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Systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer

Authors
Johanna Bendell, MD
Harry H Yoon, MD, MHS
Panos Fidias, MD
Section Editor
Richard M Goldberg, MD
Deputy Editor
Diane MF Savarese, MD

INTRODUCTION

Cancers of the upper gastrointestinal (GI) tract are highly lethal malignancies. Locally advanced unresectable and metastatic gastroesophageal cancers are not curable conditions, and the goals of therapy include palliation of symptoms and prolongation of survival. Palliative modalities for advanced esophageal or gastric cancer can be either local or systemic. While systemic therapy is the most effective treatment modality for patients with metastatic disease and it may adequately palliate dysphagia, other symptoms such as nausea, pain, obstruction, perforation, or bleeding from a locally advanced or locally recurrent primary tumor often require multidisciplinary management using endoscopic, surgical, radiotherapeutic, or other approaches. (See "Local palliation for advanced gastric cancer" and "Endoscopic palliation of esophageal cancer".)

This topic review will cover systemic therapy for advanced unresectable and metastatic esophageal and gastric cancer. Neoadjuvant strategies for locoregionally advanced but potentially resectable esophageal and gastric cancer; the use of chemotherapy with and without radiation for patients with localized, potentially resectable disease; local methods for palliation in patients with advanced disease; and hepatic metastasectomy for the rare patient with isolated gastric cancer liver metastases are discussed separately. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus" and "Management of locally advanced unresectable and inoperable esophageal cancer" and "Adjuvant and neoadjuvant treatment of gastric cancer" and "Local palliation for advanced gastric cancer" and "Endoscopic palliation of esophageal cancer" and "Surgical management of invasive gastric cancer", section on 'Metastasectomy'.)

HISTOLOGY, ANATOMIC DISTRIBUTION, AND EVOLUTION OF CHEMOTHERAPY STRATEGY

Together, squamous cell carcinoma (SCC) and adenocarcinoma account for 93 percent of all esophageal carcinomas, but histologic and anatomic distribution has changed dramatically over the past 30 years [1]. In the 1970s, SCC accounted for approximately 70 percent of all esophageal cancers, and 22 percent of tumors were located in the upper third of the thoracic esophagus or in the cervical esophagus. Since the mid-1970s, the incidence of SCC in the United States has been declining steadily, while the incidence of adenocarcinoma in white males rose by 350 percent from 1974 to 1994. Adenocarcinoma surpassed SCC as the dominant histology in the early 1990s [2]. At the same time, there has also been a shift in location of esophageal cancers over time. At present, 86 percent of esophageal cancers arise in the distal one-third of the thoracic esophagus, 13 percent in the middle third, and only 1 percent in the upper third or cervical esophagus. (See "Epidemiology, pathobiology, and clinical manifestations of esophageal cancer".)

More than 90 percent of stomach cancers are adenocarcinomas. In 1930, most cases originated in the distal stomach (gastric body and antrum (figure 1)). Since then, the incidence of distal gastric carcinoma has declined dramatically, while the incidence of adenocarcinoma of the esophagogastric junction (EGJ) and proximal stomach has increased at a rate exceeding that of any other cancer [3]. The increasing incidence has paralleled the rise in incidence of esophageal adenocarcinoma. The term "EGJ tumor" reflects the frequent difficulty in separating the primary location of distal esophageal and proximal gastric cancers; their natural history, response to therapy, and overall prognosis appears to be similar [4]. (See "Epidemiology of gastric cancer".)

Chemotherapy drugs that were tested for esophageal cancer at a time when SCC was the predominant histology (1970s and 1980s) were those initially developed for SCC of the head and neck, including fluorouracil (FU), cisplatin, mitomycin, methotrexate, vindesine, and bleomycin. The combination of FU plus cisplatin (FP) was adopted by many as a safe and effective standard regimen, and studies focused on the benefit of adding a third agent to the FP backbone.

                                                 

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