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Role of Chemotherapy in the Treatment of Gastroesophageal Cancers

Role of Chemotherapy in the Treatment of Gastroesophageal Cancers

ABSTRACT: Esophageal, gastroesophageal junction, and gastric cancers are underpublicized but are frequently lethal, and gastroesophageal junction adenocarcinomas are increasingly common diseases in the United States and around the world. Although often grouped together in studies of chemotherapy, clear distinctions can be made in the locoregional therapy of these diseases. Esophageal squamous cell carcinomas may be treated with surgery or radiation with concurrent chemotherapy, whereas esophageal adenocarcinomas and gastroesophageal junction adenocarcinomas are often treated with all three treatment modalities. Over the past several years, it has become increasingly evident that gastric cancer is a disease that is potentially sensitive to chemotherapy. In the perioperative setting—at least in the Western world—chemotherapy and sometimes radiation are applied. However, the optimal chemotherapy for advanced gastric or esophageal cancer remains unsettled, and there is no single standard regimen. Several new chemotherapy agents have demonstrated activity in these diseases, but the best chemotherapy remains to be determined. This paper will review the role of chemotherapy in gastroesophageal cancers.

In the United States, gastric and esophageal cancers are not considered as great a public health and treatment priority as more common malignancies such as breast, lung, prostate, or colorectal cancer. Worldwide, however, gastroesophageal malignancies are a leading cause of cancer-related mortality. An estimated 22,280 new cases of gastric cancer were diagnosed in the US in 2006, with an estimated 11,430 deaths caused by the disease. Esophageal cancers are even less common, with an estimated 14,550 new cases diagnosed in 2006, and 13,770 resultant deaths.[1] Worldwide, gastric cancers were the fourth most commonly diagnosed malignancy (933,293 patients) and second leading cause of cancer-related mortality (698,030) in 2002, according to GLOBOCAN statistics. In some East Asian nations, gastric cancer is the leading cause of cancer-related mortality. Esophageal cancers constituted the eighth leading cause of cancer-related mortality in 2002, resulting in 385,877 deaths.[2] In addition, gastroesophageal junction cancers are among the most rapidly rising malignancies in the United States and the Western world.[3] Thus, further development of effective therapies for these diseases is urgently needed.

Histology and Treatment

Historically, therapeutic approaches to gastric and esophageal cancers have been considered separately, with limited consideration of (and, therefore, little data on) gastroesophageal junction (GEJ) carcinomas. When reviewing the therapy for gastric, esophageal, and GEJ cancers, the histology of the malignancy is an important consideration. Until the past several decades, in the United States, the majority of esophageal cancers were squamous cell carcinomas, often of the upper and mid-esophagus, caused primarily by exposure to tobacco and alcohol. However, with declining use of tobacco and an increase in obesity and reflux disease, distal esophageal, gastroesophageal junction, and gastric cardia adenocarcinomas have been on the rise.

It is unclear whether the differences among these diseases reflect differences in etiologies, histologies, or anatomy. Because of anatomic constraints, the surgery for esophageal cancer is distinct from that for gastric and gastroesophageal cancers. Perhaps as a result of this, the approaches to multimodality therapy also differ for esophageal and gastric cancers, as we will discuss later.

Chemotherapy in Metastatic Gastric Cancer

In attempting to assess the activity of chemotherapy in advanced gastric and esophageal cancers, we will first review the data in the metastatic setting. There are no definitive data (in the form of randomized clinical trials) regarding the activity of chemotherapy in esophageal cancer. Typically, assessments of activity of chemotherapy for squamous cell carcinomas of the esophagus have been extrapolated from findings in head and neck cancers. Recently, patients with adenocarcinomas of the esophagus have been enrolled in clinical trials for gastric cancer. For both disease types, there is no single standard therapy for the management of metastatic disease. This element of the review will focus on the available data for metastatic gastric and esophageal adenocarcinomas.

Unlike some malignancies, such as breast cancer and acute leukemias, where the antitumor activity of chemotherapy has been deemed to be so evident as not to require clinical trials to demonstrate efficacy, three clinical trials have been performed in metastatic gastric cancer, comparing chemotherapy to supportive care alone. Although these studies were small and evaluated different fluoropyrimidine-based chemotherapeutic regimens, the results were consistent, with a statistically significant but clinically limited improvement in median survival, from 3-5 months with supportive care, to 8-12 months with chemotherapy (Table 1).[4-6]

Fluoropyrimidines and Single-Agent Chemotherapy

As with colorectal cancers, fluoropyrimidines historically have been the standard and core of therapy for advanced gastric cancers. Indeed, several phase III clinical trials have been performed comparing single-agent fluorouracil (5-FU) to combinations of chemotherapy.[7-10] The results with 5-FU have been disappointing, with response rates of 11% to 26%, and median survivals of 6 to 8 months.[7-11] Unfortunately, although response rates were greater with combination regimens such as cisplatin/5-FU or mitomycin/5-FU, investigators found no survival benefit for patients treated with combination chemotherapy (Table 2). Both Cullinan and Ohtsu reported significant improvements in progression-free survival, albeit at the cost of greater myelotoxicity, nausea, vomiting, and diarrhea.[8,10]

Based on these results, 5-FU may be considered a reasonable therapy, producing an overall survival similar to the cisplatin/5-FU combination, with less toxicity. Because of the greater progression-free survival, some investigators, including those at the US Food and Drug Administration (FDA), believe that combination chemotherapy—in particular 5-FU/cisplatin-based therapy—represents the standard therapy for advanced gastric cancer. This view has been buttressed by a recent meta-analysis.[12]

Nonetheless, as combination chemotherapy has not definitively been proven to be superior to single-agent 5-FU, a reasonable avenue of exploration is to investigate fluoropyrimidines or other antifolates that are either better tolerated or easier to administer. In particular, capecitabine (Xeloda) has been studied in phase II trials and has been reported to produce response rates of about 20% to 25%, with modest toxicity, similar to studies in colorectal cancer.[13,14] Another oral fluoropyrimidine, S-1, which is combined with inhibitors of dihydropyrmidine dehydrogenase and pyrimidine phosphoribosyl transferase to optimize the activity and minimize the toxicity of the compound, is also undergoing investigation in gastric cancer.[15]

The multitargeted antifolate pemetrexed (Alimta) has undergone limited evaluation in gastric cancer in patients who also received folic acid. The single-agent activity of pemetrexed was similar to that of other single agents, with a 21% response rate in 38 patients, and a median survival of 7.8 months. Therapy was well tolerated in these patients, with the most common toxicity being asymptomatic neutropenia.[16]

As noted in Table 3, other third-generation chemotherapy agents, including docetaxel (Taxotere),[17,18] paclitaxel,[19] and irinotecan (Camptosar),[20] have demonstrated modest single-agent anticancer activity in this setting with acceptable toxicity, resulting in further investigations of these agents, in various combinations, in phase II and III studies.

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