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New Treatments for Stomach Cancer

In gastric cancer there has been a shift from the more endemic gastric cancer, associated with the high risk countries, to stomach cancer, gastric cancer an cardioesophageal junction lesion which is occurring in the United States quite frequently. And we don’t really know what the etiology of that is. The endemic form of gastric cancer are two different types of gastric cancer now that are of importance. One is the endemic form which is associated with intestinal metaplasia of the stomach, with chronic gastritis, with H. pylori infection. And the other is the proximal, poorly differentiated generally, adenocarcinoma of the cardioesophageal junction which is actually increasing in incidence. But the endemic form has gone down very significantly over the last 50 years in the United States. It looks like it clearly is related to the environment. It’s clearly related to what we put in our mouths. In the early part of this century there was no widespread use of refrigeration. Fresh fruits, fresh vegetables were not eaten very much. Things like sauerkraut, things like preserved and salted vegetables were eaten. Fresh meat was not eaten. Then in the 1920’s there was the introduction of refrigerated railroad cars and actually gastric cancer began to fall about 10-15 years after, in the early 1930’s is when it began to take its real dip. And it’s very clear that when you don’t eat highly salted meats, you don’t eat a lot of meats that are preserved with nitrites, you have a lower incidence of gastric cancers.

There has been a rapid increase in incidence of gastric cancer between 1975 and 1990 in the rate per thousand of - it’s gone up about four times - of adenocarcinoma of the distal esophagus, proximal stomach in white males. This is really a very rapidly increasing tumor. It’s said that only melanoma is increasing more frequently than this tumor. And we really don’t have a good clue as to why that is. It’s most common in Caucasian men, typically between the ages of 40-70.

What about other etiologies of gastric cancer? Prior gastrectomy is one. I’m sure most of you have not seen many patients who have had partial gastrectomies for ulcer disease in the past. Twenty-five years ago when I was training that was quite common. People did antrectomies and vagotomies and pyloroplasties to essentially decrease the gastric acid production in patients with ulcers. And it is known that there is an increased risk of gastric cancer after those procedures. The latent period is greater than 15 years.

Now H2 antagonists, were thought of as, "Gee, if we make the stomach achlorhydric do we increase the risk of gastric cancer?" and short term risk has been looked at, actually. This is an article from almost ten years ago now and there was an increased risk of gastric cancer within five years of going on H2 antagonists, and the situation here was thought to be that the reason.

Well, what about symptoms and diagnosis of gastric cancer? With most GI cancers the symptoms of the tumor are either related to bleeding, since all GI cancers, all carcinomas of the GI tract, begin in the mucosa. So you can get irritation in the mucosa, ulceration, what have you, and bleeding. Or the other symptom is an alteration of function. What kinds of alterations of functions can you have? Well, if you have a cardioesophageal junction lesion you can have obstruction. If you have a big lesion in the stomach, you can have early satiety if the stomach.

There is one tumor of the stomach that will bleed massively and that’s leiomyosarcoma. Of course to make things interesting for people taking the Boards, we have changed the name of leiomyosarcoma in the last four or five years to gastrointestinal stromal tumor, so GIST. But those are the tumors that can bleed massively. If you look at the frequency of symptoms, and this has to do with early diagnosis, they are relatively non-specific; some weight loss, some abdominal pain and it’s not a direct, specific symptoms of gastric cancer.

This is just an endoscopic ultrasound just to show you an ultrasound of the stomach. Because this is an increasing important technique used in managing patients with gastric cancer, it becomes particularly important because, as you will see, we are beginning to use a fair amount of neoadjuvant therapy. When you use neoadjuvant therapy you have to have some monitor of how effective the treatment is going to be. You also want to know what you are starting with. This endoscopic ultrasound just shows you the various layers of a normal stomach. Endoscopic ultrasound is very effective at staging the tumor.

The treatment of gastric cancer is really surgical resection. This just shows you the stomach. Again, as a general rule, in the GI tract the organs are - except for the liver and the pancreas - are really hollow visci. In mammals hollow visci are hung on a lymphovascular pedicle. So you have this lymphovascular pedicle and surgical management of gastric cancer entails removing the tumor wherever it happens to be, with a wide margin and also taking some of the lymph nodes. Now how many lymph nodes you take and whether or not you increase the cure by taking a more extensive lymph node dissection is one of the areas of real contention in gastric cancer.

Surgery data, on gastric cancer survival with surgery. If you had very early disease, and Ia is essentially mucosal gastric cancer - rarely seen in this country - surgery is highly curative. If you have the typical gastric cancers seen in this country, which are node-positive, IIIa, IIIb, the chance of survival with surgery alone is somewhere around 20%.

This just shows you what I went over before. The literature has changed so this slide is a little bit old. These should really be D0, D1, D2 rather than R1, but what it refers to is the type of nodal dissections. This is the one that is of quite interest. The D2 or R2 dissection because worldwide, particularly in the Far East and particularly in Japan, this has been the standard of care for 30 years. That you do an extensive en bloc nodal dissection, taking the nodes down to the celiac access.

Now there is a benefit for doing a D2 dissection and these are interesting data. This is probably, in regard to surgery, this will probably be the most important thing in regard to the primary treatment of gastric cancer that I will show you. This is a very interesting paper that was published in January of 1995 and it was from the Dutch group again. What they did was a real interesting thing. They took their patients who were having D2 dissections and they said, Okay, to their pathologists, they said, "Stage these patients as if they only had a D1 dissection." In other words, only look at the nodes within 3 cm of the primary tumor and give us a stage, and then go on and stage the rest of the specimen.

What about adjuvant therapy? If you look at … we can talk about staging. Interestingly enough, in the United States in an adjuvant study that I am going to report to you shortly, about 80% of the patients that were referred for adjuvant therapy were node-positive. So they were IIIa or IIIb patients essentially. We know that 80-85% of those patients relapse after surgery. So what about adjuvant chemotherapy, for example? This is really the largest adjuvant chemotherapy study that’s been reported in the United States, a prospectively randomized study.

If adjuvant chemotherapy with the combinations we have now is not adequate adjuvant therapy, what might be reasonable adjuvant strategies? One thing that makes a lot of sense when you are dealing with solid tumors, is to understand the pattern of relapse. Because you might be able to design adjuvant therapy using modalities of therapy that are targeted towards that particular pattern of relapse. This just looks at the sites of failure in patients with gastric cancer.