ABSTRACT: Gastric cancer is often advanced and unresectable at diagnosis. Even when a curative resection is possible, the 5-year survival rate for patients with T2 or higher tumors is less than 50%. Survival rates are even lower if lymph node metastases are present at surgery. Many phase III trials of adjuvant therapy have been conducted around the world during the past 4 decades, but their interpretation varies in the East and West. In the West, postoperative treatment modalities have not proven to be superior to postsurgical observation alone. Thus, at present, the routine use of postoperative therapy should be discouraged. In the Orient, however, routine use of postoperative chemotherapy and/or immunotherapy is common after a surgical procedure. Further investigations that correlate treatment response with molecular markers are needed. Improved clinical trial designs, including better preoperative staging, standardized surgical techniques, inclusion of adequate numbers of patients, and the continued use of a surgery-alone control group, are essential. In addition, the incorporation of newer active agents, radiotherapy, and new strategies, such as preoperative therapy and selection of patients based on tumor biology, would result in much-needed advances. Less toxic approaches with novel mechanisms of action, such as antiangiogenesis therapy, tumor vaccines, monoclonal antibodies, and matrix metalloproteinase inhibitors, also hold promise. [ONCOLOGY 13(11):1485-1494, 1999]
Gastric cancer is a global health problem. Although the incidence of this cancer is declining in many industrialized nations, gastric cancer remains the second most frequently diagnosed malignancy worldwide. It accounts for 9.9% of all new cancer diagnoses and is responsible for 12.1% of all cancer-related deaths. In the United States, it is estimated that 21,900 cases of gastric cancer will be diagnosed in 1999 and 13,500 persons will die of this disease.
Gastric cancer is often advanced and unresectable at diagnosis—a fact that contributes to its high morbidity and mortality. The stomach is a hollow organ, and the abdominal cavity is large and compliant to distention. Because of the large potential space, patients often develop symptoms only when the cancer is far advanced. Outside of Japan, an industrialized nation where gastric cancer is common, early detection of gastric cancer is not attempted.
Reports based on large German and Korean databases show that 57% to 63% of gastric cancer patients undergoing resection of the primary tumor have lymph node metastases.[3,4] In the United States, data suggest that 85% of patients enrolled in a recently completed adjuvant trial had lymph node metastases [personal communication, J. S. Macdonald, MD, November 1998].
Worldwide, large amounts of resources have been expended in the search for an effective adjuvant therapy to reduce the risk of postoperative relapse. Numerous phase III clinical trials have been published over the past few decades. The results of these trials, however, have often been disappointing or equivocal and are sometimes conflicting. Adjuvant therapy trials in western countries and Asia published between 1984 and 1997 were recently reviewed by Shimada and Ajani. In this article, we review various approaches to adjuvant therapy.
Selection of appropriate patients for adjuvant therapy is extremely important. In addition to TNM stage, recent advances in the field of molecular diagnostics will likely affect the selection of gastric cancer patients for such therapy, as well as identify new prognostic markers. Current studies correlating clinical outcomes with the status of genes, such as p53, thymidylate synthase, ERCC1, and many others, may help direct therapy for individual patients.
Based on TNM staging criteria, the depth of invasion (T), presence of lymph node metastases, and number of lymph nodes involved (N) predict the risk of relapse. This was confirmed in a large German multicenter trial published by Siewert et al in 1998. The study involved 1,654 patients undergoing surgical resection of gastric tumors.
A significant survival advantage was found for the 1,182 patients (71.5%) who underwent an R0 resection (ie, no residual disease and no cancer cells at the resection margins). In addition to the depth of invasion and nodal status, the ratio between involved and removed lymph nodes proved to be an important independent prognostic factor.
The prognostic importance of R0 resection, depth of invasion, nodal status, and the ratio between involved nodes and removed nodes was confirmed in a large Korean study involving 10,783 patients. In this study, an R0 resection was achieved in 4.8% of patients.
The American College of Surgeons also has published a large analysis of gastric cancer patients. This study was based on a tumor registry review of 25 consecutive patients from each participating institution seen in the years 1982 and 1987. Data on a total of 18,365 patients were analyzed.
Despite the large number of patients, however, the results of this analysis are not easy to interpret. This was a retrospective study that involved a large
number of heterogeneous institutions. Symptoms at presentation may have important prognostic value. Weight loss was the most common symptom, reported in 61.6% of patients. However, the presence or absence of weight loss was not correlated with clinical outcome, and the degree of weight loss was not specified. Similarly, 42% of patients who underwent surgical resection with clear margins received adjuvant chemotherapy or radiation therapy. However, patient characteristics and type of therapy given were not specified. The 5-year survival rates based on pathologic stage after resection were reported as 50%, 29%, 13%, 3% for stages I, II, III, and IV, respectively. These survival rates are significantly worse in every stage category than those reported in the German and Korean studies.
Histologic tumor type may influence patterns of failure. The liver is a frequent site of failure in intestinal-type tumors, whereas peritoneal carcinomatosis is more common with the diffuse type.[7-9] Diffuse histology is on the rise throughout the world.
Advances in molecular diagnostics have opened new avenues for predicting clinical outcome. One area of active research is the determination of p53 mutations. In early-stage, T1 tumors, p53 overexpression correlates with depth of invasion and lymph node involvement.
Another area of active research is the correlation of in vivo response to chemotherapy with genetic phenotype. Fluorouracil, which is the most commonly used agent for gastric cancer, targets the enzyme thymidylate synthase. Lenz et al found that low thymidylate synthase messenger RNA (mRNA) expression was predictive of response and survival in patients treated with fluorouracil and cisplatin (Platinol). More recently, however, Fata et al found high thymidylate synthase mRNA expression to be a predictor of favorable survival.
The excision repair cross-complementing gene (ERCC1) was studied in 33 patients treated with preoperative fluorouracil and cisplatin. In this study, ERCC1 expression correlated with response to therapy. Furthermore, when thymidylate synthase and ERCC1 expression were both low, 11 (85%) of 13 patients responded to therapy; in contrast, when both thymidylate synthase and ERCC1 expression were high, only 2 (20%) of 10 patients responded.
The current National Comprehensive Cancer Network (NCCN) practice guidelines for gastric cancer recommend the following tests and examinations as the minimum preoperative work-up: history, physical examination, complete blood counts (including platelets), SMA-12, computed tomography (CT) of the abdomen, chest roentgenogram, esophagogastroduodenoscopy, and, in female patients, CT or ultrasound of the pelvis.
Increasingly, laparoscopy also is being recommended prior to a major resection. The use of laparoscopy may be supported by the fact that an R0 resection cannot be performed in 30% to 40% of patients undergoing surgery. In the German study, 29.3% of the patients had M1 disease at laparotomy. In these patients, median survival was less than 12 months.
At the University of Texas M. D. Anderson Cancer Center, 83 patients were enrolled in preoperative chemotherapy trials, 73% of whom underwent a curative resection. In the group who could not receive a curative resection, 55% of patients avoided nontherapeutic laparotomy because of an extensive preoperative work-up.
A number of controversies exist in the surgical management of gastric cancer. The most important of these is the extent of lymphadenectomy.
A D1 resection entails a gastrectomy with the removal of all perigastric nodes and the removal of the greater and lesser omenta. In addition to these structures, for a D2 dissection the surgeon removes the omental bursa portion of the transverse mesocolon and the nodes along the left gastric, celiac , and splenic arteries. For a D3 dissection, in addition to the standard
D2 dissection, lymph nodes in the hepatoduodenal ligament, along the superior mesenteric vein, posterior to the common hepatic artery, and on the posterior surface of the pancreatic head are also removed. A D4 dissection involves the removal of lymph nodes around the abdominal aorta, in addition to all of the structures mentioned above.
In the East, extensive lymphadenectomy (D2 through D4) is commonly practiced without excessive complications. Recently, the Japan Clinical
Oncology Group conducted a randomized study of D2 dissection with or without para-aortic node dissection; these researchers reported no treatment-related deaths but a 6% rate of major complications. In the West, the extent of lymph node dissection is more controversial. Western surgeons usually do not perform D2 dissections due to the high rate of complications.
The Dutch Gastric Cancer Group randomized 711 patients with all stages of disease to either a D1 or D2 dissection. Patients who underwent a D2 resection had a higher rate of complications, more postoperative deaths, longer hospital stays, and no improvements in 5-year survival. However, assuming that the ratio of involved lymph nodes to resected nodes predicts outcome, removal of more negative nodes, which occurs during an extended node dissection, may improve long-term survival.
Subgroup analyses of the German and Korean databases show that D2 dissection benefited patients with stage II disease in both studies and benefited patients with stage IIIA disease in the Korean study. However, subgroup analyses are fraught with difficulties. The level of surgical expertise needed to perform an extended node dissection appears to have an impact on surgical morbidity and mortality.
An analysis by Estes et al shows that operative documentation needs improvement. These investigators reviewed operative reports from more than 300 surgeons given a checklist for documentation prior to participating in a national protocol. Inadequate documentation was common. The status of the primary tumor, lymph nodes, liver, peritoneum, and omentum was not stated in 6%, 10%, 17%, 28%, and 28% of operative reports, respectively. Also, the reports often lacked sufficient information about the extent of dissection.
At present, D1 dissection should be considered the minimum resection for patients with potentially curable gastric carcinoma. Estes et al found that 54.2% patients undergoing “curative” resection of gastric cancer had a D0 dissection. This indicates that adequate resection and staging are not being practiced. D2 resection, a proper oncologic surgical procedure, should be considered by experienced surgeons who frequently perform gastric cancer surgery.
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