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From OncoLog, August 2011, Vol. 56, No. 8

Graphic: Compass
Compass, a quarterly supplement to OncoLog, discusses cancer types for which no standard treatment exists or more than one standard treatment is available.

Early- and Intermediate-Stage Gastric Cancer

By Sunni Hosemann

This discussion addresses early- and intermediate-stage gastric adenocarcinomas—those that have not metastasized and are considered surgically resectable. Most adenocarcinomas arise in the mucosal layer of the stomach; however, very few gastric cancers are diagnosed while still confined to the gastric mucosa (T1a tumors). Most gastric cancers are not discovered until they are more advanced.

Surgery is the definitive treatment for early- and intermediate-stage gastric cancers that have not metastasized. In most patients, however, surgery alone is considered insufficient. Chemotherapy and radiation therapy have both been shown to prolong survival in patients who undergo surgery for these tumors, but when these treatments should be done and in what order has yet to be defined by large randomized trials.

Traditionally, surgery has been the initial treatment for gastric cancers, and until recently, staging was not considered complete until the tumor was surgically removed and subjected to pathological analysis. However, gastric cancers are often found to be more advanced at surgery than initially thought. Also, because occult metastases are common in patients with gastric cancer, the disease may advance—particularly in the peritoneum—despite an R0 resection (the removal of the tumor with clear pathological margins). For these reasons, MD Anderson physicians believe that pretreatment staging is crucial to planning and implementing effective treatment.

Preoperative evaluation

A gastric tumor is considered resectable if there is no evidence of metastasis to the viscera or peritoneum as determined by a thorough preoperative workup. At MD Anderson, this workup includes preoperative staging of the tumor by endoscopic evaluation of the stomach, including ultrasonography, and a laparoscopic evaluation of the abdomen. “While important, imaging studies are inadequate for full staging of gastric cancer,” said Keith Fournier, M.D., an assistant professor in the Department of Surgical Oncology, who added that as many as 40% of gastric tumors may go undetected by positron emission tomography.

During the diagnostic laparoscopy, peritoneal washings are obtained for cytological analysis. “About 20% of the time, evidence of metastasis is found in the peritoneal washings, even in patients who don’t have observable metastases,” Dr. Fournier said. “Unfortunately, those laparoscopic findings have the same significance as visible metastatic lesions—they indicate stage IV disease, which is not considered resectable.” Peritoneal washings may be repeated to restage the patient’s disease after the patient has undergone treatment with chemotherapy or chemoradiation. Surgery may be reconsidered in very select patients who have no other evidence of metastatic disease and whose washings show no metastases after chemotherapy.

Flowchart: Gastric Cancers: Standard Options for Early and Immediate Stages
Click to view larger image.

Also during the diagnostic laparoscopy, a feeding tube may be placed in the jejunum to maintain the patient’s nutritional status if the patient is expected to undergo a course of neoadjuvant therapy.

Treatment options

Endoscopic mucosal resection

According to Jeffrey H. Lee, M.D., a professor in the Department of Gastroenterology, Hepatology and Nutrition, preoperative tumor staging by endoscopic ultrasonography, which can show the degree of tumor invasion in the very fine layers of the stomach wall, can help determine whether a patient should undergo gastrectomy or endoscopic mucosal resection (EMR). EMR is a minimally invasive operation that is usually done as an outpatient procedure and can be repeated if necessary. Patients with T1a gastric cancers are candidates for EMR.

In EMR, an indigo-colored saline solution is injected between the mucosa and submucosa of the stomach to separate these layers—in effect, the submucosa is ballooned away from the mucosa so that tumor-bearing tissue may be carefully resected. A suction mechanism on the endoscope is used to lift the tumor, which is captured by a snare and excised. Because each of the tissue layers is only millimeters thick, the surgery is very intricate work; the obvious potential complication is a perforation of the stomach wall.

EMR for gastric cancers differs notably from that performed relatively routinely for other gastrointestinal lesions, such as polypoid lesions of the colon. Adenocarcinomas of the gastric lining tend to be flatter than polypoid lesions and are thus more difficult to snare. As a result, EMR for gastric tumors is a very specialized procedure that is not widely available outside comprehensive cancer centers.

Surgical resection

Surgery—either total or subtotal gastrectomy—is the definitive curative treatment for patients with T1a tumors who do not have access to EMR and for patients with resectable T1b–T3 tumors. The surgery is a traditional open procedure, the goal of which is to achieve an R0 resection, Dr. Fournier said.

In addition to the tumor, regional lymph nodes are resected at the time of surgery. According to Dr. Fournier, an extended (D2) lymphadenectomy is recommended, which includes perigastric (D1) nodes as well as nodes adjacent to vessels such as the left gastric, hepatic, and splenic arteries. “A D1 resection is probably not sufficient,” Dr. Fournier said, “and D3 resections, which include a splenectomy, are associated with increased morbidity and mortality and have not been shown to improve survival in Western patients, so they are not usually considered necessary.” He said that at least 15 lymph nodes should be removed for examination.

Tumor size and location affect the extent of surgery. Tumors in the antrum are often amenable to subtotal gastrectomy, whereas tumors in the proximal stomach and larger tumors may require more extensive surgery. According to Dr. Fournier, total gastrectomy is done only if necessary to achieve adequate clear margins—beyond that goal, total gastrectomy has no oncological advantage.

Chemotherapy and radiation therapy

Given the aggressive behavior of gastric tumors and the fact that occult disease has been identified in a significant number of patients with these tumors, additional therapy—chemotherapy or chemoradiation—is strongly considered for patients with T1b–T3 tumors. “Surgery alone is insufficient treatment in most patients with localized gastric cancer,” said Jaffer Ajani, M.D., a professor in the Department of Gastro intestinal Medical Oncology.

About Gastric Cancer

Gastric cancer is the fourth most common cancer in the world and the second leading cause of cancer-related deaths. According to recent estimates by the World Health Organization, more than 900,000 new cases of gastric cancer—and more than 740,000 deaths related to the disease—occur each year, with the highest incidence in the Western Pacific Region countries, notably Japan. Although the incidence of gastric cancer has declined over past decades in the United States, it remains one of the deadliest cancers in the nation. According to the most recent National Cancer Institute estimates, some 21,000 Americans will be diagnosed with stomach cancer in the coming year, and more than 10,000 are expected to die of the disease. The current 5-year overall survival rate for patients with very early–stage (T1) gastric cancers is estimated to be 71%. Unfortunately, most gastric cancers are not discovered until they are more advanced; the 5-year overall survival rate for patients with gastric cancer of any stage is about 28%.

Studies have shown that the addition of neoadjuvant and/or adjuvant therapy to surgery offers higher cure rates than does surgery alone. Improvements have been documented in overall and disease-free survival durations with each of the two approaches. However, each therapy has potentially serious side effects and toxicities.

Two neoadjuvant chemotherapy regimens commonly used with radiation therapy for adenocarcinoma are modified epirubicin, cisplatin, and 5-fluorouracil and modified docetaxel, cisplatin, and 5-fluorouracil. Only fluoropyrimidines are recommended with radiation therapy in the adjuvant setting. The choice of a certain combination and schedule depends on multiple variables, including the patient’s overall condition and nutritional status.

Treatment sequence

There are numerous options for sequencing treatment modalities. Preoperative chemotherapy may be given by itself or as induction therapy followed by chemoradiation therapy. Chemotherapy also may be given postoperatively, with or without radiation therapy.

No large randomized trials have directly compared preoperative treatments to postoperative treatments; however, preoperative treatment is preferred at MD Anderson. “In our experience, the efficacy of additional treatment is similar whether given pre- or postoperatively, but preoperative treatment is better tolerated,” Dr. Ajani said.

According to Prajnan Das, M.D., an associate professor in the Department of Radiation Oncology, therapy for gastric tumors can be delivered more accurately before surgery than after. “We know exactly where the tumor is,” he said, “so we can design the radiation field with greater precision.” He added that the radiation field can sometimes be smaller before surgery than after surgery. This, along with the fact that some irradiated tissue is subsequently removed during surgery, means that less tissue is exposed to radiation, with a concomitant reduction in side effects. In addition, when radiation therapy is given after all or part of the stomach has been resected, adjacent organs and tissues like the small bowel fall into the radiation field, which increases these tissues’ vulnerability to radiation damage.

Radiation therapy may also be more effective when given preoperatively because the blood supply is intact and the tissue is oxygenated.

Dr. Fournier said that preoperative chemotherapy treats lymph nodes, which often become involved early in gastric cancer. In addition, he said that preoperative treatment may help to “sterilize” the surgical field of cancer cells so that fewer cancer cells are shed into the abdomen during surgery. The ability to observe tumor response to treatment is another advantage of neoadjuvant therapy over adjuvant-only therapy.

Because the multimodality treatments necessary to achieve a cure are rigorous, perhaps the most compelling reason to favor preoperative therapy is that it is easier to tolerate than postoperative therapy. Thus, patients are more likely to receive the complete course of recommended treatments. “Among patients who only receive adjuvant treatments, approximately 30% drop out before finishing because of symptoms they find intolerable,” Dr. Fournier said.

Hereditary Diffuse Gastric Cancer Syndrome

Up to 3% of gastric cancers are caused by an inherited mutation in the CDH1 gene that disrupts the function of E-cadherin, a protein necessary for cells and tissues to adhere to each other in a normal fashion. The cancer that occurs in almost 100% of patients with this mutation is an insidious one. Rather than forming a discrete mass, it starts between the layers of the stomach and spreads throughout the layers, extending around the perimeter of the stomach and beyond it into adjacent gastrointestinal linings. This condition, known as linitis plastica, thickens and hardens the stomach wall and is often not seen on endoscopy or biopsy because it occurs between tissue layers. Patients who have a strong family history of gastric cancer or close relatives with early-stage gastric cancer should be screened with genetic tests for the CDH1 mutation and counseled to undergo prophylactic gastrectomy if they carry the mutation.

Adjuvant treatments are recommended for patients whose disease is found to be more advanced than presurgical staging indicated, patients referred after surgery has already been done, and patients whose postoperative pathological analysis indicates that an R0 resection was not achieved. However, these are less-than-optimal situations, underscoring the need for close multidisciplinary collaboration before treatment begins. According to Dr. Ajani, this collaboration should occur not as a series of sequential referrals and treatments but simultaneously in all planning and treatment phases; such teamwork almost always requires the infrastructure of a comprehensive cancer center. “Patients need this collaboration to have the maximum chance of a cure,” he said.

On the horizon

Researchers continue to seek better treatments for gastric cancer. One important development relates to the presence of the HER2 protein, which is found in 10% of gastric tumors. Dr Ajani explained that the HER2 protein triggers a signaling pathway that stimulates cancer cells to multiply. When trastuzumab, a monoclonal antibody that interferes with HER2 receptors, is used to block the signaling pathway, tumor growth is stopped. More important, cells susceptible to trastuzumab release a chemical “panic signal,” and the immune system responds with killer T cells. “Cancer cells that have managed to evade the immune system by appearing as ‘self’ are then recognized as non-self,” Dr. Ajani said. “And the immune system is able to kill the cell.”

Other tumor characteristics may soon enable physicians to identify which gastric cancer patients are likely to benefit from specific therapies, thanks in part to the research of Ju-Seog Lee, Ph.D., an assistant professor in the Department of Systems Biology, and his colleagues. Dr. Lee is analyzing tissue samples from gastric tumors to identify genomic signatures that could be used to guide treatment. Using tissue samples from collaborators at four institutions, Dr. Lee is mapping the samples’ genetic patterns of expression using an array of more than 300 genes. Eventually, he expects to identify 5–10 genes that would become the basis for testing biopsied tissue to identify patients whose tumors are likely to respond to radiation therapy and specific chemotherapy drugs. “This would occur before the patient is treated,” Dr. Lee said, “and would be a basis for individualizing treatment.”

Because he is able to collaborate directly with clinicians, Dr. Lee is optimistic about being able to translate this research to practice, which would give physicians another preoperative screening tool with which to tailor therapy for each patient.

Contributing Faculty
The University of Texas MD Anderson Cancer Center

Photo: Jaffer A. Ajani

Jaffer A. Ajani, M.D.
Professor, Gastrointestinal Medical Oncology

Photo: Dr. Prajnan Das

Prajnan Das, M.D.
Associate Professor, Radiation Oncology

Photo: Dr. Keith F. Fournier

Keith F. Fournier, M.D.
Assistant Professor, Surgical Oncology

Photo: Dr. Jeffrey H. Lee Jeffrey H. Lee, M.D.
Professor, Gastroenterology, Hepatology and Nutrition
Photo: Dr. Ju-Seog Lee Ju-Seog Lee, Ph.D.
Assistant Professor, Systems Biology

References
American Cancer Society. Stomach Cancer Overview, 2011.
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology, Gastric Cancer, V1.2011 [PDF, subscription only].
World Health Organization. Fact Sheet No. 297, February 2011.

For more information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.

Other articles in OncoLog, August 2011 issue:

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