Editor(s): John H. Donohue, M.D. Reviewers: Steven T. Brower, MD; Leonard L. Gunderson, MD; Scott A. Hundahl,MD; Paul F. Mansfield,MD; Carol Scott-Conner,MD

General Reviews

Karpeh MS, Kelsen DG, Tepper JE. Cancer of the stomach. In DeVita VT Jr., Hellman S, Rosenberg SA (eds). Cancer: Principles and Practice of Oncology, 6th Ed. Philadelphia, PA: Lippincott-Raven;2001:1092-1126.

Stomach. In Fleming ID, Cooper JS, Henson DE, Hutter RVP, Kennedy BJ, Murphy GP, O'Sullivan B, Sobin LH, Yarbro JW (eds). AJCC Cancer Staging Manual, 5th Ed. Philadelphia, PA: Lippincott-Raven, 1997:71-76.

Etiology

Hansson LE, Nyren O, Hsing AW, Bergstrom R, Josefsson S, Chow WH, Fraumeni JF, Jr, Adami HO. The risk of stomach cancer in patients with gastric or duodenal ulcer disease. N Engl J Med 1996;335:242-249.

Using a national patient registry, the incidence of gastric cancer was shown to be significantly increased with gastric, but not duodenal, ulcers. While all three diseases are induced by H. pylori, the variables associated with duodenal ulcers are protective for gastric carcinoma.

You W-C, Zhang L, Gail MH, Chang Y-S, Liu W-D, Ma J-L, Li J-Y, Jin M-L, Hu Y-R, Yang C-S, Blaser MJ, Correa P, Blot WJ, Fraumeni JF Jr, Xu G-W. Gastric dysplasia and gastric cancer: Helicobacter pylori, serum vitamin C, and other risk factors. J Natl Cancer Inst 2000;92:1607-1612.

This large study from an area in China where gastric cancer is epidemic showed the following: 1) a significant increased risk of endoscopic progression to dysplasia or cancer with H. pylori infestation (odds ratio [OR] 1.8, 95% CI=1.2-2.6, p=0.003); 2), moderate increased risk of progression to dysplasia or cancer related to number of years smoking (OR: 1.6, 95% CI=1.0-2.7, p=0.04); and 3) significant reduced risk of epithelial progression to dysplasia or cancer with high serum levels of ascorbic acid (R: 0.2; 95% CI=0.1-0.7, p=0.006).

Guilford PJ, Hopkins JBW, Grady WM, Markowitz SD, Willis J, Lynch H, Rajput A, Wiesner GL, Lindor NM, Burgart LJ, Toro TT, Lee D, Limacher J-M, Shaw DW, Findlay MPN, Reeve AE. E-Cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer. Hum Mutat 1999;14:249-255.

Rare gastric cancer families have been identified. Germline E-cadherin mutations have been identified in most of these pedigrees, in which patients usually develop diffuse gastric cancers, often before age 50.

Correa P, Fontham ETH, Bravo JC, Bravo LE, Ruiz B, Zarama G, Realpe JL, Malcolm GT, Li D, Johnson WD, Mera R. Chemoprevention of gastric dysplasia: Randomized trial of antioxidant supplements and anti-Helicobacter pylori therapy. J Natl Cancer Inst 2000;92:1881-1888.

This randomized control trial was performed in a province of Colombia with a high incidence of gastric carcinoma. Patients with atrophic gastritis, and/or intestinal metaplasia were treated with triple anti-H. pylori therapy and/or ascorbic acid, ß-carotene, or placebos. All three treatments caused significant regression of pre-cancerous changes (Relative risk [RR] 4.8, 95% CI=1.6-14.2 for H. pylori therapy; RR 5.0, 95% CI=1.7-14.4 for ascorbic acid, and RR 5.1, 95% CI=1.7-15.0 for ß-carotene). There was no additive effect of treatments on the regression of histologic changes.

Proximal Gastric Cancer

Spechler SJ. The role of gastric carditis in metaplasia and neoplasia at the gastroesophageal junction. Gastroenterology 1999;117:218-228.

This is an excellent overview of the inflammatory changes that occur around the gastroesophageal junction and potential etiologies for malignant transformations of this region.

Devesa SS, Blot WJ, Fraumeni JF, Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998;83:2049-2053.

SEER data are used to document marked increases in the incidence of adenocarcinomas of the esophagus and cardia over the last quarter century. This trend is most apparent in white men, where cardia and more distal gastric cancers now occur at comparable frequencies.

Siewert JR, Feith M, Werner M, Stein HJ. Adenocarcinoma of the esophagogastric junction. Results of surgical therapy based on anatomical/topographic classification in 1,002 consecutive patients. Ann Surg 2000;232:353-361.

Siewert has classified cancers of the esophagogastric junction into distal esophagus (type I), cardia (type II), and subcardial stomach (type III). This large series of patients demonstrates that because of lymphatic drainage directed toward proximal gastric nodes and increased mortality with an esophagectomy, an extended gastrectomy is the operation of choice for type II carcinomas.

Sakaguchi T, Watanabe A, Sawada H, Yamada Y, Tatsumi M, Fujimoto H, Emoto K, Nakano H. Characteristics and clinical outcome of proximal-third gastric cancer. J Am Coll Surg 1998;187:352-357.

This report from Japan shows that patients with proximal gastric cancer have a poor outcome compared to those with distal gastric cancer. Even in a country where gastric cancer results are generally excellent, this disease carries a guarded prognosis.

Diagnosis, screening

Greene FL. Management of gastric remnant carcinoma based on the results of a 15-year endoscopic screening program. Ann Surg 1996;223:701-708.

Upper endoscopy can detect cancer of the stomach at an early stage. This study shows the benefit of routine screening in a high-risk population.

Pollock BJ, Chak A, Sivak MV Jr. Endoscopic ultrasonography. Semin Oncol 1996;23:336-346.

This review article gives an excellent overview of the use of endoscopic ultrasonography (EUS) in treating gastric cancer patients. EUS provides accurate T staging in nearly 80% of patients. Regional lymph node involvement can not be determined as often. In many centers, EUS has become the preoperative method of choice for staging gastric cancers.

Burke EC, Karpeh MS, Conlon KC, Brennan MF. Laparoscopy in the management of gastric adenocarcinoma. Ann Surg 1997;225:262-267.

The authors found diagnostic laparoscopy to be feasible in most patients with gastric cancer. In patients without mechanical problems requiring surgical treatment, diagnostic laparoscopy prevents a nontherapeutic laparotomy.

Prognostic Variables

Bonenkamp JJ, Songun I, Hermans J, van de Velde CJ. Prognostic value of positive cytology findings from abdominal washings in patients with gastric cancer. Br J Surg 1996;83:672-674.

A positive peritoneal cytology for malignant cells has a significant adverse impact on patient survival following surgical resection for gastric cancer.

Benevolo M, Mottolese M, Cosimelli M, Tedesco M, Giannarelli D, Vasselli S, Carlini M, Garofalo A, Natali PG. Diagnostic and prognostic value of peritoneal immunocytology in gastric cancer. J Clin Oncol 1998;16:3406-3411.

Immunohistochemical (IHC) staining of peritoneal washings increases the yield of positive results by one third. A positive peritoneal cytology imparts a poor prognosis whether found on routine or IHC techniques.

Roder JD, Bottcher K, Busch R, Wittekind C, Hermanek P, Siewert JR. Classification of regional lymph node metastasis from gastric carcinoma. Cancer 1998;82:621-631.

This and several other reports have confirmed the better prediction of prognosis by the number of regional lymph nodes involved by metastases, rather than the distance of nodal involvement from the primary gastric tumor. These studies support the new AJCC/UICC staging system for N1 (1-6), N2 (7-15) and N3 (>15 involved lymph nodes).

Ishida K, Katsuyama T, Sugiyama A, Kawasaki S. Immunohistochemical evaluation of lymph node micrometastases from gastric carcinomas. Cancer 1997;79:1069-1076.

Nearly twice as many nodal metastases were detected by immunohistochemical (IHC) stains compared to standard H&E evaluation. IHC micrometastases were of prognostic importance, but this technique is labor intensive and not of proven value at present.

Hundahl SA, Phillips JL, Menck HR. The national Cancer Data Base report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy. Fifth edition American Joint Committee on Cancer staging, proximal disease, and the "different disease" hypothesis. Cancer 2000;88:921-932.

Data from the National Cancer Data Base (NCDB) for gastric carcinoma were evaluated. Japanese Americans had better survival rates than other Americans because of fewer adverse prognostic factors, including fewer proximal cancers, a lower percentage of male patients, and less common resection of adjacent organs. Evidence of stage migration and surgical undertreatment for many American gastric cancer patients was apparent in that improved stage-stratified survival was noted ³ 15 if lymph nodes were examined.

Differences in Gastric Cancer between Japan and the Western World

Noguchi Y, Yoshikawa T, Tsuburaya A, Motohashi H, Karpeh MS, Brennan MF. Is gastric carcinoma different between Japan and the United States? A comparison of patient survival among three institutions. Cancer 2000;89:2237-2246.

In comparing patients with gastric cancer treated at large medical centers in Japan and the United States, several significant differences were noted that affect overall results. American patients more commonly have more advanced stage disease at presentation, have a higher frequency of proximal gastric cancers (51% vs 17%), and less accurate staging of the tumor (based on the number of lymph nodes examined). When correcting for these differences, similar patient survivals were seen for most patients with carcinoma of the stomach.

Schlemper RJ, Itabashi M, Kato Y, Lewin KJ, Riddell RH, Shimoda T, Sipponen P, Stolte M, Watanabe H, Takahashi H, Fujita R. Differences in diagnostic criteria for gastric carcinoma between Japanese and Western pathologists. Lancet 1997;349:1725-1729.

This study shows that Japanese pathologists are more likely to diagnose gastric carcinoma, while Western pathologists interpret the same slides as dysplasia. This could account for the high incidence of early gastric cancer in Japan, but little of the difference in overall gastric cancer survival statistics.

Noda N, Sasako M, Yamaguchi N, Nakanishi Y. Ignoring small lymph nodes can be a major cause of staging error in gastric cancer. Br J Surg 1998;85:831-834.

Regional lymph nodes involved by metastatic cancer are frequently small (£5 mm). The failure to pathologically examine these small nodes will lead to tumor downstaging in more than 10% of patients. Part of the survival differences between Japan and the West are likely due to a more thorough histologic evaluation in Japan.

Theuer CP, Kurosaki T, Ziogas A, Butler J, Anton-Culver H. Asian patients with gastric carcinoma in the United States exhibit unique clinical features and superior overall and cancer-specific survival rates. Cancer 2000;89:1883-1892.

Using a California database of >2,400 gastric cancer patients, people of Asian ancestry were significantly more likely to have variables with a favorable prognosis. These included lymph node negative disease (OR 1.61, 95% CI=1.23-2.10), fewer cancers of the esophagogastric junction (OR 0.22, 95% CI=0.15-0.31), and less likely to be > 50 years old (OR 0.58, 95% CI=0.43-0.77). Asian gastric cancer patients had double the five-year survival rate (20.9% vs 10.2%; p<0.0001) of non-Latino white patients.

Subtotal vs Total Gastrectomy

Gouzi JL, Huguier M, Fagniez PL, Launois B, Flamant Y, Lacaine F, Paquet JC, Hay JM. Total versus subtotal gastrectomy for adenocarcinoma of the gastric antrum. A French prospective controlled study. Ann Surg 1989;209:162-166.

Bozzetti F, Marubini E, Bonfanti G, Miceli R, Piano C, Gennari L. Subtotal versus total gastrectomy for gastric cancer. Five-year survival rates in a multicenter randomized Italian trial. Italian Gastrointestinal Tumor Study Group. Ann Surg 1999;230:170-178.

In these controlled trials of distal gastric cancer patients treated with curative intent, total gastrectomy offered no benefit over subtotal gastrectomy. Total gastrectomy should be reserved for extensive gastric cancers and most proximal gastric cancers.

Harrison LE, Karpeh MS, Brennan MF. Total gastrectomy is not necessary for proximal gastric cancer. Surgery 1998;123:127-130.

A proximal gastrectomy performed via a transabdominal approach provided equally good results for tumor control as did total gastrectomy. However, this experience represented only a quarter of all proximal gastric cancers resected, most of whom required esophagogastrectomy for tumor clearance.

Limited (D1) vs Extended (D2) Lymph Node Dissection

Sasako M, McCulloch P, Kinoshita T, Maruyama K. New method to evaluate the therapeutic value of lymph node dissection for gastric cancer. Br J Surg 1995;82:346-351

Sasako and colleagues evaluated the results of 1281 gastric cancer patients, most treated with D2 lymphadenectomy. The survival of patients with nodal metastases at individual nodal stations (Japanese General Rules for Gastric Cancer Study in Surgery and Pathology) were determined without regard to other nodal involvement. Patients with involvement of second-tier lymph nodes generally showed survival benefit (range 0-10.5%) for a D2 dissection, irrespective of the primary tumor location.

Siewert JR, Bottcher K, Stein HJ, Roder JD. Relevant prognostic factors in gastric cancer. Ten-year results of the German Gastric Cancer Study. Ann Surg 1998;228:449-461.

This is a prospective, but non randomized trial. The findings included improved survival with a more extensive lymphadenectomy. D2 resections were performed only by certain surgeons, implying that differences in surgical technique affect patient outcome.

Bonenkamp JJ, Hermans J, Sasako M, van de Velde CJ. Extended lymph node dissection for gastric cancer. Dutch Gastric Cancer Group. N Engl J Med 1999;340:908-914.

This is a multicenter, randomized, prospective trial comparing D1 and D2 nodal dissections for gastric cancer. Despite pre-protocol training and a carefully written protocol, there were significant discrepancies in the extent of nodal dissection in both patient cohorts. A D2 dissection increased morbidity and mortality postoperatively without any improvement in patient survival.

Cuschieri A, Weeden S, Fielding J, Bancewicz J, Craven J, Joypaul V, Sydes M, Fayers P. Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Surgical Co-operative Group. Br J Cancer 1999;79:1522-1530.

The results of this smaller controlled trial are very similar to the Dutch trial, namely increased complications with a D2 resection, especially if a distal pancreatectomy was performed, with no difference in 5-year survival compared to a D1 resection.

Adjuvant Therapy

Hermans J, Bonenkamp JJ, Boon MC, Bunt AMG, Ohyama S, Sasako M, Van de Velde CJ. Adjuvant therapy after curative resection for gastric cancer: Meta-analysis of randomized trials. J Clin Oncol 1993;11:1441-1447. Hermans J, Bonenkamp H. Adjuvant therapy after curative resection for gastric cancer: Meta-analysis of randomized trials. Reply to Letters to the Editor. J Clin Oncol 1994;12:879-880.

This meta-analysis of controlled trials involving adjuvant therapy for gastric cancer showed a trend in favor of treatment (odds ratio for mortality of 0.88 (95% CI:0.78 to 1.08), but no significant difference compared to no adjuvant therapy. In response to letters to the editors, two additional trials were added to the meta-analysis. With these new data, there proved to be a significant survival benefit for adjuvant chemotherapy in gastric cancer patients (odds ratio 0.82 with 95% CI: 0.68 to 0.98). While the revised study showed benefit for chemotherapy, no standardized regimen could be recommended.

Shimada K, Ajani JA. Adjuvant therapy for gastric carcinoma patients in the past 15 years. A review of Western and Oriental trials. Cancer 1999;86:1657-1668.

This is an overview of published Occidental and Oriental adjuvant treatment protocols for gastric cancer. It concludes that adjuvant therapy remains investigational, a conclusion made obsolete by the soon to be published Intergroup INT-0116 results (see below).

Neri B, de Leonardis V, Romano S, Andreoli F, Pernice LM, Bruno L, Borrelli D, Valeri A, Fabbroni S, Intini C, Cini G. Adjuvant chemotherapy after gastric resection in node-positive cancer patients: a multicentre randomized study. Br J Cancer 1996;73:549-552.

This modest-sized study (103 patients) showed a significant improvement in survival for gastric cancer patients with nodal metastases treated with adjuvant epidoxorubicin, leucovorin and 5-fluorouracil compared to surgical resection alone.

Kim S-Y, Park HC, Yoon C, Yoon HJ, Choi YM, Cho KS. OK-432 and 5-fluorouracil, doxorubicin, and mitomycin C (FAM-P) versus FAM chemotherapy in patients with curatively resected gastric carcinoma. A randomized Phase III trial. Cancer 1998;83:2054-2059.

Chemoimmunotherapy has been more thoroughly evaluated in the Orient. The addition of a streptococcal antigen (OK-432) to an old chemotherapy regimen (FAM) resulted in borderline improvement in survival. Other forms of immune enhancement will likely be tried in future adjuvant trials.

Yu W, Whang I, Suh I, Averbach A, Chang D, Sugarbaker PH. Prospective randomized trial of early postoperative intraperitoneal chemotherapy as an adjuvant to resectable gastric cancer. Ann Surg 1998;228:347-354.

The peritoneal cavity is at high risk for recurrence after curative gastric resection, especially with locally advanced disease. This trial showed a trend toward better results with adjuvant intraperitoneal chemotherapy compared to surgery alone, but significant difference only occurred with subset analysis.

Lowy AM, Mansfield PF, Leach SD, Pazdur R, Dumas P, Ajani JA. Response to neoadjuvant chemotherapy best predicts survival after curative resection of gastric cancer. Ann Surg 1999;229:303-308.

Neoadjuvant treatments are increasingly used for gastroesophageal junction tumors and locally advanced gastric cancers. Not surprisingly, better response rates improve tumor resectability and patient survival. Several ongoing trials are attempting to further improve these results.

Zhang Z-X, Gu X-Z, Yin W-B, Huang G-J, Zhang D-W, Zhang R-G. Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC) - Report on 370 patients. Int J Radiat Oncol Biol Phys 1998;42:929-934.

This randomized trial from Beijing, China, compared preoperative radiation therapy and resection to surgery alone in 370 patients with proximal gastric carcinoma. The resectability rate was significantly higher in the combination group with no significant increase in major complications. At 5- and 10-years, the irradiated cohort enjoyed a significantly better survival with fewer local and regional disease failures.

MacDonald JS, Smalley SR, Benedetii J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. New Engl J Med 2001; 345:725-730.

This study demonstrates a significant survival advantage to combined chemoradiation in gastric cancer. INT-0116 was designed to evaluate postoperative adjuvant chemoradiation in resected gastric cancer. Patients with stages Ib through IV M0 adenocarcinoma of the stomach or gastroesophageal junction who had undergone gastric resection with curative intent were randomized to postoperative follow up or chemoradiation. The treatment consisted of one cycle of 5-FU (425 mg/m2)/Leucovorin (LV) (20 mg/m2) in a daily x5 regimen followed by 4,500 cGy (180 cGy/day) given with 5-FU/LV (400 mg/m2 and 20 mg/m2) on days 1 through 4, and on the last 3 days of radiation. One month after completion of radiation, two cycles of daily x5 5-FU/LV (425 mg/m2 and 20 mg/m2) were given at monthly intervals. Between 8/1/91 and 7/15/98, 603 patients were accrued to this study, 47 (8%) of which were ineligible. Nodal metastases were present in 85% of cases. There were 3 (1%) toxic deaths. OS and DFS analyses were based on intention to treat. With 3.3 years of median follow up, 3-year DFS is 49% for treatment and 32% for observation (p=0.001); 3-year OS is 52% for treatment and 41% for observation (p=0.03). P values are two-sided. These results demonstrate a 44% improvement in relapse-free survival (hazard ratio of 1.44), and a 28% improvement in survival with median survival of 27 months in the observation arm vs 42 months in the treatment arm (hazard ratio 1.28). Postoperative chemoradiation may now be considered a standard of care for high-risk RO resected adenocarcinoma of the stomach and GE junction.

Selectecd Abstracts - 2000 - 2001

SSO Abstract #50: Hundahl S, MacDonald J, Benedetti T, Fitzsimmons T, The Southwest Oncology Group. Surgical treatment variation in a prospective randomized trial of adjuvant chemoradiation in gastric cancer - The impact of undertreatment. SSO Cancer Symposium Abstract Book 2001:p21

A recently reported prospective, randomized trial, SWOG 9008 (Intergroup 0116), has demonstrated both disease-free and overall survival benefit for adjuvant postoperative chemoradiation for gastric cancer. As part of this trial, detailed information concerning surgical treatment was collected. Eligibility criteria for this trial included completion of a surgical checklist confirming absence of extra-regional disease, confirming resection of all gross disease, and documenting surgical management of major nodal stations. D-level was assigned using the Japanese General Rules. We used the Maruyama Program to estimate the likelihood of disease in unresected regional node stations, we defined the sum of these estimates as the "Maruyama Index of Unresected Disease (MI)." Surgical and pathologic variables for 553 eligible patients were included as covariates in a Cox regression analysis of disease-free survival (DFS) and overall survival (OS). Fifty-four percent of patients participating in this trial underwent D-0 lymphadenectomy, 36% D-1 lymphadenectomy, and 10% D-2 lymphadenectomy. We were unable to demonstrate a prognostic effect for D-level for either DFS or OS. MI did prove to be a significant prognostic factor, both by univariate analysis (p<0.001) and in the Cox regression analysis with adjustment for T-stage and number of nodes positive (p<0.03). Median survival by quartile varied from 42 months for MI < 25, to 20 months for MI > 135. Interestingly, we detected no significant interaction between the adjuvant treatment and any surgical or pathologic variable (i.e., we were unable to detect differential treatment effect in any of the surgical or pathologic subgroups). "Marayama Index of Unresected Disease (MI)," a measure of unresected regional nodal disease, is an independent predictor of survival in gastric cancer, but we were unable to detect such an effect for D-level. The positive treatment effect documented in this trial applied to all surgical and pathologic subgroups, thus cementing adjuvant chemoradiation as the new standard for the treatment of gastric cancer.

ASCO Abstract #604: Kodera Y, Nakanishi H, Ito S, Yamamura Y, Tatematsu M. Quantitative detection of free cancer cells in the peritoneal washing by real-time RT-PCR: A significant prognostic determinant for gastric carcinoma. ASCO Proc. 2001;20:152a.

Peritoneal lavage cytology (CY) by the Papanicolaou staining detects free cancer cells in the abdominal cavity and is an excellent predictor of peritoneal carcinomatosis, the commonest pattern for failure for gastric carcinoma patients. To further improve on the sensitivity, a novel protocol using LightCycler technology was established, and a correlation between the results of the new protocol and the clinical outcome was evaluated. Peritoneal washes were obtained at the beginning of surgery from 190 gastric carcinoma patients operated on between 1994 and 1998. The samples underwent quantitative detection of carcinoembryonic antigen (CEA) mRNA using a real-time fluorescence PCR system with hybridization probes as fluorophores, besides being examined by the conventional cytology. The patients underwent postoperative surveillance of at least 2 years, and receiver operation characteristics analysis of the patients with and without peritoneal relapse was performed to determine a cutoff value for the CEA mRNA levels. Differences in survival of the patients stratified by the results of CY and PCR were then evaluated by Kaplan and Meier curves. At the optimal cutoff value by which a sensitivity of 84% was achieved, the 50% survival time observed for the 30 Cy(-) PCR(+) patients was 40 months, which was intermediate between the 34 CY(+)PCR(+) patients (11 months) and the 126 PCR(-) patients (not reached). Recurrence as peritoneal carcinomatosis was observed in 64% of PCR(+) patients as opposed to 6%of PCR(-) patients. Multivariate analysis revealed that PCR(+)was a significant independent prognostic factor (p=0.036) along with presence of node metastasis (p=0.016) and peritoneal deposits (p=0.017),while CY(+) was not (p=0.349). CEA RT-PCR of the peritoneal washing can replace cytology examination as a tool to identify gastric carcinoma patients with a high risk for the recurrent disease. Future trials for adjuvant chemotherapy could be focused upon the PCR(+) patients with no other evidence of residual disease.

ASCO Abstract #652: Yoshida M, Ohtsu A, Boku N, Muto M, Nagashima F, Yoshida S, Yamamoto S. Long-term survival of patients (pts) with unresectable gastric cancer (GC) treated with chemotherapy in the Japan Clinical Oncology Group (JCOG) Study. ASCO Proc 2001;20:164a

(Background and Objective) Long-term survival of unresectable GC patients remains unclear. The aim of this analysis was to clarify an impact of chemotherapy on long-term results in patients with unresectable GC and to identify characteristics of long-term survivors. (Patients and Methods) A total of 643 patents were enrolled onto four phase II and one phase III studies in JCOG (8501, 8804, 8903, 9001, 9205) between January 1985 and April 1997. Chemotherapy consisted of the following regimens: tegafur + mitomycin C, UFT + mitomycin C, 5'doxiluridine+ CDDP, etoposide + doxorubicin + CDDP, 5-FU + CDDP, and continuous infusion of 5-FU. In order to adjust patients' eligibility between the five studies, 497 patients (77%) who met the following criteria were selected: evidence of unresectable disease, histologically proven adenocarcinoma of the stomach, having measurable or assessable lesions, age £ 75, PS £ 2, no prior chemotherapy, adequate organ functions, and no serious complications. Survival was updated in November 2000, with a minimum follow-up of four years in survivors. (Results) Baseline patients' backgrounds were as follows: median age of 61 (19-75), 364/133 male/female, 176/238/86 with PS0 1/1/2, 84 with prior gastrectomy, 137 with scirrhous type,228/266 with intestinal/diffuse type adenocarcinoma histologically, 232/236/86 with abdominal lymph nodes/liver/peritoneal metastases, 314/149/34 with one/two/more metastatic sites. Objective responses were seen in 127 (26%) patients. Thirty-nine (8%) and nine (2%) patients have survived longer than two and five years. Cox regression analysis revealed that good PS, no liver metastasis, non-scirrhous type, and only one metastatic site were associated with better prognosis. Between 39 2-year survivors and the remaining 458 with shorter survival, significant differences were observed in the incidences of objective response (80%, 21%, p<0.01), PS £ 1 (100%, 81%, p=0.01), and prior gastrectomy (31%, 16%, p=0.03). (Conclusion) Chemotherapy offers some hope of achieving long-term survival in patients with unresectable GC. Objective response, better PS, and prior gastrectomy appear to be favorable factors for long survival..

ASCO Abstract #2280: Kitagawa Y, Kubota T, Ango N, Watanabe M, Otani Y, Ozawa S, Hasegawa H, Furukawa T, Kumai K, Fujii H, Mukai M, Kubo A, Suto A, Kitajimi M. Sentinel node navigation for esophageal, gastric and colorectal cancer. ASCO Proc 2001;20:132b.

Although radio-guided detection of sentinel nodes (SN) has been used to identify regional metastases in patients with malignant melanoma and breast cancer, the validity of the sentinel node concept in gastrointestinal (GI) cancer is still controversial. We have studied the diagnostic significance of SN in GI cancer using radio-guided method and would like to present up-dated data. Objective: To test the feasibility and validity of the intraoperative radioguided sentinel node (SN) mapping for diagnosis of lymph node micrometastasis in gastrointestinal cancers. Patient population and methods: Consecutive 206 patients with gastrointestinal cancers who underwent radical surgery with standard lymphadenectomy (esophagus:33, stomach:121, colorectum:52) have been enrolled in this study (1999.1-2000.10). Endoscopic injection of technetium-99m Sn (tin) colloid (0l.15r-4.0 mCi) was performed preoperatively and radioactive SN were identified with an intraoperative hand-held gamma probe (Navigator, AutoSuture, Japan). Standard radical resection with lymphadenectomy was performed for all of these patients and all resected nodes were evaluated by routine histopathological examination. Results. Diagnostic significance of SN mapping is summarized in the table as follows: Esophageal Ca Gastric Ca Colorectal Ca SN identified (%) 30/33 (91%) 114/121 (94%) 45/52 (87%) Accuracy (%) 27/30 (90%) 112/114 (98%) 43/45 (96%) Sensitivity (%) 17/20 (85%) 16/18 (89%) 10/12 (83%) Resected LN 64.3 46 34 Number of SN 4.8 3.6 3.7 Conclusions: Intraoperative radio-guided sentinel node mapping was viable for patients with GI cancers. We would like to conclude by suggesting that it is worthwhile to continue evaluating this technique as sensitive and specific diagnostic method for micrometastasis in regional lymph node of GI cancers to establish novel minimally invasive approaches.

4th IGCC Abstract #S14: Peek RM Jr. Helicobacter pylori modulation of the gastric epithelial cell cycle. International Gastric Cancer Congress Abstract Book, 2001:p21.

Chronic gastritis induced by H. pylori increases the risk for distal gastric adenocarcinoma, yet only a minority of colonized persons develop neoplasia. Enhanced risk may be related to differences in specific bacterial products, to differences in host responses to the bacteria, or to particular interactions between host and microbe. H. pylori strain-specific properties such as production of a functional cytotoxin encoded by vacA augment the risk for non-cardia gastric cancer. Host responses to H. pylori, such as apoptosis, also may be important in lowering the carcinogenic threshold; however, heterogeneity exists in levels of apoptosis among infected clinical populations. Compared to wild-type H. pylori, vacA null mutants attenuate epithelial cell cycle progression and apoptosis in vitro, and when expressed in epithelial cells, recombinant vacA inserts into the mitochondrial membrane, induces the release of cytochrome c, and activates caspase-3, an effector of apoptosis. H. pylori urease can induce apoptosis by ligation of class II MHC molecules on epithelial cell surfaces, and differing levels of apoptosis in vivo may therefore reflect heterogeneity of class II MHC host genotypes within an infected population. H. pylori also induces apoptosis in vitro by activating Fas, and gastric T-cell lines are synergistic with H. pylori in enhancing apoptosis and Fas expression on gastric epithelial cells. Particular polymorphisms of the human IL-1b gene promoter are genetic risk factors for atrophic gastritis and gastric adenocarcinoma among H. pylori-infected persons, and since IL-1b can activate intracellular cascades that regulate apoptosis, differing mucosal levels of IL-1b may influence apoptotic indices. Collectively, these data suggest that heterogeneity in levels of apoptosis among infected clinical populations is likely dependent upon the tremendous genetic diversity that exists between isolates of H. pylori and between human hosts.

4th IGCC Abstract #S43: Macdonald JS, Smalley S, Benedetti J, Hundahl SA, Estes N, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup M, Martenson JA. Postoperative combined radiation and chemotherapy improves disease-free survival (DFS) and overall survival (OS) in resected adenocarcinoma of the stomach and gastroesophageal junction. Results of intergroup study INT-0116 (SWOG 908). International Gastric Cancer Congress Abstract Book 2001:p661.

The cure rate for patients with resected gastric cancer is 5%-40%. INT-0116 was designed to evaluate postoperative adjuvant chemoradiation in resected gastric cancer. Study Design: Patients with stages Ib through IV M0 adenocarcinoma of the stomach or gastroesophageal junction who had undergone gastric resection with curative intent were randomized to postoperative follow-up or chemoradiation. The treatment consisted of one cycle of 5-FU (425 mg/m2)/Leucovorin (LV) (20 mg/m2) in a daily x5 regimen followed by 4,500 cGy (1809 cGy/day) given with 5-FU/LV (400 mg/m2 and 20 mg/m2) on days 1 through 4, and on the last 3 days of radiation. One month after completion of radiation, two cycles of daily x5 5-FU/LV (425 mg/m2 and 20 mg/m2) were given at monthly intervals. Results: Between 8/1/91 and 7/15/98, 603 patients were accrued in this study, 47 (8%) of which were ineligible. Nodal metastases were present in 85% of cases. The combined modality regimen in this program was tolerable. There were 3 (1%) toxic deaths. Grade 3 and grade 4 toxicity occurred in 41% and 32% of cases, respectively. The ³gr. 3 toxicities were: hematologic (54%), GI (33%), infection (6%), neurologic (4%). OS and DFS analyses were based on intention to treat. With 3.3 years of median follow-up, 3-year DFS is 49% for treatment and 32% for observation (p=0.001); 3-year OS is 52% for treatment and 41% for observation (p=0.03). these results demonstrate a 44%improvementin relapse-free survival (hazard ratio of 1.44), and a 28% improvement in survival with median survival of 27 months in the observation arm vs. 42 months in the treatment arm (hazard ratio 1.28). Postoperative chemoradiation may now be considered a standard of care for high-risk R0 resected locally advanced adenocarcinoma of the stomach and GE junction.

4th IGCC Abstract #S47: Hartgrink HH, van de Velde CJH, Dutch Gastric Cancer Group: Update of the Dutch D1 vs D2 gastric cancer trial. International Gastric Cancer Congress Abstract Book 2001:p665.

In the Netherlands, 80 hospitals participated in a randomized trial to compare morbidity, hospital mortality, survival, and cumulative relapse risk after D1 or D2 lymph node dissection for gastric cancer. Between 1989 and 1993, 996 patients were centrally randomized, of whom 711 patients (380 D1 and 332 D2) underwent the allocated treatment with curative intent. Strict quality control measures were taken in the Dutch Gastric Cancer Trial (DGCT) to guarantee the intended difference between these two resection types. After curative resection, D2 patients had a higher postoperative mortality (10% versus 4% for D1; p=0.004). They also had significantly more complications (43% versus 25% for D1; p<0.001), which led to prolonged hospital stay for patients with a D2 dissection. Five-year survival rates were not different: 45% for D1 patients and 47% for D2 patients. However, patients with lymph nodes limited to the first echelon (N1), generally with stage II or IIIa disease, significantly benefited from a D2 dissection. A problem remains in preoperative patient selection for a D2 dissection. Furthermore, the results achieved demonstrated a more refined surgical approach: pancreatectomy and splenectomy "de necessite" should be applied instead of "de principe." An update with nine years follow-up of the Dutch Gastric Cancer Trial will be presented.

4th IGCC Abstract #589: Bryan RT, Cruickshank NR, Needham SJ, Moffitt DD, Young JA, Hallissey MT, Fielding JW. Laparoscopic peritoneal lavage in staging gastric and oesophageal cancer. International Gastric Cancer Congress Abstract Book 2001:p637.

Aims. Accurate staging of gastric, oesophageal, and oesophagogastric cancer is essential to avoid unnecessary laparotomies in patients where only palliation is appropriate. This requires a multimodality approach utilizing endoscopy, computed tomography, and laparoscopy. Previous authors have found that the presence of free peritoneal tumour cells (FPTCs) detected at laparoscopy or laparotomy confers a worse prognosis. However, various methods of peritoneal lavage are described and its clinical usefulness is still unclear. The aim of this study was to evaluate the prognostic value of our technique of peritoneal lavage in an attempt to standardize this procedure. Methods. Eighty-eight staging laparoscopies combined with peritoneal lavage were carried out during a two-year period on patients eligible for attempted curative resection of a gastric, oesophageal, or oesophagogastric cancer. During laparoscopy, the pelvis was irrigated with 200 mls of normal saline, with 100 mls aspirated and examined cytologically. The results of the cytological examination of the aspirate were not used to influence the proposed surgery. Patients were followed up until nine months after the end of the study period when initial analysis of the results led to discontinuation of the study. Results. Eleven patients had FPTC-positive cytology with a; median survival following laparoscopy of 122 days (95% CI 82, 161); only a single patient survived for more than one year. In the FPTC-negative group, median survival was 378 days (95% CI 256,-). Log-rank chi-squared = 16.7, p<0.001. Peritoneal lavage status (FPTC-positive or negative) and lymph node status (positive or negative) were identified as the only significant independent prognostic factors. FPTC-positive patients had four-times the hazard of death compared to FPTC-negative patients (95% CI 1.23, 15.52). Conclusions. The presence of free peritoneal tumour cells detected by our technique is a contraindication to attempted curative resection - medical or surgical palliation is the most appropriate form of treatment.

Clinical Trials

(E7296) ECOG Phase II neoadjuvant chemotherapy plus adjuvant chemoirradiation for high risk gastric cancer.

30-42 patients with potentially curative, but high risk cancers of the GEJ or stomach will be treated. Patients receive 3 cycles of preoperative cisplatin and paclitaxel. Following surgical resection, patients receive adjuvant 5-FU and Leucovorin in a regimen like the INT-0116 protocol (one cycle before radiation, two during radiation, and two more cycles afterwards). This is a rigorous treatment regimen looking to improve outcomes by combined pre- and postoperative systemic therapy.

(E-8296) ECOG Phase II adjuvant chemotherapy for adenocarcinoma of the esophagus, GEJ and cardia.

55 patients with nodal metastases or transmural involvement of the primary tumor who have had a curative resection will be entered in this study. Patients will receive 4 cycles of paclitaxel and cisplatin given once every three weeks. Results of this study and other trials evaluating pre- and postoperative therapy will likely be used to develop future Phase III protocols for proximal and other high risk gastric cancers.

(MRC-ST02) Phase III Medical Research Council protocol comparing perioperative ECF chemotherapy with surgery alone for gastric cancer.

This study is scheduled to accrue 500 gastric cancer patients with clinical Stage II and III disease. Patients are randomized to receive constant infusion 5-FU plus cisplatin and epirubicin for three cycles of treatment preoperatively and an additional three courses starting within 6-12 weeks postoperatively or surgical resection alone. Patient entry to this trial may fall if participants feel that the results of INT-0116 warrant routine adjuvant therapy.

(EORTC-40954) Phase III European trial comparing neoadjuvant chemotherapy plus resection and surgery alone for locally advanced gastric cancer.

Patients with clinical Stages II-IV (no distant metastases, although positive peritoneal cytology are allowed) are randomized to receive two courses of bolus cisplatin every two weeks x3 and bolus 5-FU plus leucovorin weekly x5 followed by surgery or proceed immediately to operative resection. The study is scheduled to accrue a total of 360 patients. As with the MRC trial, patient entry may suffer with the publication of the results from INT-0116.

(JCOG 9501) Phase III Japanese trial to evaluate para-aortic lymphadenectomy for gastric cancer.

Patients with T2 (subserosal)-T4 cancers and negative peritoneal cytology eligible for an R0 resection are randomized into standard D2 resection or extended resection (including para-aortic lymph nodes). No adjuvant therapy is given. A total of 520 patients are scheduled to be entered with an expected completion date of March 2001.