From OncoLog, April 2004, Vol. 49, No. 4
Gastric Cancer Studies Focus on Prolonging Survival and Finding Molecular Markers for Targeted Therapies
by Katie Prout Matias
During the last century, the incidence of gastric cancer in the western hemisphere decreased dramatically with the advent of better nutrition, refrigeration, and lower rates of Helicobacter pylori infection. What used to be the number one cause of cancer-related death among U.S. men is now uncommon, with about 21,000 cases diagnosed annually in the United States. Because patients are not typically screened for gastric cancer, most cases are diagnosed at a late stage, and many patients in whom it develops die of the disease.
Localized cancer
The five-year overall survival rates for patients with localized gastric cancer are daunting: 78% for patients with stage Ia cancer, 58% for stage Ib, 34% for stage II, 20% for stage IIIa, and 8% for stage IIIb. Currently, the only known curative therapy for nonmetastatic gastric cancer is a gastrectomy performed by experienced surgeons. However, even with successful surgery, the five-year survival rate is approximately 35%; with adjuvant chemoradiotherapy in selected patients, the survival rate is 40%.
To improve survival rates in patients with localized gastric cancer, clinicians and researchers at The University of Texas M. D. Anderson Cancer Center have developed a strategy for treating select patients with preoperative therapy, a practice that is still investigational, cautioned Jaffer Ajani, M.D., a professor in the Department of Gastrointestinal Medical Oncology. In an ongoing clinical trial at M. D. Anderson, patients with operable gastric cancer are receiving chemotherapy followed by chemoradiotherapy followed by surgery.
According to Dr. Ajani, patients with operable gastric cancer tolerate therapy better before the stomach has been removed. Furthermore, preoperative therapy likely increases the chances of a successful surgery, and several studies have shown that a response to preoperative therapy is a powerful predictor of survival. “One thing we know for sure is that good surgery is an important factor for cure,” Dr. Ajani said. “One approach is to reduce the size of the cancer before surgery. If you can reduce the stage before surgery, that patient’s cancer is going to behave as if it were [always] at an earlier stage, and this could mean an advantage for the patient.”
The results of a multi-institutional study of preoperative chemoradiotherapy, which was led by Dr. Ajani, were presented at the 1998 annual meeting of the American Society of Clinical Oncology and will soon be published. A significant number of patients—approximately 30%—had had a complete pathologic response by the time of surgery. However, only phase III trials will determine the value of the preoperative approach for patients with localized gastric cancer, said Dr. Ajani.
Metastatic disease
The five-year survival rate for patients with metastatic, stage IV gastric cancer is 7% or less. Because most metastatic gastric cancers are inoperable, they are treated with combination chemotherapy. “This is one disease where response to chemotherapy doesn’t always translate into improvement in survival,” said James Yao, M.D., an assistant professor in the Department of Gastrointestinal Medical Oncology. “Gastric cancers are relatively aggressive tumors. Although they respond to treatment, they quickly become resistant to treatment.”
New research initiatives and more effective therapies are clearly needed for patients with metastatic gastric cancer. In the largest clinical trial ever completed in patients with advanced gastric cancer, the interim results of which were presented at the 2003 annual meeting of the American Society of Clinical Oncology, Dr. Ajani led researchers from 14 nations in studying the addition of docetaxel to 5-fluorouracil (5-FU) and cisplatin, which is the most commonly used regimen. In this phase III trial of 223 patients, adding docetaxel caused more tumors to shrink, delayed tumor growth, and prolonged survival. This is the first study in which more than 50% of patients with late-stage gastric cancer lived for almost one year (10.2 months or longer), compared with a median survival duration of 8.5 months for patients receiving the control regimen.
Dr. Ajani is also investigating the efficacy of S-1 (a prodrug of 5-FU that contains a compound that prevents the breakdown of 5-FU) combined with cisplatin in phase II trials of patients with advanced gastric cancer. This combination has been tested in Japan, where the response rates were as high as 70% but the effects on survival were limited.
The key to prolonging survival with chemotherapy, according to Dr. Ajani, lies in increasing the time to tumor progression: “The longer that time to progression, the longer the patient is going to live.”
To prolong the time to tumor progression in patients with gastric cancer, Dr. Ajani proposes that oncologists change the treatment agent the moment they know that maximum response has occurred rather than continuing treatment once the cancer has started to progress. “That is the period where you’re treating unnecessarily,” he explained. “Essentially, the cancer is growing, and you’re giving the same treatment that may be harming the patient. So, we would like to [achieve the maximum response with chemotherapy and then] bring in another [nonchemotherapy] treatment, something very simple that is not going to lower the patient’s quality of life.”
Molecular biology and translational research
At M. D. Anderson, a number of people from a variety of disciplines are coordinating translational and molecular research efforts to discover new targets for therapy and to understand the mechanisms of resistance to chemotherapy and radiotherapy. “To make an impact, we probably need to go beyond the chemotherapy paradigm and incorporate newer treatment strategies, molecular and targeted treatments," Dr. Yao said.
One approach is to add targeted biologic therapy to chemotherapy and chemoradiotherapy. “Targeted agents may selectively increase the response to chemoradiation, which is important since many of the combinations of chemotherapy and radiotherapy in past gastric cancer studies have had significant gastrointestinal side effects,” said Christopher Crane, M.D., an associate professor in the Department of Radiation Oncology. According to Dr. Crane, future studies will include targeted agents with chemoradiation based on preliminary work done at M. D. Anderson in pancreatic cancer.
Using a tumor database developed from almost 3,000 patients’ tissue samples, Dr. Yao and other researchers at M. D. Anderson are looking for molecular markers of gastric cancer that could be targeted in therapy and trying to correlate them with patient outcome and survival. These markers include tumor suppressor genes p53 and fragile histidine triad, the adhesion molecules E-cadherin and cluster of differentiation 44, the tyrosine kinases epidermal growth factor receptor and platelet-derived growth factor, and vascular endothelial growth factor (VEGF), which plays an important role in angiogenesis.
Keping Xie, M.D., Ph.D., an associate professor in the departments of Gastrointestinal Medical Oncology and Cancer Biology, was recently awarded a five-year grant from the American Cancer Society to study molecular markers for gastric cancer. “If certain molecular markers can consistently predict a patient’s outcome,” explained Dr. Xie, “we can better understand gastric cancer development and progression and design more effective strategies to block or reverse its malignant phenotype.”
Based on his previous research with pancreatic cancer, Dr. Xie is focusing on a transcription factor called Sp1. Sp1 is overactivated in human gastric cancers, and abnormal Sp1 activation has been linked with the overexpression of many genes downstream of Sp1 that are involved in aggressive tumor behavior.
For example, Sp1 controls the expression of VEGF. Using human gastric cancer specimens, Dr. Xie and colleagues at M. D. Anderson investigated
the expression level of Sp1 and its relationship to VEGF and microvessel density, or the angiogenic phenotype. They found that elevated Sp1 expression and the related overexpression of VEGF were directly associated with microvessel density and predicted a poor outcome for the patient. The results of their study were published in Clinical Cancer Research in December 2003.
Dr. Xie and his research group are also investigating Sp1’s relationship to other prognostic markers, including genes related to metastasis, apoptosis resistance, and proliferation, as well as other factors involved in angiogenesis.
“Sp1 is much, much better than the molecules we have looked at so far in predicting patients’ outcomes. Because this molecule is pivotal in controlling many aspects of cancer biology, it can be a consistent tumor marker as well as a very good target for therapy. [Through Sp1], you can trap the tumor quite easily and control tumor growth and eventually metastasis,” Dr. Xie said.
Future directions
According to Dr. Ajani, gastric cancer should be investigated from all angles. By joining efforts, gastroenterologists, pathologists, medical oncologists, radiation oncologists, and surgical oncologists can improve the clinical outcomes of patients with gastric cancer. At the same time, the discoveries made by molecular biologists, molecular pathologists, gastrointestinal biologists, and molecular epidemiologists are helping to overcome the challenges posed by gastric carcinoma.
For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.
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