Neoadjuvant therapy for upper gastrointestinal tract cancers

Esophageal, gastric, and pancreatic cancers frequently present with extensive local regional disease, which can be difficult to resect or to definitively control with radiation therapy given as a single modality. In addition, these patients are at high risk for the development of distant metastasis. Neoadjuvant chemotherapy is a promising experimental approach for the use of combined modality treatments that involve a systemic component. The theoretical background for the use of chemotherapy followed by an operation or chemotherapy plus radiation in these tumors has been extensively described. For esophageal cancer, many phase II trials have demonstrated tolerance to systemic chemotherapy; chemotherapy plus radiation prior to operation has more toxicity. Definitive phase III studies testing the hypothesis that this approach is superior to operation alone have recently been performed in the United States and Europe. These data are currently being analyzed. For the use of combined modality therapy of chemoradiation, random assignment trials have demonstrated an improvement in cure rate for patients with squamous cell carcinomas of the esophagus. Preliminary data suggest a similar outcome for adenocarcinoma, but the number of patients who have been studied is smaller. Newer phase III studies involve the use of new systemic agents that have demonstrated activity in metastatic disease (such as paclitaxel) or the use of higher doses of radiation therapy. For gastric cancer, a substantial number of phase II trials have again demonstrated tolerance to preoperative chemotherapy with no increase in operative morbidity or mortality. Small-scale phase III trials have been performed that suggest an improvement in outcome. Definitive studies are in the planning stage. Finally, for pancreatic carcinoma, in which local control is an even more difficult issue, a major stumbling block remains the development of newer systemic therapies that have activity in this disease. The recent identification of gemcitabine as having modest activity as a single agent and its potential use with radiation therapy is being explored in the neoadjuvant setting.