Abstract
Purpose
To evaluate the efficacy and tolerability of systematic treatment of unresectable advanced or metastatic gastric cancer (A/MGC) based on EOF5 regimen (the combination of epirubicin, oxaliplatin and 5-day continuous infusion of 5-fluorouracil).
Patients and methods
Twenty-six patients (18 males, 8 females; age range, 35–72 years) with histologically confirmed metastatic (n = 23) or unresectable advanced (n = 3) gastric adenocarcinoma with (n = 6) or without previous chemotherapy (n = 20) were consented to receive EOF5 (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1, followed by continuous infusion of 5-fluorouracil 375–425 mg/m2 day−1 on day 1–5), and the treatment cycle was repeated every 3 weeks. Responses to treatment and toxicity were evaluated every 2 cycles.
Results
In the first-line treatment group of 20 patients, complete (CR) and partial (PR) remission were observed in two (10%) and six (30%) patients, respectively with an overall response rate of 40%). Eleven (55%) patients showed stable (SD) and one (5%) progressive disease (PD). One-year survival rate, time to progression (TTP) and median overall survival (OS) were 45%, 9.7 and 12.5 months, respectively. In the second-line treatment group of six patients, the numbers of CR, PR, SD and PD were 0, 1, 4 and 1, respectively. Symptomatic response rates were 88.2, 76.9, 89.5, and 88.9% for abdominal pain, distention, anorexia and weight loss. The mean Karnofsky performance status score was increased (P < 0.001) and maintained after two and four cycles treatment. The major adverse events were nausea/vomiting, oral mucositis, peripheral neuropathy, phlebitis, constipation and myelosuppression. CTC grade 3 or 4 hematologic toxicities included leucopenia (7.7%), neutropenia (15.4%), thrombocytopenia (19.2%), and anemia (3.8%). No treatment-related deaths were recorded.
Conclusions
EOF5 regimen shows good efficacy and an acceptable safety profile in A/MGC patients, and would be a suitable alternative regimen for this indication.
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References
Al-Batran SE, Atmaca A, Hegewisch-Becker S, Jaeger D, Hahnfeld S, Rummel MJ, Seipelt G, Rost A, Orth J, Knuth A, Jaeger E (2004) Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer. J Clin Oncol 22:658–663
André T, Bensmaine A, Louvet C, Francois E, Lucas V, Desseigne F, Beerblock K, Bouche O, Carola E, Merrouche Y, Morvan F, Dupont-Andre G, de Gramont A (1999) Multicenter phase II study of bimonthly high-dose leucovorin, 5-fluorouracil infusion and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin regimen (FOLFOX 3/4). J Clin Oncol 17:3560–3568
Bamias A, Hill ME, Cunningham D, Norman AR, Ahmed FY, Webb A, Watson M, Hill AS, Nicolson MC, O’Brien ME, Evans TC, Nicolson V (1996) Epirubicin, cisplatin, and protracted venous infusion of 5-fluorouracil for esophagogastric adenocarcinoma: response, toxicity, quality of life, and survival. Cancer 77:1978–1985
Bouché O, Ychou M, Burtin P, Bedenne L, Ducreux M, Lebreton G, Baulieux J, Nordlinger B, Martin C, Seitz JF, Tigaud JM, Echinard E, Stremsdoerfer N, Milan C, Rougier P (2005) Adjuvant chemotherapy with 5-fluorouracil and cisplatin compared with surgery alone for gastric cancer: 7-year results of the FFCD randomized phase III trial (8801). Ann Oncol 16:1488–1497
Cunningham D, Rao S, Starling N, Iveson T,Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR (2006) Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer: The REAL 2 trial. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I. vol 24, no. 18S (June 20 Supplement), LBA4017
De Vita F, Orditura M, Matano E, Bianco R, Carlomagno C, Infusino S, Damiano V, Simeone E, Diadema MR, Lieto E, Castellano P, Pepe S, De Placido S, Galizia G, Di Martino N, Ciardiello F, Catalano G, Bianco AR (2005) A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients. Br J Cancer 92:1644–1649
Extra JM, Espie M, Calvo F, Ferme C, Mignot L, Marty M (1990) Phase I study of oxaliplatin in patients with advanced cancer. Cancer Chemother Pharmacol 25:299–303
Findlay M, Cunningham D, Norman A, Mansi J, Nicolson M, Hickish T, Nicolson V, Nash A, Sacks N, Ford H (1994) A phase II study in advanced gastro-esophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol 5:609–616
Kim DY, Kim JH, Lee SH, Kim TY, Heo DS, Bang YJ, Kim NK (2003) Phase II study of oxaliplatin, 5-fluorouracil and leucovorin in previously platinum-treated patients with advanced gastric cancer. Ann Oncol 14:383–387
Kim YH, Shin SW, Kim BS, Kim JH, Kim JG, Mok YJ, Kim CS, Rhyu HS, Hyun JH, Kim JS (1999) Paditaxel, 5-fluorouracil and cisplatin combination chemotherapy for the treatment of advanced gastric carcinoma. Cancer 85:295–301
Lordick F, Lorenzen S, Stollfuss J, Vehling-Kaiser U, Kullmann F, Hentrich M, Zumschlinge R, Dietzfelbinger H, Thoedtmann J, Hennig M, Seroneit T, Bredenkamp R, Duyster J, Peschel C (2005) Phase II study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer. Br J Cancer 93:190–194
Louvet C, Andre T, Tigaud JM, Gamelin E, Douillard JY, Brunet R, Francois E, Jacob JH, Levoir D, Taamma A, Rougier P, Cvitkovic E, de Gramont A (2002) Phase II study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients. J Clin Oncol 20:4543–4548
MoiseyenkoVM, Ajani JA, Tjulandin SA, Majlis A, Constenla M, BoniC, Anelli A, Yver AJ, Van Cutsem E (2005) Final results of a randomized controlled phase III trial (TAX 325) comparing docetaxel (T) combined with cisplatin (C) and 5-fluorouracil (F) to CF in patients (pts) with metastatic gastric adenocarcinoma (MGC). Proc Am Soc Clin Oncol 24:abstr 4002
Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S (2003) Randomized phase III trial of fluorouracil alone v fluorouracil plus cisplatin v uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol 21:54–59
Parkin DM (1998) Epidemiology of cancer global patterns and trends. Toxicol Lett 102–103:227–234
Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108
Pendyala L, Creaven P (1993) In vitro cytotoxicity, protein binding, red blood cell partitioning, and biotransformation of oxaliplatin. Cancer Res 53:5970–5976
Raymond E, Buquet-Fagot C, Djelloul S, Mester J, Cvitkovic E, Allain P, Louvet C, Gespach C (1997) Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers. Anticancer Drugs 8:876–885
Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A (2002) Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 20:1996–2004
Roth AD, Maibach R, Martinelli G, Fazio N, Aapro MS, Pagani O, Morant R, Borner MM, Herrmann R, Honegger H, Cavalli F, Alberto P, Castiglione M, Goldhirsch A (2000) Docetaxel (Taxotere)-/cisplatin (TC): an effective drug combination in gastric carcinoma. Swiss Group for Clinical Cancer Research (SAKK), and the European Institute of Oncology (EIO). Ann Oncol 11:301–306
Rubin P, Williams JP, Okunieff P, Rosenblatt JD, Sitzmann JV (2001) Statement of the clinical oncologic problem. In: Rubin P, Williams JP (eds) Clinical oncology A multidisciplinary approach for physicians and students, 8th edn. Elsevier, New York, pp 1–32
Trotti A, Byhardt R, Stetz J, Gwede C, Corn B, Fu K, Gunderson L, McCormick B, Morrisintegral M, Rich T, Shipley W, Curran W (2000) Common toxicity criteria:version 2.0. An improved reference for grading the acute effects of cancer treatment: impact on radiotherapy. Int J Radiat Oncol Biol Phys 47:13–47
Vanhoefer U, Rougier P, Wilke H, Ducreux MP, Lacave AJ, Van Cutsem E, Planker M, Santos JG, Piedbois P, Paillot B, Bodenstein H, Schmoll HJ, Bleiberg H, Nordlinger B, Couvreur ML, Baron B, Wils JA (2000) Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin v etoposide, leucovorin, and fluorouracil v 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 Oncol 18:2648–2657
Waters JS, Norman A, Cunningham D, Scarffe JH, Webb A, Harper P, Joffe JK, Mackean M, Mansi J, Leahy M, Hill A, Oates J, Rao S, Nicolson M, Hickish T (1999) Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer 80:269–272
Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, Oates J, Nicolson M, Hickish T, O’Brien M, Iveson T, Watson M, Underhill C, Wardley A, Meehan M (1997) Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15:261–267
World Health Organization (1979) WHO handbook for reporting results of cancer treatment. Geneva, Switzerland, World Health Organization, WHO Offset Publication No. 48
Yang L (2006) Incidence and mortality of gastric cancer in China. World J Gastroenterol 12:17–20
Zaniboni A, Barni S, Labianca R, Marini G, Pancera G, Giaccon G, Piazza E, Signaroldi A, Legnani W, Luporini G (1995) Epirubicin, cisplatin, and continuous infusion 5-fluorouracil is an active and safe regimen for patients with advanced gastric cancer. An Italian Group for the Study of Digestive Tract Cancer (GISCAD) report. Cancer 76:1694–1699
Acknowledgments
We thank Professor Jin Li, Dr. Leiping Wang, Dr. Chunlei Zheng for their sincere help in conducting this trial. We also thank Ms. Xiaofeng Gu in the documentation of the study data and the secretarial assistance.
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Zhu, X., Leaw, J., Gu, W. et al. Phase II clinical trial of advanced and metastatic gastric cancer based on continuous infusion of 5-fluorouracil combined with epirubicin and oxaliplatin. J Cancer Res Clin Oncol 134, 929–936 (2008). https://doi.org/10.1007/s00432-008-0376-4
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DOI: https://doi.org/10.1007/s00432-008-0376-4