Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 5, pp 1215–1222 | Cite as

Phase II study of FOLFOX4 with “wait and go” strategy as first-line treatment for metastatic colorectal cancer

  • Mitsugu Kochi
  • Wataru Ichikawa
  • Eiji Meguro
  • Hiroyuki Shibata
  • Takuji Fukui
  • Michitaka Nagase
  • Yutaka Hoshino
  • Masahiro Takeuchi
  • Masashi Fujii
  • Toshifusa Nakajima
Original Article



To evaluate the efficacy and safety of FOLFOX4 using “wait and go” strategy in treating metastatic colorectal cancer.


The conventional FOLFOX4 was repeated every 2 weeks. We waited until the recovery of symptoms from persistent neurotoxicity within an added period of 2 weeks, before performing the next cycle (“wait and go” strategy).


We enrolled 58 patients, in whom a total of 481 cycles were administered (median 8 per patient; range 1–16). Toxicity was evaluated in 58 patients and response in 55. The major toxic effect was grade 3/4 neutropenia (33%). Painful paresthesia or persistent functional impairment was observed in 4 patients (7%). The response rate was 40% (95% confidence interval; 27.1–52.9%). The median progression-free survival time was 10.2 months, the 1-year survival rate was 89%, and the median overall survival time was 27.6 months.


These findings indicate that this “wait and go” strategy reduces the frequency of persistent neuropathy while maintaining efficacy against metastatic colorectal cancer.


FOLFOX Neuropathy Metastatic colorectal cancer Oxaliplatin “Wait and go” 



We are grateful to W. Koizumi, Y. Shimada, and S. Maetani for their kind advice and to M. Kurihara, H. Takahashi, and A. Kawano who constituted out the independent review committee. We also thank S. Koyama and Y. Kakehashi for their data managements. This study has been presented in part at the 7th Annual Meeting of the Japanese Society of Medical Oncology, Aichi, Japan, 2009. This study was supported by the Japan Clinical Cancer Research Organization (JACCRO). The authors are indebted to Prof. J. Patrick Barron of the Department of International Medical Communications of Tokyo Medical University for his review of this manuscript.

Conflict of interest

No authors have any conflict of interest.


  1. 1.
    Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A (2004) Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343–2351. doi: 10.1056/NEJMoa032709 PubMedCrossRefGoogle Scholar
  2. 2.
    Andre T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A (2009) Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27:3109–3116. doi: 10.1200/JCO.2008.20.6771 PubMedCrossRefGoogle Scholar
  3. 3.
    Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671. doi: 10.1200/JCO.2008.20.8397 PubMedCrossRefGoogle Scholar
  4. 4.
    Cassidy J, Bjarnason G, Hickish T, Topham C, Provencio G, Bodoky G, Landherr L, Koralewski P, Lopez-Vivanco G, Said G (2006) Randomized double blind (DB) placebo (Plcb) controlled phase III study assessing the efficacy of xaliproden (X) in reducing the cumulative peripheral sensory neuropathy (PSN) induced by oxaliplatin (Ox) and 5-FU/LV combination (FOLFOX4) in first line treatment of patients (pts) with metastatic colorectal cancer (MCRC). J Clin Oncol 24(Suppl):18S (Abstr 3507)Google Scholar
  5. 5.
    de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947PubMedGoogle Scholar
  6. 6.
    Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28:4697–4705. doi: 10.1200/JCO.2009.27.4860 PubMedCrossRefGoogle Scholar
  7. 7.
    Eng C (2009) Toxic effects and their management: daily clinical challenges in the treatment of colorectal cancer. Nat Rev Clin Oncol 6:207–218. doi: 10.1038/nrclinonc.2009.16 PubMedCrossRefGoogle Scholar
  8. 8.
    Gamelin L, Boisdron-Celle M, Morel A, Poirier AL, Berger V, Gamelin E, Tournigand C, de Gramont A (2008) Oxaliplatin-related neurotoxicity: interest of calcium-magnesium infusion and no impact on its efficacy. J Clin Oncol 26:1188–1189; author reply 1189–1190. doi: 10.1200/JCO.2007.15.3767 Google Scholar
  9. 9.
    Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30. doi: 10.1200/JCO.2004.09.046 PubMedCrossRefGoogle Scholar
  10. 10.
    Grothey A (2005) Clinical management of oxaliplatin-associated neurotoxicity. Clin Colorectal Cancer 5(Suppl 1):S38–S46PubMedCrossRefGoogle Scholar
  11. 11.
    Grothey A, Nikcevich D, Sloan J, Kugler J, Silberstein P, Dentchev T, Wender D, Novotny P, Chitaley U, Alberts S, Loprinzi C (2010) Intravenous calcium and magnesium For oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7J Clin Oncol published online on December 28, 2010. doi: 10.1200/JCO.2010.1231.5911
  12. 12.
    Hochster HS, Grothey A, Childs BH (2007) Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol 25:4028–4029. doi: 10.1200/JCO.2007.13.5251 PubMedCrossRefGoogle Scholar
  13. 13.
    Kuebler JP, Wieand HS, O’Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N (2007) Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 25:2198–2204. doi: 10.1200/JCO.2006.08.2974 PubMedCrossRefGoogle Scholar
  14. 14.
    Land SR, Kopec JA, Cecchini RS, Ganz PA, Wieand HS, Colangelo LH, Murphy K, Kuebler JP, Seay TE, Needles BM, Bearden JD III, Colman LK, Lanier KS, Pajon ER Jr, Cella D, Smith RE, O’Connell MJ, Costantino JP, Wolmark N (2007) Neurotoxicity from oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: NSABP C-07. J Clin Oncol 25:2205–2211. doi: 10.1200/JCO.2006.08.6652 PubMedCrossRefGoogle Scholar
  15. 15.
    Leonard GD, Wright MA, Quinn MG, Fioravanti S, Harold N, Schuler B, Thomas RR, Grem JL (2005) Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer. BMC Cancer 5:116. doi: 10.1186/1471-2407-5-116 PubMedCrossRefGoogle Scholar
  16. 16.
    Levi F, Misset JL, Brienza S, Adam R, Metzger G, Itzakhi M, Caussanel JP, Kunstlinger F, Lecouturier S, Descorps-Declere A et al (1992) A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. High antitumor effectiveness against metastatic colorectal cancer. Cancer 69:893–900PubMedCrossRefGoogle Scholar
  17. 17.
    Levi FA, Zidani R, Vannetzel JM, Perpoint B, Focan C, Faggiuolo R, Chollet P, Garufi C, Itzhaki M, Dogliotti L et al (1994) Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. J Natl Cancer Inst 86:1608–1617PubMedCrossRefGoogle Scholar
  18. 18.
    Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, Hart LL, Gupta S, Garay CA, Burger BG, Le Bail N, Haller DG (2003) Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 21:2059–2069. doi: 10.1200/JCO.2003.11.126 PubMedCrossRefGoogle Scholar
  19. 19.
    Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019. doi: 10.1200/JCO.2007.14.9930 PubMedCrossRefGoogle Scholar
  20. 20.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  21. 21.
    Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22:229–237. doi: 10.1200/JCO.2004.05.113 PubMedCrossRefGoogle Scholar
  22. 22.
    Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Carola E, Etienne PL, Rivera F, Chirivella I, Perez-Staub N, Louvet C, Andre T, Tabah-Fisch I, de Gramont A (2006) OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer-a GERCOR study. J Clin Oncol 24:394–400. doi: 10.1200/JCO.2005.03.0106 PubMedCrossRefGoogle Scholar
  23. 23.
    Trotti A, Colevas AD, Setser A, Basch E (2007) Patient-reported outcomes and the evolution of adverse event reporting in oncology. J Clin Oncol 25:5121–5127. doi: 10.1200/JCO.2007.12.4784 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Mitsugu Kochi
    • 1
  • Wataru Ichikawa
    • 2
  • Eiji Meguro
    • 3
  • Hiroyuki Shibata
    • 4
  • Takuji Fukui
    • 5
  • Michitaka Nagase
    • 6
  • Yutaka Hoshino
    • 7
  • Masahiro Takeuchi
    • 8
  • Masashi Fujii
    • 1
  • Toshifusa Nakajima
    • 9
  1. 1.Department of Digestive SurgeryNihon University School of MedicineItabashi-kuJapan
  2. 2.Department of Clinical OncologyNational Defense Medical CollegeTokorozawaJapan
  3. 3.Department of SurgeryHakodate Goryokaku HospitalHakodateJapan
  4. 4.Department of Clinical OncologyInstitute of Development, Aging and Cancer, Tohoku UniversitySendaiJapan
  5. 5.Department of SurgeryMidori Municipal HospitalNagoyaJapan
  6. 6.Department of Clinical OncologyJichi Medical University School of MedicineShimotsukeJapan
  7. 7.Department of Organ Regenerative Surgery, Fukushima Medical UniversityFukushimaJapan
  8. 8.Division of BiostatisticsKitasato University School of Pharmaceutical SciencesMinato-kuJapan
  9. 9.Japan Clinical Cancer Research OrganizationKoto-kuJapan

Personalised recommendations