An Update on Biochemotherapy of Advanced Gastric and Gastroesophageal Adenocarcinoma

Gastric and gastroesophageal adenocarcinoma (GGA) are significant worldwide health problems. With most patients presenting with advanced disease, palliative chemotherapy plays a significant role in treatment. Results from recent phase III studies of cytotoxic agents in combination therapy, such as docetaxel, oxaliplatin, irinotecan, capecitabine, and S-1, have been encouraging and provide patients with additional therapeutic options. Although these forthcoming regimens have allowed for more flexible patient-tailored therapy, survival continues to be suboptimal. Although still in its infancy, targeted biotherapy, including inhibitors of the vascular endothelial and epidermal growth factor receptors, seems to be promising and its incorporation into the next generation of clinical trials will hopefully improve outcomes and help advance future treatments. This article reviews current active chemotherapeutic regimens and explores the role of novel targeted therapies in advanced GGA.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Correspondence: Tanios Bekaii-Saab, MD, Division of Hematology/Oncology, The Arthur G. James Comprehensive Cancer Center, The Ohio State University, B407 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210-1240. E-mail: Tanios.Bekaii-Saab@osumc.edu
  • 1.

    ParkinDBrayFFerlayJ. Global cancer statistics, 2002. CA Cancer J Clin2005;55:74108.

  • 2.

    PohlHWelchHG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst2005;97:142146.

    • Search Google Scholar
    • Export Citation
  • 3.

    National Cancer Institute. Surveillance Epidemiology and End Results: cancer of the stomach (on-line). Available athttp://seer.cancer.gov/statfacts/html/stomach.html. Accessed March 1 2008.

    • Search Google Scholar
    • Export Citation
  • 4.

    GlimeliusBEkströmKHoffmanK. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol1997;8:163168.

    • Search Google Scholar
    • Export Citation
  • 5.

    MacDonaldJSScheinPSWoolleyPV. 5-fluorouracil, doxorubicin, and mitomycin (FAM) combination chemotherapy for advanced gastric cancer. Ann Intern Med1980;93:533536.

    • Search Google Scholar
    • Export Citation
  • 6.

    WilsJAKleinHOWagenerDJ. Sequential high-dose methotrexate and fluorouracil combined with doxorubicin—a step ahead in the treatment of advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group. J Clin Oncol1991;9:827831.

    • Search Google Scholar
    • Export Citation
  • 7.

    VanhoeferURougierPWilkeH. Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol2000;18:26482657.

    • Search Google Scholar
    • Export Citation
  • 8.

    KimNKParkYSHeoDS. A phase III randomized study of 5-fluorouracil and cisplatin versus 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil alone in the treatment of advanced gastric cancer. Cancer1993;71:38133818.

    • Search Google Scholar
    • Export Citation
  • 9.

    CullinanSAMoertelCGWieandHS. Controlled evaluation of three drug combination regimens versus fluorouracil alone for the therapy of advanced gastric cancer. North Central Cancer Treatment Group. J Clin Oncol1994;12:412416.

    • Search Google Scholar
    • Export Citation
  • 10.

    OhtsuAShimadaYShiraoK. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer. J Clin Oncol2003;21:5459.

    • Search Google Scholar
    • Export Citation
  • 11.

    FindlayMCunninghamDNormanA. A phase II study in advanced gastro-esophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol1994;5:609616.

    • Search Google Scholar
    • Export Citation
  • 12.

    WebbACunninghamDScarffeJH. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol1997;15:261267.

    • Search Google Scholar
    • Export Citation
  • 13.

    WatersJSNormanACunninghamD. Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer1999;80:269272.

    • Search Google Scholar
    • Export Citation
  • 14.

    WagnerADGrotheWBehlS. Chemotherapy for advanced gastric cancer (review). Cochrane Database Syst Rev2005;CD004064.

  • 15.

    RidwelskiKGebauerTFahlkeJ. Combination chemotherapy with docetaxel and cisplatin for locally advanced and metastatic gastric cancer. Ann Oncol2001;12:4751.

    • Search Google Scholar
    • Export Citation
  • 16.

    RothADFazioNStuppR. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol2007;25:32173223.

    • Search Google Scholar
    • Export Citation
  • 17.

    AjaniJAFodorMBTjulandinSA. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol2005;23:56605667.

    • Search Google Scholar
    • Export Citation
  • 18.

    Van CutsemEMoiseyenkoVMTjulandinS. 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. J Clin Oncol2006;24:49914997.

    • Search Google Scholar
    • Export Citation
  • 19.

    LeeJKangWKKwonJM. Phase II trial of irinotecan plus oxaliplatin and 5-fluorouracil/leucovorin in patients with untreated metastatic gastric adenocarcinoma. Ann Oncol2007;18:8892.

    • Search Google Scholar
    • Export Citation
  • 20.

    BamiasAPapamichaelDSyrigosK. Phase II study of irinotecan and mitomycin C in 5-fluorouracil-pretreated patients with advanced colorectal and gastric cancer. J Chemother2003;15:275281.

    • Search Google Scholar
    • Export Citation
  • 21.

    BouchéORaoulJLBonnetainF. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study—FFCD 9803. J Clin Oncol2004;22:43194328.

    • Search Google Scholar
    • Export Citation
  • 22.

    DankMZaluskiJBaroneC. Randomized phase 3 trial of irinotecan (CPT-11) + 5FU/folinic acid (FA) vs CDDP + 5FU in 1st-line advanced gastric cancer patients [abstract]. J Clin Oncol2005;23(Suppl 1):Abstract 4003.

    • Search Google Scholar
    • Export Citation
  • 23.

    MiwaMUraMNishidaM. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer1998;34:12741281.

    • Search Google Scholar
    • Export Citation
  • 24.

    KangYKangWKShinDB. Randomized phase III trial of capecitabine/cisplatin (XP) vs. continuous infusion of 5-FU/cisplatin (FP) as first-line therapy in patients (pts) with advanced gastric cancer (AGC): efficacy and safety results [abstract]. J Clin Oncol2006;24(Suppl 1):Abstract LBA4018.

    • Search Google Scholar
    • Export Citation
  • 25.

    SumpterKHarper-WynneCCunninghamD. Report of two protocol planned interim analyses in a randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer receiving ECF. Br J Cancer2005;92:19761983.

    • Search Google Scholar
    • Export Citation
  • 26.

    CunninghamDStarlingNRaoS. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med2008;358:3646.

  • 27.

    ShirasakaTShimamatoYOhshimoH. Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs1996;7:548557.

    • Search Google Scholar
    • Export Citation
  • 28.

    KoizumiWNaraharaHHaraT. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol2008;9:215221.

    • Search Google Scholar
    • Export Citation
  • 29.

    BokuNYamamotoSShiraoK. Randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912) [abstract]. J Clin Oncol2007;25(Suppl 1):Abstract LBA4513.

    • Search Google Scholar
    • Export Citation
  • 30.

    AjaniJALeeFCSinghDA. Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol2006;24:663667.

    • Search Google Scholar
    • Export Citation
  • 31.

    CholletPSchöffskiPWeigang-KöhlerK. Phase II trial with S-1 in chemotherapy-naïve patients with gastric cancer. A trial performed by the EORTC Early Clinical Studies Group (ECSG). Eur J Cancer2003;39:12641270.

    • Search Google Scholar
    • Export Citation
  • 32.

    LenzHJLeeFCHallerDG. Extended safety and efficacy data on S-1 plus cisplatin in patients with untreated, advanced gastric carcinoma in a multicenter phase II study. Cancer2007;109:3340.

    • Search Google Scholar
    • Export Citation
  • 33.

    KarayiannakisAJSyrigosKNPolychronidisA. Circulating VEGF levels in the serum of gastric cancer patients: correlation with pathological variables, patient survival, and tumor surgery. Ann Surg2002;236:3742.

    • Search Google Scholar
    • Export Citation
  • 34.

    MaedaKChungYSOgawaS. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer1996;77:858863.

  • 35.

    ShahMARamanathanRKIlsonDH. Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol2006;24:52015206.

    • Search Google Scholar
    • Export Citation
  • 36.

    BangYKangYKangW. Sunitinib as second-line treatment for advanced gastric cancer: preliminary results from a phase II study [abstract]. J Clin Oncol2007;25(Suppl 1):Abstract 4603.

    • Search Google Scholar
    • Export Citation
  • 37.

    TokunagaAOndaMOkudaT. Clinical significance of epidermal growth factor (EGF), EGF receptor, and c-erbB-2 in human gastric cancer. Cancer1995;75:14181425.

    • Search Google Scholar
    • Export Citation
  • 38.

    PintoCDi FabioFSienaS. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol2007;18:510517.

    • Search Google Scholar
    • Export Citation
  • 39.

    HanSParkSLeeK. Phase II study and biomarker analysis of cetuximab in combination with oxaliplatin 5-fluorouracil and leucovorin as first-line treatment in patients with recurrent or metastatic gastric cancer [abstract]. Presented at the 2008 Gastrointestinal Cancers Symposium; January 25–27 2008; Orlando Florida. Abstract 20.

    • Search Google Scholar
    • Export Citation
  • 40.

    RojoFTaberneroJAlbanellJ. Pharmacodynamic studies of gefitinib in tumor biopsy specimens from patients with advanced gastric carcinoma. J Clin Oncol2006;24:43094316.

    • Search Google Scholar
    • Export Citation
  • 41.

    DoiTKoizumiWSienaS. Efficacy, tolerability and pharmacokinetics of gefitinib (ZD1839) in pretreated patients with metastatic gastric cancer [abstract]. J Clin Oncol2003;22(Suppl 1):Abstract 1036.

    • Search Google Scholar
    • Export Citation
  • 42.

    DragovichTMcCoySFenoglio-PreiserCM. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol2006;24:49224927.

    • Search Google Scholar
    • Export Citation
  • 43.

    MarsanWATytgatGNTen KateFJ. Differences and similarities of adenocarcinomas of the esophagus and the esophagogastric junction. J Surg Oncol2005;92:160168.

    • Search Google Scholar
    • Export Citation
  • 44.

    PeraMManterolaCVidalO. Epidemiology of esophageal adenocarcinoma. J Surg Oncol2005;92:151159.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 72 67 8
PDF Downloads 5 5 2
EPUB Downloads 0 0 0