Advertisement

Gastric Cancer

, Volume 21, Issue 6, pp 1050–1057 | Cite as

Salvage chemotherapy with the combination of oxaliplatin, leucovorin, and 5-fluorouracil in advanced gastric cancer refractory or intolerant to fluoropyrimidines, platinum, taxanes, and irinotecan

  • Chihiro Kondoh
  • Shigenori Kadowaki
  • Azusa Komori
  • Yukiya Narita
  • Hiroya Taniguchi
  • Takashi Ura
  • Masashi Ando
  • Kei Muro
Original Article
  • 434 Downloads

Abstract

Background

Although nivolumab showed survival benefit in patients with advanced gastric cancer (AGC) progressing after standard chemotherapy, there is a lack of data regarding oxaliplatin-based chemotherapy in this clinical setting.

Methods

We retrospectively evaluated the efficacy and safety of oxaliplatin with l-leucovorin and bolus/continuous infusion of 5-fluorouracil as salvage treatment in patients with AGC refractory or intolerant to fluoropyrimidines, cisplatin, taxanes, and irinotecan.

Results

Overall, 50 patients treated between December 2009 and December 2013 were included in this analysis. The overall response rate (ORR) was 21.2% among 33 patients with measurable disease. The median time to treatment failure (TTF) and overall survival (OS) were 2.4 and 4.2 months. In multivariate analysis, factors associated with OS included poor performance status [hazard ratio (HR) 3.20; 95% confidence interval (CI) 1.55–6.60], shorter time from the start of first-line therapy (HR 2.20; 95% CI 1.18–4.12), and higher neutrophil/lymphocyte ratio value (HR 4.87; 95% CI 2.32–10.25). In patients (n = 35) with at most one risk factor, the ORR, median TTF, and OS were 26.1%, 3.6, and 6.7 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (30%), anemia (22%), febrile neutropenia (8%), and peripheral neuropathy (8%). Initial and subsequent dose reduction was performed in 18 (36%) and 23 (46%) patients. There was one treatment-related death caused by septic infection.

Conclusions

Salvage chemotherapy with the combination of oxaliplatin, leucovorin, and 5-fluorouracil has a potential activity and is tolerable for heavily treated AGC with appropriate dose modification and patient selection.

Keywords

Gastric cancer Oxaliplatin Salvage therapy Prognostic factor 

Notes

Acknowledgements

The authors would like to thank Enago (www.enago.jp) for the English language review.

Compliance with ethical standards

Conflict of interest

None of the authors have financial or personal conflicts of interest to disclose.

Human rights statement and informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or a substitute for it was obtained from all patients for being included in the study.

References

  1. 1.
    Glimelius B, Ekstrom K, Hoffman K, Graf W, Sjoden PO, Haglund U, et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol. 1997;8:163–8.CrossRefGoogle Scholar
  2. 2.
    Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA, Rausch M. Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer. 1993;72:37–41.CrossRefGoogle Scholar
  3. 3.
    Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, 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;24:4991–7.CrossRefGoogle Scholar
  4. 4.
    Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36–46.CrossRefGoogle Scholar
  5. 5.
    Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009;20:666–73.CrossRefGoogle Scholar
  6. 6.
    Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008;9:215–21.CrossRefGoogle Scholar
  7. 7.
    Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008;26:1435–42.CrossRefGoogle Scholar
  8. 8.
    Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, et al. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naive patients with advanced gastric cancer. Ann Oncol. 2015;26:141–8.CrossRefGoogle Scholar
  9. 9.
    Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31–9.CrossRefGoogle Scholar
  10. 10.
    Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014;15:78–86.CrossRefGoogle Scholar
  11. 11.
    Kang JH, Lee SI, Lim do H, Park KW, Oh SY, Kwon HC, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012;30:1513–8.CrossRefGoogle Scholar
  12. 12.
    Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer–a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011;47:2306–14.CrossRefGoogle Scholar
  13. 13.
    Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224–35.CrossRefGoogle Scholar
  14. 14.
    Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 2016;34:1448–54.CrossRefGoogle Scholar
  15. 15.
    Kang Y-H, Satoh T, Ryu M-H, Chao Y, Kato K, Chung H-C, et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-blinded, randomized, phase III trial. J Clin Oncol. 2017;35:4s. (suppl; abstract 2).CrossRefGoogle Scholar
  16. 16.
    Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, et al. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013;31:4438–44.CrossRefGoogle Scholar
  17. 17.
    Kawakami T, Machida N, Yasui H, Kawahira M, Kawai S, Kito Y, et al. Efficacy and safety of irinotecan monotherapy as third-line treatment for advanced gastric cancer. Cancer Chemother Pharmacol. 2016;78:809–14.CrossRefGoogle Scholar
  18. 18.
    Nishimura T, Iwasa S, Nagashima K, Okita N, Takashima A, Honma Y, et al. Irinotecan monotherapy as third-line treatment for advanced gastric cancer refractory to fluoropyrimidines, platinum, and taxanes. Gastric Cancer. 2017;20:655–62.CrossRefGoogle Scholar
  19. 19.
    Makiyama A, Arimizu K, Hirano G, Makiyama C, Matsushita Y, Shirakawa T, et al. Irinotecan monotherapy as third-line or later treatment in advanced gastric cancer. Gastric Cancer. 2017.  https://doi.org/10.1007/s10120-017-0759-9.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Pendyala L, Creaven PJ. In vitro cytotoxicity, protein binding, red blood cell partitioning, and biotransformation of oxaliplatin. Cancer Res. 1993;53:5970–6.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Fracasso PM, Blessing JA, Morgan MA, Sood AK, Hoffman JS. Phase II study of oxaliplatin in platinum-resistant and refractory ovarian cancer: a gynecologic group study. J Clin Oncol. 2003;21:2856–9.CrossRefGoogle Scholar
  22. 22.
    Chollet P, Bensmaine MA, Brienza S, Deloche C, Cure H, Caillet H, et al. Single agent activity of oxaliplatin in heavily pretreated advanced epithelial ovarian cancer. Ann Oncol. 1996;7:1065–70.CrossRefGoogle Scholar
  23. 23.
    Kim DY, Kim JH, Lee SH, Kim TY, Heo DS, Bang YJ, et al. Phase II study of oxaliplatin, 5-fluorouracil and leucovorin in previously platinum-treated patients with advanced gastric cancer. Ann Oncol. 2003;14:383–7.CrossRefGoogle Scholar
  24. 24.
    Suh SH, Kwon HC, Jo JH, Cho YR, Seo BG, Lee DM, et al. Oxaliplatin with biweekly low dose leucovorin and bolus and continuous infusion of 5-fluorouracil (modified FOLFOX 4) as a salvage therapy for patients with advanced gastric cancer. Cancer Res Treat. 2005;37:279–83.CrossRefGoogle Scholar
  25. 25.
    Jeong J, Jeung HC, Rha SY, Im CK, Shin SJ, Ahn JB, et al. Phase II study of combination chemotherapy of 5-fluorouracil, low-dose leucovorin, and oxaliplatin (FLOX regimen) in pretreated advanced gastric cancer. Ann Oncol. 2008;19:1135–40.CrossRefGoogle Scholar
  26. 26.
    Seo HY, Kim DS, Choi YS, Sung HJ, Park KH, Choi IK, et al. Treatment outcomes of oxaliplatin, 5-FU, and leucovorin as salvage therapy for patients with advanced or metastatic gastric cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2009;63:433–9.CrossRefGoogle Scholar
  27. 27.
    Kim YS, Hong J, Sym SJ, Park SH, Park J, Cho EK, et al. Oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX-4) combination chemotherapy as a salvage treatment in advanced gastric cancer. Cancer Res Treat. 2010;42:24–9.CrossRefGoogle Scholar
  28. 28.
    Tsuji K, Yasui H, Onozawa Y, Boku N, Doyama H, Fukutomi A, et al. Modified FOLFOX-6 therapy for heavily pretreated advanced gastric cancer refractory to fluorouracil, irinotecan, cisplatin and taxanes: a retrospective study. Jpn J Clin Oncol. 2012;42:686–90.CrossRefGoogle Scholar
  29. 29.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.CrossRefGoogle Scholar
  30. 30.
    Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3:32–5.CrossRefGoogle Scholar
  31. 31.
    Murahashi S, Takahari D, Wakatsuki T, Fukuda N, Ichimura T, Ogura M. A retrospective analysis of ramucirumab monotherapy in previously treated Japanese patients with advanced or metastatic gastric adenocarcinoma. Int J Clin Oncol. 2017.  https://doi.org/10.1007/s10147-017-1192-0.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kang EJ, Im SA, Oh DY, Han SW, Kim JS, Choi IS, et al. Irinotecan combined with 5-fluorouracil and leucovorin third-line chemotherapy after failure of fluoropyrimidine, platinum, and taxane in gastric cancer: treatment outcomes and a prognostic model to predict survival. Gastric Cancer. 2013;16:581–9.CrossRefGoogle Scholar
  33. 33.
    Crumley AB, McMillan DC, McKernan M, McDonald AC, Stuart RC. Evaluation of an inflammation-based prognostic score in patients with inoperable gastro-oesophageal cancer. Br J Cancer. 2006;94:637–41.CrossRefGoogle Scholar
  34. 34.
    Yamanaka T, Matsumoto S, Teramukai S, Ishiwata R, Nagai Y, Fukushima M. The baseline ratio of neutrophils to lymphocytes is associated with patient prognosis in advanced gastric cancer. Oncology. 2007;73:215–20.CrossRefGoogle Scholar
  35. 35.
    Lee S, Oh SY, Kim SH, Lee JH, Kim MC, Kim KH, et al. Prognostic significance of neutrophil lymphocyte ratio and platelet lymphocyte ratio in advanced gastric cancer patients treated with FOLFOX chemotherapy. BMC Cancer. 2013;13:350.CrossRefGoogle Scholar

Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2018

Authors and Affiliations

  • Chihiro Kondoh
    • 1
    • 2
  • Shigenori Kadowaki
    • 1
  • Azusa Komori
    • 1
  • Yukiya Narita
    • 1
  • Hiroya Taniguchi
    • 1
  • Takashi Ura
    • 1
  • Masashi Ando
    • 1
  • Kei Muro
    • 1
  1. 1.Department of Clinical OncologyAichi Cancer Center HospitalNagoyaJapan
  2. 2.Department of Medical OncologyToranomon HospitalTokyoJapan

Personalised recommendations