Role of Chemotherapy in the Treatment of Gastroesophageal Cancers

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.

Combination Chemotherapy

Given the desire to improve on the outcome of single-agent therapy, many combinations have been evaluated, with varying results. In addition, a phase III clinical trial from the European Organisation for Research and Treatment of Cancer investigated three different combinations that were, at the time, contenders for "standard of care" in the treatment of advanced gastric cancer: FAMTX (5-FU, doxorubicin [Adriamycin], methotrexate), cisplatin/5-FU, and ELF (etoposide, 5-FU, leucovorin). Although cisplatin/5-FU again resulted in a modest improvement in response rate (20% vs 12% for FAMTX and 9% for ELF), and progression-free survival (4.1 vs 3.3 months), the investigators found no significant difference in median or 1-year survival, and they reasonably concluded that "none of these regimens can be regarded as standard."[21]

•ECF-Meanwhile, an alternative approach was piloted in the United Kingdom, based on the use of continuous-infusion 5-FU. Because of the perceived importance of anthracyclines at the time, as well as the preclinical evidence suggesting synergy between platinum and 5-FU, investigators evaluated a combination known as ECF, consisting of epirubicin (Ellence), 50 mg/m², and cisplatin, 60 mg/m², administered every 21 days with a continuous daily infusion of 5-FU, 200 mg/m²/d. Compared with FAMTX therapy, ECF produced a significant improvement in all parameters, including response rate (45% vs 21%), median survival (8.9 vs 5.7 months), and 1-year survival (36% vs 21%). Moreover, ECF was well tolerated, with only 17% of patients experiencing severe nausea/vomiting; 12%, severe neutropenia; 8%, anemia; 4%, thrombocytopenia; and 6%, severe diarrhea or mucositis.[22]

These results were essentially replicated in another randomized phase III study comparing ECF to mitomycin/cisplatin/5-FU.[23] However, because of logistical issues involved in the use of continuous-infusion 5-FU, and to some extent, questions about FAMTX as a comparator arm as well as the activity of epirubicin, ECF has not been widely accepted as the standard therapy for metastatic gastric cancer outside of the United Kingdom.

•Taxanes-More recently, combinations employing the taxanes, especially docetaxel, have been evaluated. For example, a phase II/III study demonstrated an improvement in anticancer activity with a regimen including docetaxel. Cisplatin with docetaxel, with or without 5-FU, was investigated in the phase II part of the study.[24] The investigators found no clear difference in survival between the two arms. However, because of a greater response rate (43% vs 26%), the three-drug DCF regimen (docetaxel at 75 mg/m², cisplatin at 75 mg/m² on day 1, with 5-FU at 750 mg/m²/d from days 1 to 5, every 21 days) was then compared in the phase III study to cisplatin (100 mg/m²) and 5-FU (1,000 mg/m²/d from days 1 to 5), every 28 days.

In this study of 457 patients, the DCF arm demonstrated a significant increase in all parameters, including response rate (37% vs 25%), median and 1-year survival (9.2 months and 40% compared to 8.4 months and 32%, respectively), and median time to progression (5.6 vs 3.7 months). These improvements were achieved at the cost of significant toxicity, including 29% of patients requiring hospitalization for fever or infection while neutropenic, and 82% of patients experiencing severe neutropenia. Moreover, 19% of patients receiving DCF had severe diarrhea. However, the study demonstrated no difference in the 30-day mortality rate between the two arms.[25]

As DCF demonstrated a clear improvement over cisplatin and 5-FU, it was approved by the US FDA for the treatment of patients with advanced gastric cancer, and represents a potential standard therapy, although the toxicity profile will warrant close monitoring, and aggressive implementation of supportive care. Thus, additional studies are being conducted investigating modifications of the DCF regimen, in the hope of decreasing the toxicity of the combination while maintaining its activity. These variations include docetaxel/fluoropyrimidine regimens,[26,27], lower-dose DCF regimens, and the inclusion of other platinums such as oxaliplatin (Eloxatin).

•Oxaliplatin and Capecitabine-Several other combinations are actively undergoing investigation in the treatment of advanced esophagogastric cancer and have demonstrated somewhat promising results to date. Oxaliplatin and capecitabine are analogs and derivatives of cisplatin and 5-FU, respectively. Some data suggest that these agents have at least similar (and perhaps slightly better) activity profiles in the treatment of esophagogastric cancers. The available data-highlighted by two studies reported at the 2006 American Society of Clinical Oncology meeting-suggest that, in terms of activity, oxaliplatin and capecitabine are essentially interchangeable with their parent compounds, although they do not clearly seem to be more effective.

The REAL-2 study, largely performed in the United Kingdom, was a study in patients with gastroesophageal cancer, where patients were treated with epirubicin and either cisplatin or oxaliplatin, and either continuous-infusion 5-FU or capecitabine, in a 2*2 randomization.[28] The investigators found no significant difference in comparisons of either the cisplatin and oxaliplatin arms, or of the 5-FU and capecitabine arms. Moreover, the study showed no significant difference among the four arms.[29]

A multinational study reported by Kang compared cisplatin (80 mg/m² IV every 21 days) with capecitabine (1,000 mg/m² twice daily for 14 days) to cisplatin and 5-FU (800 mg/m² IV continuous infusion for 5 days). These researchers also reported no significant difference in the treatments, in this investigation powered to be a noninferiority study.[30]

Thus, both oxaliplatin and capecitabine appear to have similar anticancer activity to that of cisplatin and 5-FU, respectively. Both agents have potential additional utility in terms of the therapeutic index of the drugs, being somewhat less toxic and more easily delivered. For example, oxaliplatin causes less nausea, vomiting, and nephrotoxicity than cisplatin, and does not require significant pre- and postadministration hydration. Capecitabine induces less myelosuppresion than 5-FU and is an oral medication.

Aside from a greater cost, however, these newer agents have other potential drawbacks. Oxaliplatin is more likely to produce neurotoxicity than cisplatin, and capecitabine, as an oral medication, elicits concerns about monitoring patient compliance, as well as being more likely to cause palmar-plantar erythrodysesthesia. Therefore, simpler regimens such as combinations of oxaliplatin with 5-FU and leucovorin (including the FOLFOX regimens initially investigated in colorectal cancer) are being studied in gastric cancer, with suggestions of activity similar to that of the more complex three-drug regimens (Table 4).[31-34]

•Irinotecan-The topoisomerase I inhibitor irinotecan has also demonstrated promising activity in the treatment of gastric cancer, both as a single agent and in combination with cisplatin or 5-FU.[35,36] In a phase III study, irinotecan plus 5-FU and leucovorin (in the FOLFIRI schedule) produced results similar to those of cisplatin and 5-FU, in terms of survival (9.0 vs 8.7 months), median time to progression (5.0 vs 4.2 months), and response rate (31% vs 25%), with less toxicity.[37]

•Other Agents-Other combinations that have been widely employed for other diseases, including carboplatin/paclitaxel[38] and cisplatin/gemcitabine (Gemzar),[39] have been investigated in gastric and esophageal cancers, and have yielded results similar to those of the more widely used regimens in these diseases (Table 4).

In summary, large, randomized phase III studies that have been reported over the past 3 years have demonstrated that newer third-generation chemotherapeutic agents including docetaxel, oxaliplatin, irinotecan, and capecitabine have activity against gastric cancer. However, the optimal agents or combination of agents remains to be identified, and there remains no universally accepted standard of care. The best median survival results in phase III studies have not exceeded 12 months.

Targeted Therapy

Despite the activity of the newer chemotherapeutic agents in advanced esophagogastric cancer, such therapy remains toxic, producing only modest, if any, improvements in survival compared to older chemotherapy. As with other disease types, the search for further improvements in the treatment of patients with advanced disease has led to evaluations of some of the targeted therapies in this setting.

•EGFR Inhibitors-The differential activity of the epidermal growth factor receptor (EGFR) antagonists in gastric, gastroesophageal, and esophageal cancers highlights the distinctions that must be made between the two disease types. It remains unclear whether the distinctions in these diseases are related to histologic or anatomic factors. For example, the EGFR tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have been studied in esophageal and gastric adenocarcinomas, with no responses in the 25 patients with gastric cancer,[40] and 3% to 15% response rates in patients with esophageal or gastroesohageal junction adenocarcinomas.[41-43] In none of these studies was any correlation with EGFR, or any activating mutation identified. Moreover, in the treatment of patients with squamous cell carcinomas of the esophagus, gefitinib has produced responses in about 10% of patients.[41-43] Clearly, EGFR inhibitors have a modest anticancer activity in the general population of patients with esophageal and gastroesophageal cancers, and attempts to identify the subset of patients who derive a true benefit of therapy continue.

•VEGF Inhibitors-Bevacizumab is a humanized monoclonal antibody against the vascular endothelial growth factor (VEGF), which is a key mediator of angiogenesis, the process by which tumors induce the development of new blood vessels and thereby survive, invade, and propagate. Although this agent appears to have modest single-agent activity, it has clearly been show to improve survival when used in combination with chemotherapy in patients with metastatic colorectal and nonsquamous, non-small-cell lung cancer. Because VEGF expression has been demonstrated to be a poor prognostic factor in patients with gastric cancer, and gastric cancer has been shown to be a somewhat chemotherapy-sensitive disease, investigators have begun evaluating bevacizumab in combination with cisplatin and irinotecan in this setting.

Shah and colleagues reported their study of 47 patients with gastric and gastroesophageal junction adenocarcinoma who were treated with this regimen, including bevacizumab at a dose of 15 mg/kg every 21 days. The activity of the regimen was exciting, producing a response rate of 65% in the first 34 evaluable patients and a median survival of 12.3 months. However, this promise was tempered by a surprising 25% incidence of venous thromboemoblic events, mostly asymptomatic. In addition, two patients-both with the primary tumor in place-experienced gastrointestinal tract perforations. Otherwise, the chemotherapy toxicity of cisplatin and irinotecan was as expected.[44]

Thus, the initial evaluations of targeted therapies have been promising, but their role in the daily therapy of patients with advanced gastroesophageal cancers is limited until our understanding of the mechanisms of action, toxicities, and optimal patient population for therapy are clarified.

Multimodality Therapy in Gastroesophageal Cancer

Surgery

Surgical extirpation of disease remains the mainstay of therapy for patients with gastric and gastroesophageal cancer. However, at least in the Western world (where the extensive D2 resection is not widely practiced), the results of surgical resection alone are suboptimal, and combined-modality therapy is employed for patients with stage IB and more advanced disease.

No direct comparisons have been made of chemoradiation vs surgery in patients with esophageal squamous cell carcinomas. However, while acknowledging the limitations of cross-study comparisons, data from numerous studies suggest that the 5-year survival rate with chemoradiation or surgery alone is about 20% to 30%.[45,46] Moreover, randomized controlled studies have demonstrated that preoperative chemoradiation[47,48] or surgery after chemoradiation (ie, trimodality therapy)[49,50] does not improve outcomes in comparison to surgery alone or chemoradiation alone, respectively. Thus, either surgery or chemoradiation are reasonable options for patients with squamous cell carcinomas of the esophagus. If a patient has been treated with chemoradiation but has persistent disease, retrospective data suggest that these patients may benefit from surgery.[49]

Much less evidence is available regarding the role of multimodality surgery for esophageal adenocarcinoma. In 1996, Walsh reported the first randomized controlled study specifically in patients with esophageal adenocarcinomas. A total of 113 patients were randomly assigned to receive surgery alone or preoperative chemoradiation followed by surgery. The patients who were treated with chemotherapy, radiation, and surgery fared significantly better, with 3-year survival rates of 32% vs 6%.[51] This study was roundly criticized because of the unexpectedly poor survival for patients in the surgery-alone arm. However, no other studies have addressed this growing population, and a consensus seems to be emerging that patients with esophageal and gastroesophageal adenocarcinomas seem to fare more poorly than those with esophageal squamous cell carcinomas, and should be treated with multimodality therapy.

Postoperative Therapy

Given the activity of chemotherapy in the metastatic setting, and the importance of systemic disease in the demise of patients with gastric and esophageal cancers, the role of chemotherapy in the perioperative setting has been extensively evaluated. The initial studies assessed postoperative chemotherapy and chemoradiation. The studies of postoperative (adjuvant) chemotherapy revealed conflicting results. However, four meta-analyses consistently demonstrated a small but statistically significant increase in survival with chemotherapy.[52-54]

In the United States, the Intergroup (INT) 116 study demonstrated that postoperative chemoradiation clearly improved survival in comparison to surgery alone in 603 patients with resected, stage IB-IV gastric cancers (including 20% with gastric cardia that could include involvement of the gastroesophageal junction). The patients in the experimental arm were treated with bolus 5-FU/leucovorin on the Mayo clinic schedule for one cycle, followed by radiation with concurrent 5-FU/leucovorin, then an additional two cycles of chemotherapy. The patients in the experimental arm consistently had better outcomes than those who were observed, in terms of median survival (36 vs 27 months), 3-year survival (50% vs 41%, hazard ratio 1.35), and 3-year relapse-free survival (48% vs 31%).

Thus, in the United States, in patients with gastric cancers (and perhaps gastroesophageal adenocarcinomas) who undergo initial surgical resection, postoperative chemoradiation is the standard of care.[55] However, INT 116 was criticized for the surgery that was performed, as only about 10% of patients underwent the extensive D2 resection that was recommended, resulting in the hypothesis that rather than truly curing patients, postoperative chemoradiation simply makes up for inadequate surgery by eradicating persistent disease. Nonetheless, such resections are rarely performed in the community setting in the United States, reinforcing the importance of multimodality therapy in this country. Given the postoperative approach, the next measures undergoing investigation involve improvements in systemic adjuvant therapy with ECF rather than bolus 5-FU and leucovorin.

Preoperative Therapy

The potential benefits of preoperative therapy for patients with gastric cancer are similar to other malignancies. The main goal of preoperative therapy is to administer systemic therapy early in the course of the disease to eradicate microscopic metastatic disease, and thereby increase a patient's chance of survival. In addition, if preoperative therapy is successful, the extent of surgery may be diminished. Indeed, successful neoadjuvant therapy may even allow a patient with unresectable disease to become potentially resectable. Wilke et al reported that this was possible in 40% of patients with unresectable gastric cancer in a small series treated with a regimen of etoposide, doxorubicin, and cisplatin, which ultimately proved to be too toxic for routine use.[56] In addition, preoperative therapy may allow an early assessment of the tumor's susceptibility to chemotherapy. Finally, studies in rectal cancer patients suggest that preoperative therapy may be better tolerated than postoperative therapy.

With this background, the recently reported Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) study was performed. A total of 503 patients with potentially resectable gastroesophageal cancer (25% lower-esophageal or gastroesophageal cancers) were randomly assigned to receive three cycles of preoperative and three cycles of postoperative chemotherapy with ECF or surgery alone.[57] Only 40% of patients received all six cycles of chemotherapy, and only 60% even started the postoperative chemotherapy. Nonetheless, perioperative chemotherapy clearly improved outcomes, including 5-year overall survival (36.3% vs 23.0%, hazard ratio = 0.75) and progression-free survival (hazard ratio = 0.66), without an increase in operative morbidity.

The relative contributions of preoperative and postoperative chemotherapy to these outcomes are uncertain, but that preoperative chemotherapy had an impact on the malignancy is suggested by a higher frequency of T1/2 disease (52% vs 37%) and lower incidence of N2/3 disease (16% vs 29%) in the preoperative chemotherapy arm.[57] Regardless of the relative contributions of preoperative and postoperative chemotherapy, the program clearly improved patient outcomes in comparison to surgery alone, with no significant detriment to patients.

Thus, for patients with locally advanced, but potentially resectable gastric and gastroesophageal adenocarcinomas, multimodality therapy should be administered. In the absence of randomized controlled studies, it is unclear whether a preoperative or postoperative approach for chemotherapy, with or without radiation therapy, is preferred. Until and unless such information becomes available, the decision about the preferred approach becomes the subject of discussion between the medical oncologist, surgical oncologist, radiation oncologist, and patient, based on many factors including patient preference, symptoms, and comorbidities.

Conclusions

With the increasing incidence of gastroesophageal malignancies in the United States and the Western world, increasing interest has focused on the treatment of these diseases, matching the attention paid in eastern Asia, where gastric cancer is one of the two leading causes of cancer-related mortality. It is increasingly clear that chemotherapy plays a key role in the treatment of these cancers.

For esophageal squamous cell carcinomas, radiation with concurrent chemotherapy appears to produce survival rates similar to those expected from esophagectomy alone. For esophageal and gastroesophageal adenocarcinomas, surgery preceded by or followed by radiation and chemotherapy is frequently administered, although data in these diseases remains somewhat scant. In patients with gastric cancer that has been resected in the West, perioperative chemotherapy or postoperative chemoradiation improve survival in comparison to surgery alone, although there remain questions about the optimal surgery for gastric cancer.

Unfortunately, metastatic gastroesophageal cancer remains an incurable disease, and there is no standard therapy. Even the most widely administered therapies, such as single-agent fluoropyrimidines, or combinations of epirubicin, cisplatin, and infusional 5-FU are plagued by limited response rates, modest survival, drug-induced toxicities, and logistical difficulties. Newer chemotherapy agents including docetaxel, oxaliplatin, irinotecan, and capecitabine have demonstrated some promise, with modest improvements in response and survival, or at least improvements in toxicity profiles or ease of administration. However, the median survival with current therapies for metastatic gastric cancer remains less than 12 months. Targeted therapy in gastroesophageal cancers is still in its infancy, but early evidence suggests that targeting EGFR or VEGF may hold promise as therapy for these malignancies.

Disclosures:

Dr. Hwang is an investigator, speaker, and consultant for Sanofi-Aventis, Genentech, Amgen, and Pfizer, and is an investigator for Bristol-Myers Squibb.

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