Introduction: Esophageal and gastric cancer

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THIS ISSUE OF Seminars in Oncology is devoted to a review of current concepts in the study and treatment of esophageal and gastric cancers. The title itself indicates a substantial evolution in our thinking regarding tumors arising in these two organs. Rather than have separate issues on esophageal and on gastric cancer (as has been the case in the past), changes in the epidemiology of tumors arising in these two sites, the beginnings of a better understanding of their molecular biology, and similar approaches in clinical care all support combining an overview of both in the same issue.

Dr Valerie Rusch discusses the similarities and differences between squamous cell carcinomas of the esophagus, and adenocarcinomas of the esophagus, gastroesophageal junction (GE-J), body, and antrum of the stomach. Should they be approached as two or three separate diseases? The implications for management are outlined. She points out that differences in various staging systems may seriously hamper our ability to compare data from various institutions and countries, making it more difficult to address some of the points of controversy.

Drs Crew and Neuget review the substantial changes in the epidemiology of upper gastrointestinal tract malignancies that have occurred in the last 15 to 20 years. While cancers of the esophagus and stomach are still among the most common malignancies affecting humans (of the approximately 10 million new cases of cancer seen throughout the world each year, almost 1.3 million arise in either the esophagus or the stomach), in the last 10 to 20 years, the distribution of cancer within the two organs has changed dramatically. They point out that squamous cell carcinoma of the esophagus has a stable or declining incidence in the Western world; cancers arising from the body and antrum of the stomach, especially intestinal type tumors, have also declined. The increase in incidence of cancers of the lower esophagus, GE-J, and cardia is most pronounced in Western countries, especially among Caucasian males, and is rising more rapidly than almost any other tumor.

Drs Sarbia, Becker, and Hofler review the pathology of cancers arising in the three sites. The pathology of squamous cell carcinoma is relatively straightforward. By light microscopy, body and antrum gastric cancers continue to be divided using the Lauren classification. The primary site of a distal esophageal, GE-J, or cardia tumor may be difficult to determine pathologically. As does Dr Rusch, they suggest that the classification of Seiwert and Stein may be helpful in this regard. Molecular profiling may be crucial in the future.

Drs Lin and Beer further expand on the molecular biology of esophageal and gastric cancers. They support the view that metaplasia in epithelium from Barrett’s esophagus eventually gives rise to adenocarcinomas of the distal esophagus and GE-J. While we have a substantial understanding for colorectal cancer, a great deal remains to be learned regarding the molecular events leading to the adenocarcinomas of both proximal (GE-J and cardia) and distal stomach cancers.

Prevention and, if that fails, early diagnosis, are crucial in improving the cure rate for solid tumors in general; esophageal and gastric cancer are certainly among the most important tumors in which the ability to prevent or to find the malignancy at the earliest possible stage would be a major step forward. Drs Brown and Shaheen review the results of screening programs for upper gastrointestinal tract malignancies. They discuss earlier attempts, particularly in high-risk areas such as some provinces in China, using balloon cytology. They then cover the value of upper endoscopy for both squamous cell and for adenocarcinomas of the distal esophagus. The progression from metaplasia to low-grade, and in some patients, high-grade dysplasia in Barrett’s epithelium affects a substantial number of Americans each year.

The need for prevention and improved screening is obvious. Almost a third of patients with high-grade dysplasia will develop adenocarcinoma within three years. Chronic reflux esophagitis and obesity (which may well be linked) may identify patients at highest risk as candidates for screening. For gastric cancer, mass screening has been performed in Japan for many years. While the data from Japan suggest that mass screening is effective, similar studies in other countries have not been as fruitful. Brown and Shaheen indicate that the development of a gene-based screening test to identify patients at highest risk would be most useful.

The use of molecular biology to screen patients and to establish early diagnosis is reviewed by Drs Lambert, Hainaut, and Parkin. They focus on premalignant lesions in the esophagus and stomach. The pathway from metaplasia to dysplasia and then to adenocarcinoma has been well described. The controversy regarding the appropriate definition of premalignant lesions is well outlined by Lambert and colleagues. They also review strategies for screening and prevention of premalignant tumors as well as intervention using endomucosal resection.

Once esophageal or gastric cancer has been diagnosed, therapeutic decisions depend on stage. Drs Abdalla and Pisters review staging classifications and other staging procedures, including laparoscopy. As does Dr Rusch, they discuss the controversies regarding staging and definition of GE-J adenocarcinomas and their subgroups. They also review the differences in staging between gastric and esophageal tumors. Standard of care staging procedures for both esophageal and gastric cancer are outlined.

Drs Weber and Ott follow with a review of current data using imaging techniques for staging esophageal and gastric cancers. The accuracy of endoscopic ultrasonography (EUS), computerized tomography, and fluorodeoxyglucose positron emission tomography (FDG PET) scans are outlined. Depending on the treatment plan (particularly on the use of neoadjuvant treatment), the data gained by EUS and PET may become more crucial. Drs Weber and Ott point out that PET scans may also have a role in assessing response to therapy.

The treatment for esophageal or gastric cancer is then discussed depending on whether or not the disease is localized and potentially curable, or whether stage IV disease has been found and palliation is the goal. Dr J.J. Bonenkamp reviews the important issues facing surgical management of gastric and esophageal cancers in 2004. For both of these diseases the extent of surgical resection remains controversial. Random assignment trials in gastric cancer have not yet shown a significant difference in outcome for patients undergoing extensive lymph node dissections (D2) versus those undergoing formal but more limited operations (D1). It also remains controversial as to whether postoperative chemoradiation therapy, as used in US Intergroup trial 1116, would have the same favorable effect on survival in patients undergoing more formal lymph node dissections versus those undergoing a less than D1 operation. Future clinical trials may address this issue. Similarly, in esophageal cancer more extensive surgery using a transthoracic esophagectomy has not yet shown a clear survival advantage over a more limited operation, transhiatal esophagectomy. This also is an area of considerable controversy. Lastly Dr Bonenkamp touches on the role of minimally invasive surgery for upper gastrointestinal tract tumors.

Drs Brenner, Ilson, and Minsky review the database for therapy of local regional esophageal cancer. They point out that the best definitive management remains controversial. For selected patients the use of either surgery or chemoradiation is defensible. Both appear to yield similar cure rates. Surgery is favored for distal lesions and chemoradiation for proximal tumors. The data for investigational approaches using combined modality therapy including chemoradiation, or neoadjuvant chemotherapy prior to surgery are also reviewed. While more information has become available recently, it is not yet possible to draw conclusions regarding a clear advantage for either approach over operation alone or chemoradiation alone.

Dr Jack Macdonald reviews the currently available data for adjuvant therapy of gastric cancer. The role of postoperative chemoradiation for patients undergoing potentially curative surgery has been demonstrated in a large US Intergroup trial. However, he also notes that the optimal chemotherapy regimen has not been identified, and the possibility that better surgical techniques might obviate the need for radiation in some patients should be tested.

Drs Shah and Schwartz review the status of palliative treatment for patients with advanced esophageal and gastric cancer. There is reasonably solid data that in gastric cancer, palliative chemotherapy has a modest but real effect on survival, when compared to best supportive care. This has not been demonstrated to date in esophageal cancer, although the number of studies is smaller. Cisplatin plays an important role in both tumors. Although squamous cell carcinoma of the esophagus is declining in incidence, at present, cytotoxic chemotherapy regimens are similar for all three tumor sites. This may change in the future as targeted therapy is further developed. New agents that are promising include the taxanes and irinotecan. Whether one combination chemotherapy regimen is superior to another is controversial. New biologics, such as bevicizumab and small molecule tyrosine kinase inhibitors, are being studied in both gastric and esophageal cancers.

In summary, cancers of the esophagus and stomach are still very common tumors. They may well represent three biologically distinct malignancies: squamous cell carcinoma of the esophagus, adenocarcinoma of the distal esophagus/GE-J and cardia, and adenocarcinoma of the body and antrum of the stomach. While certain etiologic factors may be common to all three tumors (eg, smoking), there are also obvious differences. Preventing squamous cell carcinoma of the esophagus may best be achieved by avoiding tobacco and alcohol abuse. A similar strategy will probably not significantly decrease the incidence of adenocarcinoma of the GE-J and stomach. The different biologies of the tumors also have implications for staging techniques (eg, the roles of PET scans and laparoscopy), as well as therapeutic implications. The prevention and treatment of these diseases will be aided by careful study of their molecular biology. Finally, even with currently available therapies, we have seen a modest but real improvement in outcome for cancers of the upper gastrointestinal tract. The encouraging advances in another gastrointestinal tumor, colorectal cancer, give us hope that further progress will be made in gastric and esophageal cancers.