Hello, Mr. Choi

You came in last week complaining of unexplained weight loss, abdominal discomfort, and bloating of the abdomen after small meals. Although these symptoms could be attributed to other digestive problems, the last symptom you mentioned is very typical of stomach cancer, which is why you underwent an upper endoscopy--the most common test used to find cancerous tumors in the stomach[1] . I regret to inform you that the test results came back positive; you have been diagnosed with stage 1 stomach cancer, otherwise known as gastric cancer--a cancer of the stomach lining. It is a relatively rare form of cancer, the 16th most common in the US, but is known to have a low 5-year survival rate[2] . Although, the incidence and mortality of this cancer have fallen steadily over the past decade--most likely due to improved preservation of foods--they have just recently begun to increase again. Hypotheses about this sudden rise in incidence center around the fact that diets have recently began to include lots of smoked and salted foods, which increases the risk of developing gastric cancer. Being an Asian-American male who has surpassed the age of 50, you are part of one of the most at-risk demographics for having stomach cancer. The incidence of stomach cancer increases strikingly at the age of 50 and Asian/Pacific Islanders are the second most prone to developing this cancer, after African-Americans[3] . This is most likely due to their respective diets, and also because the proper storage and refrigeration of food was not commonplace in Southeastern Asia until recent decades.

Although we are still awaiting your results from the biopsy, if I were to pinpoint the reason for the development of this cancer in your particular case I would attribute it to an infection by a bacteria known as Helicobacter pylori; this infection accounts for over 60% of all stomach cancer cases. You noted that your symptoms include discomfort in the abdomen and also a sense of fullness after eating a small meal. This is most likely due to the fact that the Helicobacter pylori bacteria has infected your upper gastrointestinal tract, inducing gastritis (an inflammation of the stomach lining). This inflammation occurs as a result of the bacteria burrowing into the mucus lining of the stomach. It does this to avoid the acidic conditions of the inner stomach and to reach the more neutral pH levels of the cells underneath the lining[4] .

However, judging from your physical history and lifestyle I would also have to bring in your diet and smoking habits as strong contributors to the development of this cancer. Smoking and having a diet high in smoked and salted foods, along with pickled vegetables, are known to be prominent risk factors that increase your chances of developing stomach cancer. I understand that the diet of most Asian cultural households include high amounts of sodium due to such pickled vegetables and salted foods, which was most likely contributory to your development of the disease. Although not noted in your particular health records, having close relatives that had or have this disease would be a strong risk factor as well.

It's a good thing you came in as early as you did to get your symptoms checked out because after your positive upper endoscopy test, we performed an endoscopic ultrasound which revealed that the cancerous cells have not spread to nearby tissues yet. If the cancer had spread, your estimated 5 year survival rate would be 28.3%[5] . However, your cancer is still in the early stages--namely what we call stage 1 gastric cancer--which places your chances of survival at approximately 63%. Stage 1 gastric cancer means that the cancerous cells have formed within the innermost layer of the stomach wall, but have not spread any further. This is what we call an adenocarcinoma of the stomach, which indicates that the proliferation of cancerous cells has stemmed from the mucosa--the inner lining of the stomach[6] .

While the success of eradicating stomach cancer varies depending on a number of factors, 11,000 of the 22,000 individuals that were estimated to be diagnosed this year with this cancer are also estimated to die from it. Due to the deadly nature of stomach cancer, it is important that we discuss your treatment options as soon as possible to increase your chances of overcoming and surviving this disease. Currently, there are four different standard treatments for gastric cancer: (1) Surgery, (2) radiation therapy, (3) chemotherapy, and (4) targeted therapy.

In order for you to make a clear and informed decision about which treatment best suits your situation, I think it's important for you to get a better understanding of your cancer and how each treatment route applies. From your biopsy results, we were able to confirm that the cancerous tumors in your stomach lining originated from a Helicobacter pylori infection and were also characterized by an over-expression of the HER2 growth-promoting gene.

As I said before, the development of gastric cancer as a result of a H. pylori bacterial infection is very common--accounting for over 60% of all cases[7] . Over two-thirds of the world has this bacteria in their bodies, but does not usually cause health problems for most people. Only when it is coupled by other risk factors for stomach cancer--in your case, your diet--does it instigate the proliferation of cancerous cells. The H. pylori bacteria induces cancerous growth in the gastric lining through two different pathways. The first pathway involves the bacteria using its helix-shape in order to burrow into the mucosa, the mucus lining of the stomach, in order to avoid the acidic environment of the gastric lumen[8] . In response to the burrowing, the immune system will up-regulate the production of CD4T helper cells, which is a signaling component of the immune system that tells other immune cells to destroy the infectious pathogen. In order to resist this immune response, the H. pylori bacteria will induce gastritis, an inflammation of the gastric lining, which is characterized by a proliferation in the production of a variety of pro-inflammatory cytokines--these proteins have been reported to be associated with an increased risk of cancer development[9] . This association is a direct result of the fact that this ongoing cellular damage increases cell turnover, resulting in an increased likelihood that cells will develop harmful mutations. These mutations are what ultimately lead to the development of cancerous cells as you will learn in the second pathway.

The second pathway that the H. pylori uses to promote gastric carcinogenesis is by directly inducing genomic damage into the gastric epithelial cells, which can ultimately lead to the activation of oncogenes (cancer-causing genes) and/or the inactivation of tumor-suppressor genes. The bacteria does this by enhancing the expression of activation-induced cytidine deaminase (AID) in the mucosal cells[10] . AID acts as an editor of DNA and RNA, and has been associated with a high mutation frequency of the TP53 gene--one of the most notable tumor-suppressor genes. Another mechanism by which the H. pylori bacteria destabilizes DNA is through increasing the levels of nitric oxide synthase. Nitric oxide synthase is known to be able to deaminate, or break down, DNA and cause mutations to other tumor suppressor genes[11] .

However, all of these detrimental effects of the H. pylori bacteria infection in your case cannot be reversed now that they have already manifested into cancerous tumors within your gastric lining. In order to avoid the development of gastric cancer as a result of H. pylori infection, you would have had to follow preventative measures regarding your health in order to evade the infection in the first place. However, due to the fact that the bacterial infection has already instigated the development of cancerous cells, normal medications to treat the H. pylori such as amoxicillin and clarithromycin are not viable as they do not target stomach cancer, but rather the infection[12] . Thus, I believe surgery to be the most appropriate method of treatment.

Surgery is a common treatment for almost any form of cancer at any stage. For stomach cancer, specifically, there are two routes of treatment: subtotal gastrectomy and total gastrectomy. A subtotal gastrectomy consists of a removal of the cancerous portion of your stomach along with nearby lymph nodes and tissues, whereas a total gastrectomy requires the removal of your entire stomach and the subsequent connection of the esophagus directly to the small intestine[13] . Given that your cancer is still in its early stages, I would discount the option of a total gastrectomy due to the post-surgical consequences that it entails--you will experience obvious chronic discomfort and large meals are improbable. A subtotal gastrectomy would be more appropriate for your particular stage of stomach cancer.

Radiation therapy consists of the use of high-energy radiation to target and kill cancer cells. The treatment process itself is painless, but it carries with it certain side effects that would contraindicate this treatment for your particular case. While radiation is quite effective in killing off cancerous cells and also lowering the risk of it coming back, it may cause unnecessary collateral harm to nearby organs[14] . Other common side effects include nausea, skin problems, and fatigue. Although the severity of side effects do vary depending on the patient and the treatment dose, the treatment regimen requires you to be treated five days a week, over a period of several months which I believe won't be necessary, considering the early stage of your cancer.

If you want to consider chemotherapy as part of your treatment, there are three different ways it can be used. It can be used before surgery, known as a neoadjuvant treatment, to shrink the tumor for an easier surgery or after surgery as an adjuvant treatment, the goal of which is to cleanse the body of small, undetectable cancer cells that may remain after surgery[15] . It can also be used as the primary form of treatment of the cancer, but is normally used in this method for stomach cancer that has already metastasized to distal organs. Chemotherapy drugs, in general, are effective because they work against cells that divide rapidly which is a fundamental property of cancer cells. However, cells in the bone marrow, hair follicles, mouth and intestines also divide at rapid rates which cause these areas to be prime targets for the drugs as well--this can result in severe side effects such as hair loss, fatigue, and an increased chance of infection[16] . Due to these chemotherapy drugs' inability to differentiate between certain types of cells and cancerous ones, I would recommend a similar form of treatment called targeted therapy.

Targeted therapy is similar to chemotherapy in that it uses drugs to stop or hinder the proliferation of cancer cells. The difference is that targeted drugs are able to attack specific genes that are involved with the growth, progression, and spread of cancerous cells, which ultimately leads to fewer side effects. For you, I would recommend targeted therapy as an adjuvant treatment. This is because the subtotal gastrectomy is currently the treatment with the greatest potential in helping you, and we do not want to delay the surgery with any neoadjuvant therapies in order to limit the progression of the cancer. An adjuvant therapy will help in decreasing your risk of relapse, once the cancerous cells have been surgically resected.

The particular targeted therapy that I would prescribe for you is a drug called Trastuzumab (Herceptin). As I said before, your tumor samples from the biopsy contained an increased level of a growth-promoting protein called HER2, which can be directly combated by this drug[17] . The HER2 gene is a member of the epidermal growth factor receptor family, which means that by binding to certain cellular domains it is able to initiate a signal transduction cascade--this is when a receptor on the surface of the gene receives a signal and translates it internally. These signals can lead to many different pathways that promote cancerous growth such as cell proliferation, migration, and differentiation[18] . Trastuzumab works against HER2 by binding to the gene's extracellular receptor and flagging it for destruction by the immune system, as shown in this figure.
external image herceptin-moa.jpg
It also works against the intracellular signaling of the HER2 gene, inhibiting the signals that call for cell proliferation[19] . As it is the best known treatment against HER2 over-expression, it was prescribed for Mr. Choi as opposed to other chemotherapy drugs. It is injected only once every 2 to 3 weeks, and the side effects are known to be very mild.

All of the aforementioned treatment options are viable possibilities to treating your stomach cancer, Mr. Choi. However, I believe that the treatment plan that I have outlined for you will maximize your chances of overcoming the disease. As I have said before, my personal recommendation would be a subtotal gastrectomy to rid your stomach of the cancerous cells, followed by an adjuvant treatment of the targeted drug Trastuzumab, in order to decrease the chances of the cancer returning. I believe this treatment plan to the optimal route in combating your stage 1 gastric cancer while minimizing side effects and post-treatment consequences.

While I suspect a high success rate for this particular treatment plan, there is always a probability of recurrent cancer which may result in unresectable or advanced metastatic gastric cancer. Due to positive results from 2 independent clinical trials, the FDA has approved a new treatment drug called Cyramza for such cases of recurrent cancer[20] . Cyramza's main mechanism of operation is through ramucirumab, an angiogenesis inhibitor, which impedes the cancer cells' ability to create new blood vessels that they will ultimately use to proliferate and grow. If your adjuvant treatment of Trastuzumab does not work against any recurring cancer cells, I would highly recommend partaking in this clinical treatment as there are no contraindications to Cyramza[21] .

Even with the improved preservation of food, gastric cancer still remains as the second most common cause of cancer-related deaths in the world, with a low 5-year survival rate even after treatment by surgery[22] . However, this is mainly due to the fact that stomach cancer is often diagnosed at already metastatic stages--this is because there is no standard screening test for stomach cancer. You were very lucky in your early diagnosis because over 50% of patients with localized gastric cancer are successfully treated without relapse[23] . Also, your treatment plan of a subtotal gastrectomy and an adjuvant targeted therapy of Trastuzumab were prescribed to directly target the originating causes of your cancer and limit the severity of side effects, while reducing the risk of the cancerous cells returning. Thus, despite the high risk of an aggressive progression of your gastric cancer as a result of both a Helicobacter pylori infection and an over-expression of HER2, we are very hopeful in your chances of overcoming your cancer. Regardless, after your treatment is complete, it is important to continue making healthier choices--eating better or exercising more--in order to lower the risk of a more aggressive and untreatable recurrent stomach cancer.
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