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Latest Research on Stomach Cancer
     
Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):715-21. Epub 2007 Dec 31.
Long-term results after intraoperative radiation therapy for gastric cancer.
Drognitz O, Henne K, Weissenberger C, Bruggmoser G, Göbel H, Hopt UT, Frommhold H, Ruf G.
Department of Surgery, Division of General and Visceral Surgery, University of Freiburg, Freiburg, Germany.

PURPOSE: We retrospectively analyzed the impact of intraoperative radiation therapy (IORT) on long-term survival in patients with resectable gastric cancer. METHODS AND MATERIALS: From 1991 to 2001, a total of 84 patients with gastric neoplasms underwent gastectomy or subtotal resection with IORT (23 Gy, 6-15 MeV; IORT-positive [IORT(+)] group). Patients with a history of additional neoadjuvant chemotherapy, histologically confirmed R1 or R2 resection, or reoperation with curative intention after local recurrence were excluded from further analysis. The remaining 61 patients were retrospectively matched with 61 patients without IORT (IORT-negative [IORT(-)] group) for Union Internationale Contre le Cancer (UICC) stage, patient age, histologic grading, extent of surgery, and level of lymph node dissection. Subgroups included postoperative UICC Stages I (n = 31), II (n = 11), III (n = 14), and IV (n = 5). RESULTS: Mean follow-up was 4.8 years in the IORT(+) group and 5.0 years
in the IORT(-) group. The overall 5-year patient survival rate was 58% in the IORT(+) group vs. 59% in the IORT(-) group (p = 0.99). Subgroup analysis showed no impact of IORT on 5-year patient survival for those with UICC Stages I/II (76% vs. 80%; p = 0.87) and III/IV (21% vs. 14%, IORT(+) vs. IORT(-) group; p = 0.30). Perioperative mortality rates were 4.9% and 4.9% in the IORT(+) vs. IORT(-) group. Total surgical complications were more common in the IORT(+) than IORT(-) group (44.3% vs. 19.7%; p < 0.05). The locoregional tumor recurrence rate was 9.8% in the IORT(+) group. CONCLUSIONS: Use of IORT was associated with low locoregional tumor recurrence, but had no benefit on long-term survival while significantly increasing surgical morbidity in patients with curable gastric cancer.

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Br Med Bull. 2008 Feb 10 [Epub ahead of print]
Gastric cancer.
Lochhead P, El-Omar EM.
Gastrointestinal Research Group, Department of Medicine and Therapeutics, Aberdeen University, Aberdeen, UK.

Background Gastric cancer remains a major cause of mortality and morbidity worldwide, and the total number of gastric cancer cases is predicted to rise as a result of population growth. The pathogenesis of gastric cancer represents a paradigm for microbially induced and inflammation-driven malignancies, and understanding this will be the best means of defeating this cancer. Sources of data We reviewed the relevant English language literature in relation to gastric cancer with particular reference to the role of Helicobacter pylori. We summarize what is known of the epidemiology, aetiology and pathogenesis of gastric cancer. We also describe current approaches to the detection and management of early gastric cancer and discuss the prevention strategies. Areas of agreement H. pylori is the most important aetiological risk factor for this cancer, and the pathogenesis involves the combined effects of host genetics, bacterial virulence and environmental factors. Areas of disagreement Although most accept that removing Helicobacter could prevent gastric cancer, there are still no definitive trials to prove this concept. There is also some anxiety about the long-term effects of removing such a prevalent chronic infection from large sections of the population. Conclusions Gastric cancer is now arguably one of the most understood malignancies, and real progress is being made towards eradicating this global killer. Much work still needs to be done to define the optimal approach for eradicating the causative agent, namely H. pylori infection.

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Presse Med. 2008 Feb 6 [Epub ahead of print]
[Gastrointestinal manifestations of Helicobacter pylori infection in adults: from gastritis to gastric cancer.]
[Article in French]
Delchier JC.
Service d’hépatogastroentérologie, Hôpital Henri Mondor, F-94010 Créteil Cedex, France.

Helicobacter pylori is a pathogenic bacteria that always causes an inflammatory reaction in the gastric mucosa. Gastric inflammation or gastritis associated withH. pylori is asymptomatic in most cases. H. pyloriis the cause of more than 70% of gastroduodenal ulcers, and they disappear on its eradication. MALT (mucosa-associated lymphoid tissue)-type small-cell gastric lymphoma may regress completely after H. pylori eradication. H. pylori gastritis may lead to intestinal atrophy and metaplasia and to gastric cancer, in 1% of cases. H. pylorieradication makes it possible to stabilize the precancerous lesions and prevent the onset of cancer. The risk of cancer depends on the bacteria's pathogenicity and the host's immune characteristics. In France, preventive eradication is recommended in first-degree relatives of subjects with gastric cancer, patients with a partial gastrectomy for cancer and patient with marked atrophy.

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Drugs. 2008;68(3):299-317.
Locally advanced and metastatic gastric cancer : current management and new treatment developments.
Field K, Michael M, Leong T.
Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.

The management of gastric cancer remains a challenge. In recent years, the most important advances have been achieved in the adjuvant setting for patients with locally advanced disease, where significant survival benefits have been demonstrated for both perioperative chemotherapy and adjuvant chemoradiotherapy. These findings have changed the standard of care for patients with resectable disease.In the setting of metastatic gastric cancer, the development of new cytotoxic regimens must consider the balance between efficacy and toxicity in patients whose overall prognosis is poor. Major advances in recent years include the development of orally administered fluoropyrimidine analogues, which can be used in place of intravenous fluorouracil, and the addition of newer agents such as oxaliplatin and docetaxel, which have demonstrated efficacy in patients with advanced disease. Targeted therapies have had a major impact on the management of certain malignancies, and while their evaluation in the treatment of advanced gastric cancer remains early, it is likely that these agents will continue to be developed and studied in combination with chemotherapy.This article reviews recent advances in the use of chemotherapy for advanced gastric cancer. Targeted therapies, their mechanisms of action and emerging data supporting their use in gastric cancer are also discussed. The two randomized phase III trials supporting adjuvant therapy for locally advanced, resectable gastric cancer are discussed in detail, together with strategies for future trials in this area. Overall, there remains optimism that further incremental gains will be achieved with future studies combining chemotherapy, radiotherapy and targeted therapies, both in the adjuvant and metastatic disease settings.

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Eur J Surg Oncol. 2008 Jan 25 [Epub ahead of print]
Advanced gastric cancer with or without peritoneal carcinomatosis treated with hyperthermic intra-peritoneal-chemotherapy: A single western center experience.
Scaringi S, Kianmanesh R, Sabate JM, Facchiano E, Jouet P, Coffin B, Parmentier G, Hay JM, Flamant Y, Msika S.
Department of Surgery, Louis-Mourier University Hospital, Assistance Publique des Hôpitaux de Paris (APHP), Paris-VII University “Denis Diderot” (GHU Nord), 178 Rue des Renouillers, 92701 Colombes Cedex, France.

INTRODUCTION: The aim of this article was to evaluate the role of hyperthermic intraperitoneal chemotherapy (HIPEC), associated or not to cytoreductive surgery (CS) in the treatment of different stages of advanced gastric cancer (AGC). PATIENTS AND METHODS: Thirty seven patients with AGC who underwent 43 HIPEC from June 1992 to February 2007 were included. HIPEC used Mitomycin-C and Cisplatin for 60-90min at 41-43 degrees C intra-abdominal temperature. The main endpoints were long-term survivals, morbidity and mortality rates. RESULTS: Eleven patients had no demonstrable sign of PC and constituted the Prophylactic-group, while 26 patients had macroscopic PC (PC-group). Five patients were Gilly 1 or 2 (nodules <0.5cm) and 21 Gilly 3 or 4 (nodules >/=0.5cm). In the PC-group a complete curative CS was achieved before HIPEC in 8 (PC-curative subgroup) and a palliative HIPEC in 18 patients (PC-palliative subgroup). The overall 30-days mortality was 5% (2 patients). Two patients in the Prophylactic group died within 6months after hospital discharge (overall mortality 11%). The estimated risk of death per procedure was 9%. Ten patients (27%) presented one or more complications. The median survival was 23.4 months in the Prophylactic group, and 6.6 months in the PC-group (p<0.05). The median survival in the PC-curative subgroup was 15 vs 3.9months in the PC-palliative subgroup (p=0.007). The median survival according to Gilly classification was significantly different (Gilly 1&2 vs Gilly 3&4, 15 vs 4months respectively, p=0.014). The global recurrence rates between the Prophylactic group and the PC-curative subgroup at 2years were 36% vs 50% respectively. The median delay to recurrence was 18.5 vs 9.7 months respectively. CONCLUSION: HIPEC might be useful to improve the survival in selected patients with ACG only when a complete cytoreduction can be achieved. Despite encouraging data, prospective studies, based on larger cohorts of patients are required to
assess the role of this procedure as a prophylactic treatment in patients with AGC.

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N Engl J Med. 2008 Jan 3;358(1):36-46.
Capecitabine and oxaliplatin for advanced esophagogastric cancer.
Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom.
Royal Marsden Hospital National Health Service Foundation Trust, Surrey and London, United Kingdom.

BACKGROUND: We evaluated capecitabine (an oral fluoropyrimidine) and oxaliplatin (a platinum compound) as alternatives to infused fluorouracil and cisplatin, respectively, for untreated advanced esophagogastric cancer. METHODS: In a two-by-two design, we randomly assigned 1002 patients to receive triplet therapy with epirubicin and cisplatin plus either fluorouracil (ECF) or capecitabine (ECX) or triplet therapy with epirubicin and oxaliplatin plus either fluorouracil (EOF) or capecitabine (EOX). The primary end point was noninferiority in overall survival for the triplet therapies containing capecitabine as compared with fluorouracil and for those containing oxaliplatin as compared with cisplatin. RESULTS: For the capecitabine-fluorouracil comparison, the hazard ratio for death in the capecitabine group was 0.86 (95% confidence interval [CI], 0.80 to 0.99); for the oxaliplatin-cisplatin comparison, the hazard ratio for the oxaliplatin group was 0.92 (95% CI, 0.80 to 1.10). The upper limit of the confidence intervals for both hazard ratios excluded the predefined noninferiority margin of 1.23. Median survival times in the ECF, ECX, EOF, and EOX groups were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively; survival rates at 1 year were 37.7%, 40.8%, 40.4%, and 46.8%, respectively. In the secondary analysis, overall survival was longer with EOX than with ECF, with a hazard ratio for death of 0.80 in the EOX group (95% CI, 0.66 to 0.97; P=0.02). Progression-free survival and response rates did not differ significantly among the regimens. Toxic effects of capecitabine and fluorouracil were similar. As compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism but with slightly higher incidences of grade 3 or 4 diarrhea and neuropathy. CONCLUSIONS: Capecitabine and oxaliplatin are as effective as fluorouracil and cisplatin, respectively, in patients with previously untreated esophagogastric cancer. (Current Controlled Trials number, ISRCTN51678883 [controlled-trials.com].). Copyright 2008 Massachusetts Medical Society.

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Eur J Cancer. 2008 Jan;44(2):182-94.
Expert opinion on management of gastric and gastro-oesophageal junction adenocarcinoma on behalf of the European Organisation for Research and Treatment of Cancer (EORTC) gastrointestinal cancer group.
Van Cutsem E, Van de Velde C, Roth A, Lordick F, Köhne CH, Cascinu S, Aapro M.
Digestive Oncology Unit, University Hospital Gasthuisberg, 3000 Leuven, Belgium.

A multidisciplinary approach is mandatory for patients with gastric cancer. Patients should be managed by an experienced team of physicians. The outcome of patients is related to the experience of the multidisciplinary team. Surgery is the cornerstone of the management of patients with resectable gastric cancer. The standard recommendations for resectable gastric adenocarcinoma are free-margin surgery with at least D1 resection combined to removal of a minimum of 15 lymph nodes. It has been shown that the outcome of patients with resectable gastric cancer can be improved by a strategy of perioperative (pre- and postoperative) chemotherapy or by postoperative chemoradiotherapy. The evidence comes from large randomised phase 3 studies. In the treatment of unresectable, locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, no chemotherapy combination was accepted as the gold standard. Cisplatin/5-FU (CF) and ECF (epirubicin plus CF) regimens have
been investigated widely in clinical studies and were until recently presented as the reference regimens. Despite a relative chemosensitivity of gastric cancer, a low rate of complete response was obtained, the response duration was short and patients' outcomes remained poor. Recently, new options have been introduced in the management of advanced gastric cancer. It has been shown that capecitabine is at least as good as 5-FU and that oxaliplatin at least as good as cisplatin in these combinations. It has also been demonstrated that the addition of docetaxel to CF resulted in statistically significant improved efficacy endpoints (including patient's quality of life), but also in an increased toxicity. The DCF regimen (docetaxel, cisplatin and 5-FU) has become, therefore, a new active option in advanced gastric cancer in selected patients in good condition. Further randomised trials are therefore to be designed to further improve chemotherapy by modifying and optimising the chemotherapy regimens, and investigating novel treatment combinations. The addition of biological agents to the optimal chemotherapy regimen may achieve further improvements in efficacy.

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Aliment Pharmacol Ther. 2007 Dec;26 Suppl 2:25-35.
Review article: Helicobacter pylori eradication for the prevention of gastric cancer.
De Vries AC, Kuipers EJ.
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. a.c.devries@erasmusmc.nl

BACKGROUND: Gastric cancer is the fourth most common cancer and second leading cause of cancer-related death worldwide. A clear association between Helicobacter pylori infection and gastric cancer was established years ago. H. pylori eradication may be an effective approach to decrease morbidity and mortality of gastric cancer. AIM: To discuss current evidence of H. pylori eradication for prevention of gastric cancer. RESULTS: Recent studies have shown that the association between H. pylori and gastric cancer has probably been underestimated. This may have resulted from negative H. pylori status in subjects after loss of colonisation in the presence of atrophic gastritis and intestinal metaplasia, prior to development of gastric cancer. The recognition of the central role of H. pylori in carcinogenesis has increased expectations of gastric cancer prevention by H. pylori eradication. A primary preventive effect of eradication in subjects with H. pylori-induced gastritis has been demonstrated. However, a secondary preventive effect in patients with pre-malignant gastric lesions is still controversial, especially in patients with intestinal metaplasia and dysplasia. CONCLUSIONS: At this moment, H. pylori eradication seems indicated at the earliest stage of gastric carcinogenesis. This treatment policy requires confirmation; results of ongoing randomised controlled trials are therefore eagerly awaited.

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Zentralbl Chir. 2007 Dec;132(6):515-22.
[Long-term survival of curatively operated gastric cancer: influence of the gender and splenectomy]
[Article in German]
Schafmayer C, Jürgens G, Jürgens I, Klomp HJ, Fändrich F, Kahlke V.
Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 7. clemens.schafmayer@uksh-kiel.de

BACKGROUND: Despite advances in operative technique long-term survival of curatively operated gastric cancer patients still remains poor with 5-year-survival of 25 %. Gender differences have been recognized in patients with colorectal carcinoma with a higher 5-year-survival of women. The long time-survival of the individual patient is closely dependent on his immunofunction. If a splenectomy has to be carried out, the postoperative immunofunction will be affected considerably. Thus, the question arises as to how far gender and splenectomy influence the long time-survival after curative gastric cancer surgery. METHODS: In a retrospective analysis of 505 patients with gastric cancer who had been treated between the years 1992 and 2002, a curative resection, i. e. R0, could be performed in 243 patients (48.1 %) with a definite classified tumour stadium according to the UICC (1997). The sociodemographic, operative, histomorphologic and postoperative data of each patient were collected, stratified by gender and compared using log-rank-test (survival) and chi-square-test (distribution). Multivariate analysis was performed by cox regression. The level of significance was set at p < 0.05. RESULTS: The sociodemographic, histopathologic and operative data between the two genders were comparable. The morbidity between men and women was not significant. However the rate of postoperative sepsis was higher in men (p < 0.05). With regard to the long-term survival, no difference could be shown between the two groups. However, splenectomy had a significant effect on long time-survival. Women with preserved spleen had a significantly improved five-year-survival rate as compared to women undergoing splencetomy and men with preserved spleen (p < 0.05). Multivariate analysis revealed only the tumour stage as a predictor for long time-survival in men, whereas in women the extend of lymphadenectomy and sepsis also influenced long time-survival. CONCLUSION: Long time-survival of curatively operated gastric cancer patients is gender dependent in terms of splenectomy. Therefore, gender differences should be taken into account in analysing long-term data of oncological patients.

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Expert Rev Anticancer Ther. 2007 Oct;7(10):1379-93.
Radiotherapy in gastric cancer: a systematic review of literature and new perspectives.
Valentini V, Cellini F.
Università Cattolica S.Cuore, Radiotherapy Department, Largo F.Vito, 1, 00168 Rome, Italy. vvalentini@rm.unicatt.it

Gastric cancer is still a major problem for oncologists. Surgery is the main therapeutic approach; a complete surgical resection is usually necessary to offer potentially curative therapy to patients with adenocarcinoma of the stomach. However, many patients with more locally advanced tumors will experience local and distal recurrences. When a recurrence occurs, only palliative therapy is possible. In operable gastric cancer, both the extent of surgery and the value of adjuvant treatment remain subject to considerable international controversies. To improve local control, surgeons address the role of standardized surgery and of more extended surgery. Radiotherapy appears to improve local control and survival in the adjuvant arms, but perspective randomized trials are scarce and reported over many years. Retrospective experience demonstrated a low local recurrence rate, but was affected by large heterogeneity. However, evidence published in the last few years, improved radiotherapy technologies, better knowledge of the at-risk areas (enabling smaller radiotherapy volumes) and growing interest in neoadjuvant approaches support the role of radiotherapy in gastric cancer.

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Br J Cancer. 2007 Sep 17;97(6):712-6.
Postoperative chemoradiotherapy in gastric cancer -- a Phase I/II dose-finding study of radiotherapy with dose escalation of cisplatin and capecitabine chemotherapy.
Jansen EP, Boot H, Dubbelman R, Bartelink H, Cats A, Verheij M.
Department of Radiotherapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. epm.jansen@nki.nl

We hypothesised that gastric cancer outcome could be improved with more effective and intensified postoperative chemoradiotherapy. This phase I/II study was performed to determine the maximal tolerated dose (MTD) and toxicity profile of postoperative radiotherapy with concurrent daily cisplatin and capecitabine. Patients were treated with capecitabine 1000 mg m(-2) twice a day (b.i.d.) for 2 weeks. Subsequently, patients received capecitabine (250-650 mg m(-2) orally b.i.d., 5 days week(-1)) and cisplatin (3-6 mg m(-2) i.v., 5 days week(-1)) according to an alternating dose-escalation schedule. Radiotherapy was given to a total dose of 45 Gy in 25 fractions. Thirty-one patients completed treatment. During chemoradiotherapy, eight patients developed nine items of grade III and one episode of grade IV (mainly haematological) toxicity. The MTD was determined to be cisplatin 5 mg m(-2) i.v. and capecitabine 650 mg m(-2) b.i.d. orally. This phase I/II study demonstrated that chemoradiotherapy with daily cisplatin and capecitabine is feasible in postoperative gastric cancer at the defined dose level and is currently being tested in a phase III multicenter study.

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Br J Cancer. 2007 Sep 3;97(5):593-7. Epub 2007 Jul 31.
Irinotecan, docetaxel and oxaliplatin combination in metastatic gastric or gastroesophageal junction adenocarcinoma.
Di Lauro L, Nunziata C, Arena MG, Foggi P, Sperduti I, Lopez M.
Division of Medical Oncology B, 'Regina Elena' Institute for Cancer Research, Via Elio Chianesi, 53, Rome 00144, Italy. dilauro@ifo.it

This phase II study was designed to evaluate the activity and safety of a combination of irinotecan, docetaxel and oxaliplatin in metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Forty patients with measurable distant metastasis received irinotecan 150 mg m(-2) and docetaxel 60 mg m(-2) on day 1, and oxaliplatin 85 mg m(-2) on day 2. Cycles were repeated every 3 weeks. The primary end point was to demonstrate a 50% improvement in time-to-progression (TTP) over historical controls. All patients were evaluable. Median TTP was 6.5 months (95% confidence interval (CI) 5.6-7.4), the overall response rate was 50% (95% CI 35-65%) and the median overall survival was 11.5 months (95% CI 8.7-14.3). Grade 3/4 neutropaenia occurred in 47.5% of patients. There were four episodes of febrile neutropaenia in three patients. Other non-haematological grade 3 toxicities included diarrhoea in four patients (10%), vomiting in three patients (7.5%) and mucositis in two patients (5%). The irinotecan, docetaxel and oxaliplatin combination chemotherapy is an active and well-tolerated novel regimen for treating metastatic gastric or GEJ adenocarcinoma and deserves further evaluation in randomised trials and in combination with molecular targeting agents.

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Am J Clin Oncol. 2007 Aug;30(4):346-9.
A phase I study of docetaxel, oxaliplatin, and capecitabine in patients with metastatic gastroesophageal cancer.
Evans D, Miner T, Akerman P, Millis R, Jean M, Kennedy T, Safran H.
Brown University Oncology Group, Providence, RI, USA. devans@lifespan.org

OBJECTIVES: Docetaxel, capecitabine, and oxaliplatin are important new agents in esophagogastric cancer. The Brown University Oncology Group initiated a phase I study to determine the maximum tolerated dose of weekly docetaxel, oxaliplatin, and capecitabine. METHODS: Patients with metastatic esophageal and gastric cancers received docetaxel and oxaliplatin on days 1 and 8 and capecitabine in divided doses, twice daily, on days 1 to 10, with each cycle repeated every 21 days. Patients were enrolled in cohorts of 3 at escalating dose levels. The docetaxel dose ranged from 30 to 35 mg/m2, the oxaliplatin dose from 40 to 50 mg/m2, and the capecitabine dose from 750 to 850 mg/m2 BID. RESULTS: Sixteen patients were enrolled over 4 dose levels. The median age was 59 years. Eight patients had esophageal cancer and 9 had gastric cancer. Grade 3/4 dose-limiting toxicities of diarrhea, nausea, fatigue, and febrile neutropenia occurred in 3 of 4 patients at dose level 3. An intermediate dose level was added (2A), reducing the capecitabine dose to 750 mg/m2. One of 6 patients had a dose-limiting toxicity at level 2A. CONCLUSIONS: Oxaliplatin 50 mg/m2 and docetaxel 30 mg/m2 day 1 and 8 with capecitabine 750 mg/m2 BID for 10 days in 21-day cycles may represent a promising, easily administered regimen for metastatic esophageal and gastric cancer. A phase II study will be initiated.

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Curr Pharm Des. 2007;13(22):2261-73.
Prevention of cancer in the upper gastrointestinal tract with COX-inhibition. Still an option?
Jiménez P, García A, Santander S, Piazuelo E.
Instituto Aragonés de Ciencias de la Salud, Service of Gastroenterology, Hospital Clínico Universitario, Zaragoza, Spain. pilarj@unizar.es

Epidemiological studies have shown that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduction of gastrointestinal cancer risk. Since up-regulation of COX-2 has been reported in different stages of the esophageal and gastric carcinogenic sequence, the cyclooxygenase-2 selective inhibitors (COXIBs) were considered a good alternative to traditional NSAIDs since they cause less injury to the gastrointestinal mucosa. However, recent chemoprevention trial data reporting an increased risk of cardiovascular events have raised serious concerns on the safety of COXIBs in chemoprevention strategies. Moreover, low expression of COX-2 has been reported in a subset of gastrointestinal cancers due to COX-2 methylation, indicating that these patients could be less responsive to treatment by specific COX-2 inhibitors. Furthermore, the COX-1 isoform may have a potential role in the angiogenic process associated with esophageal adenocarcinoma, which suggests that inhibition of COX-1 may be another effective therapeutic target in upper gastrointestinal cancer. Finally, lipoxygenase-derived products may be increased following COX-inhibition due to shunting of the arachidonic acid metabolism. Specifically, the 5-LOX pathway seems to be relevant in gastrointestinal cancer development. Taken together, these data indicate that a re-evaluation of potential chemoprevention strategies for cancers of the upper gastrointestinal tract needs to be considered.

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J Clin Oncol. 2007 Aug 1;25(22):3210-6. Comment in: J Clin Oncol. 2007 Aug 1;25(22):3188-90.
Quality of life with docetaxel plus cisplatin and fluorouracil compared with cisplatin and fluorouracil from a phase III trial for advanced gastric or gastroesophageal adenocarcinoma: the V-325 Study Group.
Ajani JA, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Awad L, Van Cutsem E; V-325 Study Group.
Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. jajani@mdanderson.org

PURPOSE: Therapy of patients with advanced gastric or gastroesophageal junction cancer should provide symptom relief and improve quality of life (QOL) because most patients are symptomatic at baseline. Using validated instruments, we prospectively assessed QOL (even after completion of protocol treatment) as one of the secondary end points of the V325 phase III trial. PATIENTS AND METHODS: Four hundred forty-five patients randomly received either docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) each on day 1 plus fluorouracil 750 mg/m(2)/d continuous infusion on days 1 to 5 every 3 weeks (DCF) or cisplatin 100 mg/m(2) on day 1 plus fluorouracil 1,000 mg/m(2)/d continuous infusion on days 1 to 5 every 4 weeks (CF). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and, where available, the EuroQOL EQ-5D questionnaire were administered every 8 weeks from baseline until progression and then every 3 months. Time to definitive deterioration of QOL parameters was analyzed. RESULTS: The proportions of patients having assessable EORTC QLQ-C30 and EQ-5D questionnaires at baseline were 86.0% and 78.7% with DCF, respectively, and 89.7% and 92.8% with CF, respectively. Time to 5% deterioration of global health status (primary end point) significantly favored DCF over CF (log-rank test, P = .01). QOL was preserved longer for patients on DCF than those on CF for all time to deterioration analyses, demonstrating the statistical superiority of DCF compared with CF. CONCLUSION: V325 represents the largest trial with the longest prospectively controlled evaluations of QOL during protocol chemotherapy and follow-up in patients with advanced gastric or gastroesophageal junction cancer. In V325, advanced gastric or gastroesophageal junction cancer patients receiving DCF not only had statistically improved overall survival and time to tumor-progression, but they also had better preservation of QOL compared with patients receiving CF.

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J Clin Oncol. 2007 Aug 1;25(22):3205-9. Comment in: J Clin Oncol. 2007 Aug 1;25(22):3188-90.
Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study Group.
Ajani JA, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Marabotti C, Van Cutsem E; V-325 Study Group.
Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. jajani@mdanderson.org

PURPOSE: For patients with advanced gastric or gastroesophageal cancer (AGGEC) providing clinical benefit with improved palliation is highly desirable. However, a prospective evaluation of clinical benefit in AGGEC patients has never before been reported in a phase III setting. PATIENTS AND METHODS: In a multinational trial (V325), 445 patients were randomly assigned and treated with either docetaxel plus cisplatin and fluorouracil (DCF) or cisplatin and fluorouracil (CF). Clinical benefit was prospectively evaluated in this trial as a secondary end point. The primary measure for clinical benefit analysis was time to definitive worsening by one or more categories of Karnofsky performance status (KPS). Secondary clinical benefit end points included time to 5% definitive weight loss, time to definitive worsening of appetite by one grade, pain-free survival (defined as time to first appearance of pain), and time to first cancer pain-related opioid intake. Clinical benefit assessments were recorded at each clinic visit. RESULTS: Clinical benefit assessments were performed in more than 75% of patients throughout V325. DCF significantly prolonged time to definitive worsening of KPS compared with CF (median, 6.1 v 4.8 months; hazard ratio, 1.38; 95% CI, 1.08 to 1.76; log-rank P = .009). Although time to definitive weight loss and time to definitive worsening of appetite favored DCF, the results were not statistically significant. Pain-free survival and time to first cancer pain-related opioid intake were comparable. CONCLUSION: To our knowledge, V325 is the first phase III trial to report clinical benefit in AGGEC patients. Clinical benefit was assessed beyond protocol-specific chemotherapy. The addition of D to CF not only significantly improved clinical benefit but also improved quality of life, time to progression, and overall survival compared with CF.

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Expert Opin Investig Drugs. 2007 Jul;16(7):1059-68.
Systemic therapy for gastric cancer and adenocarcinoma of the gastroesophageal junction: present status and future directions.
Richards DA, Boehm KA, Anthony SP.
US Oncology Research, Inc., Houston, TX 77060, USA. Donald.Richards@USOncology.com

Gastric cancer is a major worldwide problem and is a leading cause of death. The incidence of distal gastric cancer is declining; however, there has been a rapid rise in the incidence of adenocarcinoma of the gastroesophageal junction, which is a more aggressive entity. Combination chemotherapy has significant activity in the treatment of both of these diseases, improving overall survival and quality of life. Despite these improvements, median survival remains at approximately 9 months in patients who are diagnosed at stage IV. This review examines recent advances in the treatment of gastroesophageal junction adenocarcinoma and gastric cancer, newer agents and the potential agents that are in development, which can be logically applied to the treatment of this devastating disease.

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Gastric Cancer. 2007;10(2):104-11. Epub 2007 Jun 25.
Docetaxel and oxaliplatin combination in second-line treatment of patients with advanced gastric cancer.
Barone C, Basso M, Schinzari G, Pozzo C, Trigila N, D'Argento E, Quirino M, Astone A, Cassano A.
Department of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy.

BACKGROUND: In advanced gastric cancer few data are available on the efficacy or safety of new drug combination regimens after progression following first-line chemotherapy. METHODS: Patients with histologically confirmed advanced gastric cancer and Eastern Cooperative Oncology Group (ECOG) performance status (PS) less than 2, progressing after first-line chemotherapy, were eligible. Patients were treated with docetaxel 75 mg/m(2) on day 1 and oxaliplatin 80 mg/m(2) on day 2, every 3 weeks, until progression or unacceptable toxicity. RESULTS: Between May 2002 and April 2005, 38 patients were enrolled. Men accounted for 73.7% of the patients and the median age was 59 years. The primary tumor was not resected in 47.4% of the patients; the peritoneum was the most frequent metastatic site (60.5%). The first-line treatment was cisplatin, epirubicin, and infusional 5-fluorouracil (ECF) in 81.5% of the patients and cisplatin and infusional 5-fluorouracil (CF) in 15.7%. The median nu
mber of cycles was 4.3. The treatment was well tolerated, with no toxic deaths. National Cancer Institute (NCI) grade III-IV neutropenia was frequent (26.3%), but no febrile neutropenia was reported. Severe asthenia (15.7%) and severe nausea (15.7%) required dose reductions in 2 patients and treatment discontinuation in another. The overall response rate was 10.5%, and 18 patients (47.3%) experienced disease stabilization (7 of them with significant clinical benefit). Median time to progression was 4.0 months (range, 2-8 months) and median overall survival was 8.1 months (range, 3-26 months). Thirteen patients (34.2%) also received third-line chemotherapy, with an irinotecan-containing regimen, and their median overall survival was higher than that of the other patients (16.3 vs 6.0 months) CONCLUSION: The combination of oxaliplatin and docetaxel shows only marginal activity as second-line treatment, but it has a good tolerability profile. This suggests that there is room fo
r optimizing the schedule as well as for planning sequential treatments in gastric cancer.

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Gastric Cancer. 2007;10(2):75-83. Epub 2007 Jun 25.
Diet and the risk of gastric cancer: review of epidemiological evidence.
Tsugane S, Sasazuki S.
Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, 5-1-1 Tsukiji, Tokyo, Japan.

There are geographic and ethnic differences in the incidence of gastric cancer around the world as well as with its trends for each population over time. The incidence patterns observed among immigrants change according to where they live. All of these factors serve to indicate the close association of gastric cancer with modifiable factors such as diet. This review presents epidemiological evidence on the association between dietary factors and gastric cancer based on previous systematic reviews and subsequent updates. Infection with Helicobacter pylori is a strong and established risk factor of gastric cancer but is not a sufficient cause for its development. Substantial evidence from ecological, case-control, and cohort studies strongly suggests that the risk may be increased with a high intake of various traditional salt-preserved foods and salt per se and decreased with a high intake of fruit and vegetables, particularly fruit. However, it remains unclear which constituents in fruit and vegetables play a significant role in gastric cancer prevention. Among them, vitamin C is a plausible candidate supported by a relatively large body of epidemiological evidence. Consumption of green tea is possibly associated with a decreased risk of gastric cancer, although the protective effects have been, for the most part, identified in Japanese women, most of whom are nonsmokers. In contrast, processed meat and N-nitroso compounds may be positively associated with the risk of gastric cancer. In conclusion, dietary modification by reducing salt and salted food intake, as well as by increasing intake of fruit and vitamin C, represents a practical strategy to prevent gastric cancer.

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J Clin Oncol. 2007 Jun 20;25(18):2580-5.
Weekly infusional high-dose fluorouracil (HD-FU), HD-FU plus folinic acid (HD-FU/FA), or HD-FU/FA plus biweekly cisplatin in advanced gastric cancer: randomized phase II trial 40953 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group and the Arbeitsgemeinschaft Internistische Onkologie.
Lutz MP, Wilke H, Wagener DJ, Vanhoefer U, Jeziorski K, Hegewisch-Becker S, Balleisen L, Joossens E, Jansen RL, Debois M, Bethe U, Praet M, Wils J, Van Cutsem E; European Organisation for Research and Treatment of Cancer Gastrointestinal Group; Arbeitsgemeinschaft Internistische Onkologie.
Caritasklinik St Theresia, Saarbrücken, Germany. m.lutz@caritasklinik.de

PURPOSE: This multicentric, randomized, two-stage phase II trial evaluated three simplified weekly infusional regimens of fluorouracil (FU) or FU plus folinic acid (FA) and cisplatin (Cis) with the aim to select a regimen for future phase III trials. PATIENTS AND METHODS: A total of 145 patients with advanced gastric cancer where randomly assigned to weekly FU 3,000 mg/m2/24 hours (HD-FU), FU 2,600 mg/m2/24 hours plus dl-FA 500 mg/m2 or l-FA 250 mg/m2 (HD-FU/FA), or FU 2000 mg/m2/24 hours plus FA plus biweekly Cis 50 mg/m2, each administered for 6 weeks with a 1-week rest. The primary end point was the response rate. RESULTS: Confirmed responses were observed in 6.1% (two of 33) of the eligible patients treated with HD-FU, in 25% (12 of 48, including one complete remission [CR]) with HD-FU/FA, and in 45.7% (21 of 46, including four CRs) with HD-FU/FA/Cis. The HD-FU arm was closed after stage 1 because the required minimum number of responses was not met. The median progression-free survival of all patients in the HD-FU, HD-FU/FA, and HD-FU/FA/Cis arm was 1.9, 4.0, and 6.1 months, respectively. The median overall survival was 7.1, 8.9, and 9.7 months, and the survival rate at 1 year was 24.3%, 30.3%, and 45.3%, respectively. Grade 4 toxicities were rare. The most relevant grade 3/4 toxicities were neutropenia in 1.9%, 5.4%, and 19.6%, and diarrhea in 2.7%, 1.9%, and 3.9% of the cycles in the HD-FU, HD-FU/FA, and HD-/FU/Cis arms, respectively. CONCLUSION: Weekly infusional FU/FA plus biweekly Cis is effective and safe in patients with gastric cancer.

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BMC Gastroenterol. 2007 Jun 8;7:18.
Stent versus gastrojejunostomy for the palliation of gastric outlet obstruction: a systematic review.
Jeurnink SM, van Eijck CH, Steyerberg EW, Kuipers EJ, Siersema PD.
Department of Gastroenterology and Hepatology, Erasmus MC/University Medical Center Rotterdam, The Netherlands. s.jeurnink@erasmusmc.nl <s.jeurnink@erasmusmc.nl>

BACKGROUND: Gastrojejunostomy (GJJ) is the most commonly used palliative treatment modality for malignant gastric outlet obstruction. Recently, stent placement has been introduced as an alternative treatment. We reviewed the available literature on stent placement and GJJ for gastric outlet obstruction, with regard to medical effects and costs. METHODS: A systematic review of the literature was performed by searching PubMed for the period January 1996 and January 2006. A total of 44 publications on GJJ and stents was identified and reported results on medical effects and costs were pooled and evaluated. Results from randomized and comparative studies were used for calculating odds ratios (OR) to compare differences between the two treatment modalities. RESULTS: In 2 randomized trials, stent placement was compared with GJJ (with 27 and 18 patients in each trial). In 6 comparative studies, stent placement was compared with GJJ. Thirty-six series evaluated either stent placement
or GJJ. A total of 1046 patients received a duodenal stent and 297 patients underwent GJJ. No differences between stent placement and gastrojejunostomy were found in technical success (96% vs. 100%), early and late major complications 7% vs. 6% and 18% vs. 17%, respectively) and persisting symptoms (8% vs. 9%). Initial clinical success was higher after stent placement (89% vs. 72%). Minor complications were less frequently seen after stent placement in the patient series (9% vs. 33%), however the pooled analysis showed no differences (OR: 0.75, p = 0.8). Recurrent obstructive symptoms were more common after stent placement (18% vs. 1%). Hospital stay was prolonged after GJJ compared to stent placement (13 days vs. 7 days). The mean survival was 105 days after stent placement and 164 days after GJJ. CONCLUSION: These results suggest that stent placement may be associated with more favorable results in patients with a relatively short life expectancy, while GJJ is preferable
in patients with a more prolonged prognosis. The paucity of evidence from large randomized trials may however have influenced the results and therefore a trial of sufficient size is needed to determine which palliative treatment modality is optimal in (sub)groups of patients with malignant gastric outlet obstruction.

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Expert Opin Ther Targets. 2007 Jun;11(6):757-69.
Targeting Helicobacter pylori in gastric carcinogenesis.
Lee DS, Moss SF.
Rhode Island Hospital/Brown University, Department Medicine, 593 Eddy St, Providence, RI 02903, USA.

Gastric infection by Helicobacter pylori is an important risk factor for the development of gastric cancer. Recent research has identified both bacterial and host factors related to increased gastric cancer risk, including virulence-associated genes located in the cytotoxin-associated gene pathogenicity island and the vacuolating toxin A exotoxin, as well as polymorphisms in key cytokines and cytokine receptors that mediate the host's gastric inflammatory response. Early randomized trials indicate that eradicating H. pylori with antibiotics may prevent gastric cancer, although the effects so far have been modest, and are probably confined to individuals who had not developed preneoplastic lesions at the time of eradication. Targeting H. pylori to prevent gastric cancer may be best achieved through vaccination, better understanding of the molecular pathogenesis of H. pylori-associated carcinogenesis and additional chemopreventive strategies.

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Oncology (Williston Park). 2007 Apr;21(5):579-86; discussion 587, 591-2.
Role of chemotherapy in the treatment of gastroesophageal cancers.
Hwang JJ.
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA. jh96@georgetown.edu

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.

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Arch Surg. 2007 Apr;142(4):387-93.
National outcomes after gastric resection for neoplasm.
Smith JK, McPhee JT, Hill JS, Whalen GF, Sullivan ME, Litwin DE, Anderson FA, Tseng JF.
Department of Surgery, University of Massachusetts Medical School, UMass Memorial Medical Center, Worchester, MA 01605, USA.

HYPOTHESIS: That factors affecting outcomes of surgical resection in the treatment of gastric cancer can be identified using a large US database. DESIGN: Retrospective observational study. SETTING: The Nationwide Inpatient Sample from January 1, 1998, through December 31, 2003. PATIENTS: We included 13 354 patient discharges (approximately 66 096 nationally by weighted analysis) who underwent gastric resection for neoplasm. MAIN OUTCOME MEASURE: In-hospital mortality. Univariate analyses were performed by means of chi(2) tests. A multivariate logistic regression was performed to determine which variables were independently predictive of in-hospital mortality. RESULTS: During the study period, 50 738 patients (approximately 250 420 nationally) were discharged with the diagnosis of gastric neoplasm. Of those, 13 354 (26.3%) underwent gastric resection during their hospitalization. In-hospital mortality for patients undergoing surgery was 6.0%, without significant change from 1998 through 2003. Factors predictive of significantly increased in-hospital mortality included low annual hospital surgical volume (lowest [<or= 4 gastrectomies per year] vs highest [>or= 11 gastrectomies per year], 6.8% vs 4.9%; adjusted odds ratio [OR], 1.5; 95% confidence interval [CI], 1.2-1.8]), older patient age (50-69 vs <50 years, 4.0% vs 2.1%; adjusted OR, 1.5; 95% CI, 1.1-2.2) (>or =70 vs <50 years, 8.6% vs 2.1%; adjusted OR, 2.9; 95% CI, 2.0-4.3), male sex (male vs female, 6.7% vs 5.0%; adjusted OR, 1.3; 95% CI, 1.1-1.5), and procedure type (total gastrectomy vs all other resections, 8.0% vs 5.3%; adjusted OR, 1.4; 95% CI, 1.2-1.7). CONCLUSIONS: Higher annual surgical volume is predictive of lower in-hospital mortality for patients undergoing gastric resection for neoplasm. Other factors significantly associated with superior outcomes after gastric resection included diagnosis type, procedure type, younger age, female sex, and fewer comorbid conditions.

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J Natl Cancer Inst. 2007 Apr 18;99(8):601-7. Comment in: J Natl Cancer Inst. 2007 Apr 18;99(8):580-2.
Adjuvant treatment of high-risk, radically resected gastric cancer patients with 5-fluorouracil, leucovorin, cisplatin, and epidoxorubicin in a randomized controlled trial.
Cascinu S, Labianca R, Barone C, Santoro A, Carnaghi C, Cassano A, Beretta GD, Catalano V, Bertetto O, Barni S, Frontini L, Aitini E, Rota S, Torri V, Floriani I; Italian Group for the Study of Digestive Tract Cancer; Pozzo C, Rimassa L, Mosconi S, Giordani P, Ardizzoia A, Foa P, Rabbi C, Chiara S, Gasparini G, Nardi M, Mansutti M, Arnoldi E, Piazza E, Cortesi E, Pucci F, Silva RR, Sobrero A, Ravaioli A.
Universita' Politecnica delle Marche, Via Conca 60020 Ancona, Italy. cascinu@yahoo.com

BACKGROUND: Promising findings obtained using a weekly regimen of 5-fluorouracil (5-FU), epidoxorubicin, leucovorin (LV), and cisplatin (PELFw) to treat locally advanced and metastatic gastric cancer prompted the Italian Group for the Study of Digestive Tract Cancer (GISCAD) to investigate the efficacy of this regimen as adjuvant treatment for high-risk radically resected gastric cancer patients. METHODS: From January 1998 to January 2003, 400 gastric cancer patients at high risk for recurrence including patients with serosal invasion (stage pT3 N0) and/or lymph node metastasis (stage pT2 or pT3 N1, N2, or N3), were enrolled in a trial of adjuvant chemotherapies; 201 patients were randomly assigned to receive the PELFw regimen, consisting of eight weekly administrations of cisplatin (40 mg/m2), LV (250 mg/m2), epidoxorubicin (35 mg/m2), 5-FU (500 mg/m2), and glutathione (1.5 g/m2) with the support of filgrastim, and 196 patients were assigned to a regimen consisting of six monthly administrations of a 5-day course of 5-FU (375 mg/m2 daily) and LV (20 mg/m2 daily, 5-FU/LV). Disease-free and overall survival were estimated and compared between arms using hazard ratios (HRs) and Kaplan-Meier estimates. All statistical tests were two-sided. RESULTS: The 5-year survival rates were 52% in the PELFw arm and 50% in the 5-FU/LV arm. Compared with the 5-FU/LV regimen, the PELFw regimen did not reduce the risk of death (HR = 0.95, 95% confidence interval [CI] = 0.70 to 1.29) or relapse (HR = 0.98, 95% CI = 0.75 to 1.29). Less than 10% of patients in either arm experienced a grade 3 or 4 toxic episode. Neutropenia (occurring more often in the PELFw arm) and diarrhea and mucositis (more prevalent in the 5-FU/LV arm) were the most common serious side effects. Nevertheless, only 19 patients (9.4%) completed the treatment in the PELFw arm and 85 (43%) patients completed the treatment in the 5-FU/LV arm. CONCLUSIONS: Our study found no benefit from an intensive weekly chemotherapy in gastric cancer. The extent of toxicity experienced by the patients in the adjuvant setting suggests that, in gastric cancer, chemotherapy may be more safely administered preoperatively.

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Expert Opin Pharmacother. 2007 Apr;8(6):797-808.
Chemotherapy for advanced gastric cancer: across the years for a standard of care.
Scartozzi M, Galizia E, Verdecchia L, Berardi R, Antognoli S, Chiorrini S, Cascinu S.
Universita Politecnica delle Marche, Department of Clinica di Oncologia Medica, Azienda Ospedaliera Ospedali Riuniti, Ancona, Italy.

Chemotherapy is of crucial importance in advanced gastric cancer patients, in order to obtain palliation of symptoms and improve survival. The most extensively studied drugs as single agents are 5-fluorouracil, cisplatin, doxorubicin, epirubicin, mitomycin C and etoposide. Newer chemotherapeutic agents include the taxanes (docetaxel and paclitaxel), oral fluoropyrimidines (capecitabine and S-1), oxaliplatin and irinotecan. Randomised trials comparing monotherapy with combination regimens have consistently shown increased response rates in favour of combination regimens, whereas only marginally improved survival rates were usually found. Several combination therapies have been developed and have been examined in Phase III trials. However, in most cases, they have failed to demonstrate a survival advantage over the reference arm. There is no internationally accepted standard of care, and uncertainty remains regarding the choice of the optimal chemotherapy regimen. The objective of this article is to review the present literature available on major Phase II - III clinical trials, in which patients suffering from advanced gastric cancer were treated with cytotoxic chemotherapy.

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ANZ J Surg. 2007 Apr;77(4):247-52.
A pilot study of preoperative and postoperative chemotherapy in patients with operable gastric cancer: Australasian Gastrointestinal Trials Group Study 9601.
Findlay M, Storey D, Gebski V, Hargreaves C, Cullingford G, Boyer M, Trotter J, Archer S, Davidson A, Johnston P, Yuen J, Dhillon H, Della-Fiorentina S, Richardson G, Truskett P, Goldstein D; AGITG.
Wellington Cancer Centre, Wellington Hospital, Wellington, New Zealand. mp.findlay@auckland.ac.nz

BACKGROUND: With poor cure rates in gastric cancer using surgery alone, the safety, efficacy and feasibility of preoperative and postoperative chemotherapy was investigated. METHODS: Patients with advanced but operable gastric or cardio-oesophageal adenocarcinoma were staged using endoscopy, computed tomography scan and laparoscopy. If considered potentially resectable, they received chemotherapy (epirubicin, cisplatin and 5-fluorouracil) for 9 weeks before and after surgery. RESULTS: Of 59 participants entered, two were found to have metastatic disease and were excluded from the analysis. Of the participants, 10 were women and 47 men; their median age was 58 years (range 27-83 years) and median performance status 0 (range 0-1). Two of the 57 participants commencing chemotherapy did not undergo surgery (one sudden death, one new liver metastases). Grade 3 and 4 preoperative and postoperative toxicity rates were, respectively, neutropenia 22 and 18%, emesis 12 and 14% and other non-haematological toxicity <10 and <10%. Of the 55 who underwent surgery, 40 had apparently curative resections (clear or positive microscopic margins), 2 died after surgery (anastomotic leak, sepsis) and 16 had postoperative complications. Of these, 27 participants commenced postoperative chemotherapy and 21 completed it. Median progression-free survival and overall survival were 19.6 and 22 months, respectively. CONCLUSION: Epirubicin, cisplatin and protracted venous infusion of 5-fluorouracil chemotherapy was well-tolerated in the preoperative setting and did not appear to increase complication rates of surgery for advanced and operable stomach cancer. These findings demonstrate the feasibility of this strategy in the Australasian clinical setting and are in keeping with the results of a recently reported randomized trial, which demonstrated a significant survival advantage using this chemotherapy regimen.

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Anticancer Res. 2007 Jan-Feb;27(1B):667-74.
Phase II study of regional chemotherapy using the hypoxic abdominal perfusion technique in advanced abdominal carcinoma. 5-FU pharmacokinetics, complications and outcome.
Pohlen U, Rieger H, Kunick-Pohlen S, Berger G, Buhr HJ.
Department of Surgery, University of Berlin, Charite Campus Benjamin Franklin, Berlin, Germany. SU1110@aol.com

The aim of this study was to verify the rationale of a hypoxic abdominal perfusion (HAP) technique for the perfusion of 5-FU, mitomycin C and cisplatin in patients with inoperable, recurrent abdominal cancer. PATIENTS AND METHODS: In a phase II study, 59 patients with various non-resectable abdominal tumours were treated with 102 perfusions by the HAP-technique. The HAP-technique was performed by using double-balloon arterial-venous catheters that selectively isolated the abdominal vascular section and perfusion was provided by an extracorporal pump for 20 min. Thirty-four patients with unresectable colorectal cancer, 11 with unresectable gastric cancer, eight with unresectable pancreatic cancer and six with cancer of the gall bladder were included. They were treated with a combination of 5-fluorouracil (5-FU 1 g/m(2)), mitomycin C (MMC, 10 mg/m(2)) plus cisplatin (50 mg/m(2)) infused into the isolated abdominal compartment. The cytostatic concentration of 5-FU was determined intrainterventionally within the systemic and regional compartment. Toxicity- and procedure-related complications were documented. Tumour responses were assessed by computer tomography. RESULTS: 5-FU concentration was 16.3-fold higher within the regional compared to the systemic compartment at its maximum, and the area under the curve (AUC) was 7.9 times larger. During the procedure two major complications were experienced (1x perforation of the A. iliaca, lx deep vein thrombosis), no deaths occurred during surgery or in the postoperative period. Minimal systemic and local toxicities were observed (WHO grade III-IV 1%, grade I-II 33%). No complete response but 22 partial responses were observed. Median survival was 15.5 months for colorectal cancer, 12. 5 months for gastric cancer, 12.7 months for pancreatic cancer and 7.8 months for gall bladder cancer. CONCLUSION: The hypoxic abdominal perfusion is a safe and effective palliative treatment for patients with unresectable advanced colorectal, gastric and pancreatic carcinoma. The HAP has not shown promising results for advanced gall bladder cancer. These encouraging clinical results require further evaluation.

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Gastric Cancer. 2007;10(1):39-44. Epub 2007 Feb 23.
Impact of age on postoperative outcomes in 1118 gastric cancer patients undergoing surgical treatment.
Orsenigo E, Tomajer V, Palo SD, Carlucci M, Vignali A, Tamburini A, Staudacher C.
Chirurgia gastroenterologica, Department of Surgery, University Vita-Salute, San Raffaele Scientific Institute, Via Olgettina, 60-20132, Milan, Italy.

BACKGROUND: The purpose of the study was to evaluate the impact of age on outcomes in gastric cancer surgery. METHODS: Patients on the hospital database who underwent gastric resection for gastric cancer during the period 1990-2005 (n = 1118) were divided into two groups: group A, patients 75 years or older (n = 249), and group B, those younger than 75 years (n = 869). RESULTS: Overall preoperative complications were diagnosed in 92 (37%) patients of group A, compared with 147 (17%) in group B (P = 0.002). Fifty-five percent of patients underwent resection with D2 or more lymph node dissection (37% [n = 93] in group A, and 60% [n = 521] in group B; P = 0.003). Postoperative overall morbidity was higher in the elderly group (29% in group A versus 23% in group B), but the difference between the two groups was not significant (P = NS). Overall postoperative surgical complications were recorded in 201 (18%) patients; 49 (20%) in the elderly cohort, compared with 147 (17%) in the younger group (P = NS). The postoperative mortality rate was 3% (n = 7) in the elderly group, compared with 3% (n = 26) in the younger cohort (P = NS). Multivariate Cox analysis showed that age was not an independent risk factor for postoperative morbidity and mortality. Overall 5-year survival was 47% in group A and 54% in group B (P = NS). CONCLUSION: Due to improved perioperative management, resection of gastric carcinoma is the treatment of choice in elderly patients. Although comorbidities were more frequent among the elderly patients, postoperative morbidity and mortality, even after extensive resections, was low. Survival rates were comparable to those in the younger patients.

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Surg Laparosc Endosc Percutan Tech. 2007 Feb;17(1):5-9.
Endoscopic stenting for malignant gastric outlet obstruction.
Stawowy M, Kruse A, Mortensen FV, Funch-Jensen P.
Department of Surgical Gastroenterology L, Aarhus University Hospital, Aarhus, Denmark.

BACKGROUND AND AIMS: Obstruction often gives rise to disabling symptoms in non curable malignant upper gastrointestinal disease. Surgical relief is associated with high morbidity and mortality. We report outcomes of 24 patients palliated with endoscopic inserted stents. PATIENTS STUDIED: Thirteen females and 11 males, median age 66 years (range 24 to 88) suffered from gastroduodenal obstruction because of non curable malignant disease. All patients had nausea, repeated vomiting, and weight loss. The obstruction was localized in the stomach (n=5), gastrojejunostomy (n=3), or the duodenum (n=16). Self-expanding metal stents were delivered endoscopically under fluoroscopic control. RESULTS: All patients got an improved quality of life and could eat at least semisolid food. All the patients were followed until they died. The median survival time after the procedure was 6.4 (range 0.5 to 23) months. In 1 patient stenting was complicated by perforation leading to death 2 weeks later. In another patient the stent migrated during the initial placement, but a secondary stent could be placed during the same procedure. Due to a long duodenal stenosis 2 patients got 2 stents under the primary procedure. During the follow-up period, 6 patients had supplementary gastroduodenal stents placed. Nine patients had biliary stents placed before the placement of the gastroduodenal stents, 2 after. CONCLUSIONS: Our data suggest that endoscopic stenting for disabling symptoms due to gastroduodenal obstruction from non curable malignant disease, gives good symptomatic improvement with only few complications.

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Am J Surg. 2006 Dec;192(6):837-42.
Comparison of laparoscopic and open gastrectomy for gastric cancer.
Varela JE, Hiyashi M, Nguyen T, Sabio A, Wilson SE, Nguyen NT.
Department of Surgery, University of California, Irvine Medical Center, Orange, CA 92868, USA.

BACKGROUND: The role of minimally invasive gastrectomy in the treatment of gastric cancer is not well defined. The aim of the current study was to compare the operative outcomes and adequacy of resection of laparoscopic gastrectomy compared to open gastrectomy for gastric cancer. METHODS: The clinical course of 15 consecutive patients who underwent minimally invasive gastrectomy or esophagogastrectomy for gastric cancer were compared with that of 21 patients who underwent open gastrectomy. Main outcome measures included operative time, blood loss, length of stay, morbidity, 30-day mortality, and adequacy of lymphadenectomy and resection margins. RESULTS: There was no conversion to laparotomy in the laparoscopic group. Intraoperative blood loss was significantly lower in the laparoscopic group (138 mL vs. 357 mL). There was no significant differences in the mean operative time (244 vs. 241 min.), transfusion rate (6% vs. 29%), median length of stay (6 vs. 7 days), morbidity (7% vs. 24%), or number of lymph nodes harvested (15 vs. 14 nodes) between the 2 groups. Resection margins were negative in all patients. There were no leaks and the 30-day mortality was 0 in both groups. Anastomotic strictures were higher in the laparoscopic patients. CONCLUSION: Laparoscopic gastrectomy is feasible and can be performed safely with adequate lymphadenectomy compared with open gastrectomy.

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Cancer. 2006 Dec 1;107(11):2576-80.
Outcome of gastric cancer patients after successful gastrectomy: influence of the type of recurrence and histology on survival.
Rohatgi PR, Yao JC, Hess K, Schnirer I, Rashid A, Mansfield PF, Pisters PW, Ajani JA.
Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.

BACKGROUND: The effect of the location of disease recurrence after curative (R0) gastrectomy on patient survival has not been elucidated. The authors hypothesized that the location of recurrence would have a significant influence on survival. METHODS: Medical records of all patients who received treatment for gastric cancer at The University of Texas M. D. Anderson Cancer Center between 1985 and 1998 were reviewed. Patients who underwent R0 resection for gastric cancer and subsequently developed localized (anastomotic) recurrence (LR), lymph node (regional) recurrence (NR), or distant metastases (DM) were analyzed for overall survival (OS). All study factors were entered into a Cox proportional hazards model to provide multivariate hazard ratios. The model was adjusted for the effects of primary site of recurrence, histologic grade, patient age, and location of the primary tumor. RESULTS: This retrospective analysis included 227 consecutive patients. The median survival of patients who developed NR (11 months) was similar to that of patients who developed LR (10 months), but both groups had significantly longer median survival compared with patients who developed DM (7 months; log-rank P = .03). Patients who had well differentiated or moderately differentiated tumors had a longer OS (11 months) than patients who had poorly differentiated tumors (8 months; log-rank P = .02). In this cohort, location of the primary cancer and age at recurrence had no significant impact on OS. CONCLUSIONS: The data from this study suggested that, among patients who undergo R0 gastrectomy for gastric cancer, LR and NR versus DM should be considered a valid stratification factor for randomized trials based on significant differences in survival. Determining whether this stratification should apply to histologic differentiation will require further investigation in a larger multicenter cohort. (c) 2006 American Cancer Society.

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J Clin Oncol. 2006 Nov 20;24(33):5201-6.
Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma.
Shah MA, Ramanathan RK, Ilson DH, Levnor A, D'Adamo D, O'Reilly E, Tse A, Trocola R, Schwartz L, Capanu M, Schwartz GK, Kelsen DP.
Memorial Sloan-Kettering Cancer Center, New York, NY, USA. shah1@mskcc.org

PURPOSE: Bevacizumab improves survival in several solid tumor malignancies when combined with chemotherapy. We evaluated the efficacy and safety of the addition of bevacizumab to chemotherapy in the treatment of gastric and gastroesophageal junction (GEJ) adenocarcinoma. PATIENTS AND METHODS: Forty-seven patients with metastatic or unresectable gastric/GEJ adenocarcinoma were treated with bevacizumab 15 mg/kg on day 1, irinotecan 65 mg/m2, and cisplatin 30 mg/m2 on days 1 and 8, every 21 days. The primary end point was to demonstrate a 50% improvement in time to progression over historical values. Secondary end points included safety, response, and survival. RESULTS: Patient characteristics were as follows: median age 59 years (range, 25 to 75); Karnofsky performance status 90% (70% to 100%); male:female, 34:13; and gastric/GEJ, 24:23. With a median follow-up of 12.2 months, median time to progression was 8.3 months (95% CI, 5.5 to 9.9 months). In 34 patients with measurable disease, the overall response rate was 65% (95% CI, 46% to 80%). Median survival was 12.3 months (95% CI, 11.3 to 17.2 months). We observed no increase in chemotherapy related toxicity. Possible bevacizumab-related toxicity included a 28% incidence of grade 3 hypertension, two patients with a gastric perforation and one patient with a near perforation (6%), and one patient with a myocardial infarction (2%). Grade 3 to 4 thromboembolic events occurred in 25% of patients. Although the primary tumor was unresected in 40 patients, we observed only one patient with a significant upper gastrointestinal bleed. CONCLUSION: Bevacizumab can be safely given with chemotherapy even with primary gastric and GEJ tumors in place. The response rate, time to disease progression (TTP), and overall survival are encouraging, with TTP improved over historical controls by 75%. Further development of bevacizumab in gastric and GEJ cancers is warranted.

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J Clin Oncol. 2006 Nov 1;24(31):4991-7.
Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group.
Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group.
University Hospital Gasthuisberg, Leuven, Belgium.

PURPOSE: In the randomized, multinational phase II/III trial (V325) of untreated advanced gastric cancer patients, the phase II part selected docetaxel, cisplatin, and fluorouracil (DCF) over docetaxel and cisplatin for comparison against cisplatin and fluorouracil (CF; reference regimen) in the phase III part. PATIENTS AND METHODS: Advanced gastric cancer patients were randomly assigned to docetaxel 75 mg/m2 and cisplatin 75 mg/m2 (day 1) plus fluorouracil 750 mg/m2/d (days 1 to 5) every 3 weeks or cisplatin 100 mg/m2 (day 1) plus fluorouracil 1,000 mg/m2/d (days 1 to 5) every 4 weeks. The primary end point was time-to-progression (TTP). RESULTS: In 445 randomly assigned and treated patients (DCF = 221; CF = 224), TTP was longer with DCF versus CF (32% risk reduction; log-rank P < .001). Overall survival was longer with DCF versus CF (23% risk reduction; log-rank P = .02). Two-year survival rate was 18% with DCF and 9% with CF. Overall response rate was higher with DCF (chi2 P = .01). Grade 3 to 4 treatment-related adverse events occurred in 69% (DCF) v 59% (CF) of patients. Frequent grade 3 to 4 toxicities for DCF v CF were: neutropenia (82% v 57%), stomatitis (21% v 27%), diarrhea (19% v 8%), lethargy (19% v 14%). Complicated neutropenia was more frequent with DCF than CF (29% v 12%). CONCLUSION: Adding docetaxel to CF significantly improved TTP, survival, and response rate in gastric cancer patients, but resulted in some increase in toxicity. Incorporation of docetaxel, as in DCF or with other active drug(s), is a new therapy option for patients with untreated advanced gastric cancer.

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Nat Clin Pract Gastroenterol Hepatol. 2006 Nov;3(11):622-32.
Mechanisms of disease: Helicobacter pylori-related gastric carcinogenesis--implications for chemoprevention.
Romano M, Ricci V, Zarrilli R.
Dipartimento di Internistica Clinica e Sperimentale A Lanzara e F Magrassi--Gastroenterologia e CIRANAD, Seconda Universita di Napoli, II Policlinico, Ed 3, Secondo piano, Via Pansini 5, 80131 Napoli, Italy. marco.romano@unina2.it

Gastric adenocarcinoma is the second most common cause of cancer-related mortality worldwide. Infection with Helicobacter pylori is the single most common cause of adenocarcinoma of the distal stomach. Cancer risk is believed to be related to differences among H. pylori strains and inflammatory responses governed by host genetics. In particular, specific interactions between host factors that modulate the response to the infection, and bacterial virulence factors that can directly cause tissue damage seem to have a major pathogenic role in the development of gastric cancer. In addition, environmental factors can modify key growth signaling pathways within the gastric mucosa, which leads to the alteration of epithelial cell growth. Preventive strategies represent the most promising means of decreasing cancer risk, and must be aimed at the control of H. pylori infection, improvement of environmental conditions, and the identification of subjects who are genetically predisposed to the development of cancer in response to H. pylori infection. Understanding the intracellular signaling pathways that are specifically affected by H. pylori and that promote phenotypic and genotypic changes that might ultimately progress to malignant transformation could enable physicians to focus eradication therapy appropriately and design interventions targeted at the molecular level to prevent the development of gastric cancer.

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J Clin Oncol. 2006 Oct 20;24(30):4922-7.
Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127.
Dragovich T, McCoy S, Fenoglio-Preiser CM, Wang J, Benedetti JK, Baker AF, Hackett CB, Urba SG, Zaner KS, Blanke CD, Abbruzzese JL.
University of Arizona Cancer Center, Tucson, AZ 85724, USA. tdragovich@azcc.arizona.edu

PURPOSE: A phase II trial of the oral epidermal growth factor receptor (EGFR) inhibitor erlotinib in patients with gastroesophageal adenocarcinomas stratified according to primary tumor location into two groups: gastroesophageal junction (GEJ)/cardia and distal gastric adenocarcinomas. PATIENTS AND METHODS: Patients with a histologically proven diagnosis of adenocarcinoma of the GEJ or stomach (ST) that was unresectable or metastatic; presence of measurable disease; no prior chemotherapy for advanced or metastatic cancer; Zubrod performance status (PS) of 0 to 1; and adequate renal, hepatic, and hematologic function were treated with erlotinib 150 mg/d orally. Patient characteristics were median age, GEJ-63 years, ST-64 years; sex, GEJ-84% male and 16% female, ST-60 male and 40 female; Zubrod PS, GEJ-25 had a PS of 0 and 18 had a PS 1, ST-13 had a PS of 0 and 12 had a PS of 1. RESULTS: Percentage of common toxicities were skin rash, 86% and 72%; fatigue, 51% and 44%; and AST/ALT elevation, 28% and 28%, respectively for GEJ and ST. There has been one confirmed complete response, three confirmed partial responses (PRs) and one unconfirmed PR for an overall response probability of 9% confirmed (95% CI, 3% to 22%), all occurring in GEJ stratum. No responses were observed in ST stratum. The median survival was 6.7 months in GEJ and 3.5 months in ST stratum. Neither intratumoral EGFR, transforming growth factor-alpha or phosphorylated Akt kinase expression nor plasma proteomic analyses were predictive of clinical outcome. No somatic mutations of the EGFR exons 18, 19, or 21 were detected and there was no gross amplification of EGFR by fluorescence in situ hybridization. CONCLUSION: Erlotinib is active in patients with GEJ adenocarcinomas, but appears inactive in gastric cancers. The molecular correlates examined were not predictive of the patient therapeutic response.

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Tumori. 2006 Sep-Oct;92(5):379-83.
Irinotecan, fluorouracil and folinic acid (FOLFIRI) as effective treatment combination for patients with advanced gastric cancer in poor clinical condition.
Beretta E, Di Bartolomeo M, Buzzoni R, Ferrario E, Mariani L, Gevorgyan A, Bajetta E.
Medical Oncology Unit 2, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

AIMS AND BACKGROUND: Irinotecan (CPT-11) has been tested as a single agent in several studies, and response rates of 18-23% have been reported in first-line gastric cancer therapy. In the present study we report the safety and efficacy results combining CPT-11 with 5-fluorouracil (5-FU) and folinic acid (FA). PATIENTS AND METHODS: Thirty consecutive patients with metastatic gastric cancer, considered in poor clinical condition, were treated with CPT-11 and 5-FU/FA according to the FOLFIRI regimen. All enrolled cases were evaluable for toxicity and drug activity. RESULTS: The main grade 3-4 toxicity (according to the NCI-CTC criteria) was neutropenia (16%, grade 4 in 1 patient); non-hematological grade 3 toxicity consisted mainly in vomiting and diarrhea reported in 1 patient. No treatment-related serious adverse events were observed. Response was obtained in 12 patients (40%), stable disease in 2 patients (7%), while progression was documented in 16 patients (53%). CONCLUSIONS: These results are very promising, and suggest that the combination of CPT-11 plus 5-FU/FA is active and well tolerated and can be considered as useful treatment in patients with metastatic gastric cancer in poor clinical condition.
 

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