Journal of Gastroenterology

, Volume 43, Issue 4, pp 256–264 | Cite as

Chemotherapy for metastatic gastric cancer: past, present, and future

  • Atsushi Ohtsu
Review

Abstract

Despite the numerous efforts of randomized studies on advanced gastric cancer, no globally accepted standard regimen has yet been established. Two triplet regimens have already demonstrated significant survival prolongation in Western studies. However, the benefit seems to be marginal, and these regimens may be replaced by recently published newer generation regimens for which favorable survival is reported. At present, the combination of 5-fluorouracil (5-FU) and platinum analog is still the most widely accepted standard regimen worldwide: 5-FU can be replaced by S-1 or capecitabine, and cisplatin by oxaliplatin. In Japan, S-1 plus cisplatin is the most reasonable first-line standard, based on recent randomized studies. Some early clinical studies using molecular targeting agents have shown promising activity, particularly in combination with cytotoxic agents for gastric cancer. Several targeting agents such as trastuzumab, bevacizumab, and lapatinib are now under investigation in international randomized studies, including in Japan. These agents have shown a survival benefit in other tumor types. The next-generation targeting agents, including mammalian target of rapamycin inhibitor and a c-Met tyrosine kinase inhibitor, are also being evaluated in early clinical studies in association with biology research. Such agents can be advantageously used in gastric cancer studies, which, because of the ease with which tumor tissues can be obtained by endoscopy and the high incidence of gastric cancer in Japan, might advance the frontiers of biologic therapy. These efforts should result not only in further clinical advances but also in tailored medicine.

Key words

gastric cancer chemotherapy molecular targeting agent 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Inoue M, Tsugane S. Epidemiology of gastric cancer in Japan. Postgrad Med J 2005;81:419–424.PubMedCrossRefGoogle Scholar
  2. 2.
    Cullinan SA, Moertel CG, Wieand HS, O’Connel MJ, Poon MA, Krook JE, et al. Controlled evaluation of three drug combination regimens versus fluorouracil alone for the therapy of advanced gastric cancer. J Clin Oncol 1994;12:412–416.PubMedGoogle Scholar
  3. 3.
    Kim NK, Park YS, Heo DS, Suh C, Kim SY, Park KC, et al. 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. Cancer 1993;71:3813–3818.PubMedCrossRefGoogle Scholar
  4. 4.
    Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, et al. Randomized phase III trial of 5-fluorouracil alone versus 5-fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin C in patients with unresectable advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol 2003;21:54–59.PubMedCrossRefGoogle Scholar
  5. 5.
    Wils JA, Klein HO, Wagener DJ, Bleiberg H, Reis H, Korsten F, et al. 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 Oncol 1991;9:827–831.PubMedGoogle Scholar
  6. 6.
    Vanhoefer U, Rouger P, Wilke H, Ducreux MP, Lacave AJ, Van Cutsem E, et al. Final result 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 Cooperative Group. J Clin Oncol 2000;81:2648–2657.Google Scholar
  7. 7.
    Webb A, Cunningham D, Scarffe H, Harper P, Norman A, Joffe JK, et al. Randomized trial comparing epirubicin, cisplatin, and fluorouracil, versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 1997;15:261–267.PubMedGoogle Scholar
  8. 8.
    Van Cutsem E, Moiseyenko VM, Tjulandin SA, Majilis J, Constenla M, Boni C, et al. 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 Oncol 2006;24:4991–4997.PubMedCrossRefGoogle Scholar
  9. 9.
    Dank M, Zaluski J, Barone C, Valvere V, Peschel C, Wenczl M, et al. Randomized phase 3 trials of irinotecan (CPT-11) + 5FU/folinic acid (FA) vs CDDP + 5FU in 1st-line advanced gastric cancer patients. J Clin Oncol 2005;23:16S (abstr 4003).Google Scholar
  10. 10.
    Cunningham D, Starling N, Rao S, Ivelson T, Nicolson M, Coxon F, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Eng J Med 2008;358:36–46.CrossRefGoogle Scholar
  11. 11.
    Kang Y, Kang WK, Shin DB, Chen J, Xiong J, Wang J, et al. Randomized phase III trial of capecitabine/cisplatin (XP) vs. Continuous infusion of 5-FU/cisplatin (FP) as first-line therapy in patients with advanced gastric cancer (AGC). J Clin Oncol 2006;24:17S (abstr LBA4018).Google Scholar
  12. 12.
    Boku N, Yamamoto S, Shirao K, Doi T, Sawaki A, Koizumi W, et al. 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). J Clin Oncol 2007;25:18S (abstr LBA4513).Google Scholar
  13. 13.
    Narahara H, Koizumi W, Hara T, Takagane T, Akiya M, Takagi K, et al. Randomized phase III study of S-1 alone versus S-1 + cisplatin in the treatment for advanced gastric cancer (the SPIRITS trial) SPIRITS: S-1 plus cisplatin vs S-1 in RCT in the treatment for stomach cancer. J Clin Oncol 2007;25:18S (abstr 4514).Google Scholar
  14. 14.
    Ajani JA, Faust J, Ikeda K, Yao JC, Anbe H, Carr K, et al. Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma. J Clin Oncol 2005;23:6957–6965.PubMedCrossRefGoogle Scholar
  15. 15.
    Ajani JA, Lee FC, Singh DA, Haller DG, Lenz HJ, Benson AB, et al. Multi-center phase II study of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 2006;24:663–667.PubMedCrossRefGoogle Scholar
  16. 16.
    Kang YK, Lee J, Min Y, Lee K, Zang D, Ryoo B, et al. A randomized multi-center phase II trial of capecitabine (X) versus S-1 (S) as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer. J Clin Oncol 2007;25:18S (abstr 4546).Google Scholar
  17. 17.
    Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 2000;20:1S–13S.Google Scholar
  18. 18.
    Kitagawa Y, Ueda M, Ando N, Ozawa S, Shimizu N, Kitajima M. Further evidence for prognostic significance of epidermal growth factor receptor gene amplification in patients with esophageal squamous cell carcinoma. Clin Cancer Res 1996;2:909–914.PubMedGoogle Scholar
  19. 19.
    Garcia I, Vizoso F, Martin A, Sanz L, Adbel-Lah O, Raigoso P, et al. Clinical significance of epidermal growth factor receptor and HER2 receptor in respectable gastric cancer. Ann Surg Oncol 2003;10:234–241.PubMedCrossRefGoogle Scholar
  20. 20.
    Doi T, Koizumi W, Siena S, Cascinu S, Ohtsu A, Michael M, et al. Efficacy, tolerability and pharmacokinetics of gefitinib (ZD1839) in pretreated patients with metastatic gastric cancer. Proc Am Soc Clin Oncol 2003;22:abstr 1036.Google Scholar
  21. 21.
    Dragovich T, McCoy S, Fenoglio-Preiser C, Wang J, Benedetti JK, Baker AF, et al. SWOG 0127 phase II trial of erlotinib in GEJ and gastric adenocarcinoma. J Clin Oncol 2006;24:4922–4927.PubMedCrossRefGoogle Scholar
  22. 22.
    Doi T, Ohtsu A, Saijo N, Takiuchi H, Ohhashi Y, Weber D, et al. A phase I study of a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody EMD72000 (matuzumab) administered weekly in Japanese patients with advanced solid tumors; safety, PK and PD results of skin biopsies. J Clin Oncol 2005;23:16S (abstr 3077).Google Scholar
  23. 23.
    Pinto C, Di Fabio F, Siena S, Cascinu S, Rojas Llimpe FL, Ceccarelli C, et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol 2007;18:510–517.PubMedCrossRefGoogle Scholar
  24. 24.
    Lordick F, Lorenzen S, Hegewisch-Becker S, Folprecht G, Woll E, Decker T, et al. Cetuximab plus weekly oxaliplatin/5FU/FA (FUFOX) in 1st line metastatic gastric cancer. Final results from a multicenter phase II study of the AIO upper GI study group. J Clin Oncol 2007;25:18S (abstr 4526).Google Scholar
  25. 25.
    Rao S, Starling N, Benson M, Massey A, Wothersppoon A, Brown G, et al. Phase I study of the humanized epidermal growth factor receptor (EGFR) antibody EMD 72000 (matuzumab) in combination with ECX (epirubicin, cisplatin and capecitabine) as first line treatment for advanced oesophagogastric (OG) adenocarcinoma. J Clin Oncol 2005;23:16S (abstr 4028).Google Scholar
  26. 26.
    Yano T, Doi T, Ohtsu A, Boku N, Hashizume K, Nakanishi M, et al. Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Oncol Rep 2006;15:65–71.PubMedGoogle Scholar
  27. 27.
    Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowsky T, et al. Lapatinib plus capecitabine for HER-2 positive advanced breast cancer. N Eng J Med 2006;355:2733–2743.CrossRefGoogle Scholar
  28. 28.
    Iqbal S, Goldman B, Lenz HJ, Fenoglio-Preiser CM, Blanke CD. S0413: a phase II study of GW572016 (lapatinib) as first line therapy in patients (pts) with advanced or metastatic gastric cancer. J Clin Oncol 2007;25:18S (abstr 4621).Google Scholar
  29. 29.
    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669–676.PubMedCrossRefGoogle Scholar
  30. 30.
    Shah MA, Ramanathan RK, Ilson DH, Levnor A, D’Adamo D, O’Reilly E, et al. Multicenter phase II study of irinotecan, cisplatin and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 2006;24:5201–5206.PubMedCrossRefGoogle Scholar
  31. 31.
    Enzinger PC, Fidias P, Meyerhardt J, Stuart C, Fuchs M, Huberman M, et al. Phase II study of bevacizumab and docetaxel in metastatic esophageal and gastric cancer. 2006 ASCO Gastrointestinal Cancers Symposium, 2006 (abstr 68), held in Orlando, January, 2006.Google Scholar
  32. 32.
    Bang YJ, Kang Y, Kang W, Boku N, Chung H, Lanzalone S, et al. Sunitinib as second line treatment for advanced gastric cancer: preliminary results from a phase II study. J Clin Oncol 2007;25:18S (abstr 4603).Google Scholar
  33. 33.
    Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, et al. VEGF-trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002;99:11393–11398.PubMedCrossRefGoogle Scholar
  34. 34.
    Rojo F, Tabernero J, Albanell J, Van Cutsem E, Ohtsu A, Doi T, et al. Pharmacodynamic studies of gefitinib in tumor biopsy specimens from patients with advanced gastric carcinoma. J Clin Oncol 2006;24:4309–4316.PubMedCrossRefGoogle Scholar
  35. 35.
    Awada A, Cardoso F, Fontaine C, Dirix L, De Greve J, Sotiriou C, et al. The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: results of a phase I study with pharmacokinetics. Eur J Cancer 2008;44:84–91.PubMedCrossRefGoogle Scholar
  36. 36.
    Nakajima M, Sawada H, Yamada Y, Watanabe A, Tatsumi M, Yamashita J, et al. The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer 1999;85:1894–1902.PubMedGoogle Scholar
  37. 37.
    Sasaki N, Morisaki T, Hashizume K, Yao T, Tsuneyoshi M, Noshiro H, et al. Nuclear factor kappa B p65 (Rel A) transcription factor is constitutively activated in human gastric carcinoma tissue. Clin Cancer Res 2001;7:4136–4142.PubMedGoogle Scholar
  38. 38.
    Ocean AJ, Schnoll-Sussman F, Keresztes R, Chen X, Holloway S, Matthews N, et al. Phase II study of PS-341 (bortezomib) with or without irinotecan in patients (pts) with advanced gastric adenocarcinomas (AGA). J Clin Oncol 2006;24:18S (abstr 14040).Google Scholar

Copyright information

© Springer Japan 2008

Authors and Affiliations

  • Atsushi Ohtsu
    • 1
  1. 1.Division of Gastrointestinal Oncology/Digestive EndoscopyNational Cancer Center Hospital EastKashiwaJapan

Personalised recommendations