy will also tell us the histological type of the cancer. The majority of gastric cancers are adenocarcinomas (arising from the inner lining of the stomach). Occasionally we may find stromal tumours (arising from the muscle layers of the stomach) or lymphomas. It is important for us to know what is the histological type as the treatment may be different.

    The next step is a thorough staging of the cancer. By this we can establish how advanced the cancer is and whether it has spread to surrounding and distant organs. The best test is a CT scan of the abdomen. In selected cases we may also want to perform an Endoscopic Ultrasound (similar to a gastroscopy but with an ultrasound built into the tip of the scope) and a Laparoscopic Staging and Laparoscopic Ultrasound.

    After staging is completed we can decide on the most effective treatment for that particular cancer. A tumour that is confined to the stomach is suitable for potentially curative surgery. It is possible that there is spread to the surrounding lymph nodes but this can also be resected at the same time. We believe that radical resection of the regional lymph nodes by systematic dissection decreases the risk of recurrence and offers a better chance for cure. This operation was devised by the Japanese. They have the highest rates of gastric cancer in the world but they shown far better treatment results using this approach when compared to Western surgeons.

    In the Western type operation, only the lymph nodes next to the stomach (Group 1) are removed. In the Japanese type operation, we routinely remove the Group 2 lymph nodes, and occasionally, even the Group 3 and 4 lymph nodes. The spleen and left adrenal gland may also need to be removed depending on their proximity to the cancer. The pancreas and colon are not resected unless they are directly invaded by the cancer. The Japanese type of radical surgery is technically demanding and requires 3 to 4 hours to complete. Nevertheless, if the surgeon is skilled the operation is safe (mortality about 1%) and worthwhile as there is a better chance for cure.

    Depending on the location of the cancer, either the whole stomach (Total Gastrectomy) or part of the stomach (Partial Gastrectomy or Subtotal Gastrectomy), needs to be removed. The cut end of the esophagus or remaining stomach is re-connected to the small intestine. This anastomosis takes about a week to heal after surgery. The patient is slowly re-introduced to fluids, soft diet and finally solid diet. Once fully recovered, normal meals can be consumed although in reduced amounts. This is easily compensated with frequent, small meals. No dietary restriction is required.

    In the long term, some types of nutritional problems may develop after gastric surgery. It is therefore important that the patient is closely followed up. Nutritional supplements may be required, including Vitamin B12 injections, other oral B vitamins and iron tablets.

    We usually measure the outcome of surgery for cancer by the 5 year survival rates (percentage of patients considered cured after a follow up of 5 years). This depends greatly on the stage of the cancer. We can determine the stage accurately only after a complete examination of the tissue by the pathologist. If a Japanese type Radical Gastrectomy with Systematic Lymph Node Clearance is performed the 5 year survival rates are: 90% (stage I), 70% (stage II), 50% (stage IIIa), 30% (stage IIIb) and 10% (stage IV). In contrast, if the patient only had a Western type operation, the 5 year survival rates are much lower: 60% (stage I), 30% (stage II), 15% (stage IIIa), 10% (stage IIIb) and 3% (stage IV).

    There is now good data from clinical trials to show that chemotherapy in combination with radiotherapy after potentially curative surgery can improve the chances of long term survival. This combination therapy is given as soon as the patient has recovered fully from surgery. The rationale of treatment is that even if there is no visible residual cancer after a complete resection, there may be microscopic cancer cells circulating in the blood stream or elsewhere which cannot be detected by any test. The best treatment for this would be giving the combination therapy before these microscopic cells grow to become visible recurrences.

    In some patients where the tumour is very large, we may also choose to give the chemotherapy and radiotherapy before surgery to shrink the tumour. This would improve the chances of a complete resection. Chemotherapy and radiotherapy can also be given for relief of symptoms (palliation), in patients with widespread disease not suitable for surgery.

    For further information on “Gastric Cancer in Singapore”, please download this invited article published in the “Gastric Cancer Journal – official journal of the International Gastric Cancer Association“.

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