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The impact of dose/time modification in irinotecan- and oxaliplatin-based chemotherapies on outcomes in metastatic colorectal cancer

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This study was designed to evaluate (1) the impact of relative dose intensity (RDI) on tumor response and survival outcomes and (2) the influence of dose reduction and schedule modification on outcomes in patients with metastatic colorectal cancer (mCRC).


Pooled datasets from two previous phase II trials of FOLFIRI (CCOG-0502; n = 36) and mFOLFOX6 (CCOG-0704; n = 30) in patients with mCRC were analyzed retrospectively. The RDIs of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). To assess the effects of dose reduction and schedule modification, the effects of dose index (DI) and time index (TI) on outcomes were evaluated.


The median RDIs of irinotecan in FOLFIRI and oxaliplatin in mFOLFOX6 were 80 and 79 %, respectively. Higher RDI of irinotecan in FOLFIRI was associated with significant improvements in RR (65 vs. 6 %, p < 0.01), DCR (100 vs. 59 %, p < 0.01), PFS (9.9 vs. 5.6 months, p < 0.01) and OS (26.7 vs. 12.9 months, p = 0.01) and was the only independent factor associated with PFS [hazard ratio (HR) 8.48, p < 0.01). Higher RDI of oxaliplatin in FOLFOX was significantly associated with DCR (65 vs. 6 %, p < 0.01), and higher TI of oxaliplatin was the only independent factor associated with PFS (HR 2.74, p = 0.04).


RDIs of irinotecan and oxaliplatin affected clinical outcomes. Dose reductions in irinotecan, as indicated by DI, and time delays in oxaliplatin, as indicated by TI, were the only independent prognostic factors predicting PFS in patients receiving FOLFIRI and FOLFOX6, respectively.

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  1. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343:905–914

    Article  PubMed  CAS  Google Scholar 

  2. Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, Bertheaut-Cvitkovic F, Larregain-Fournier D, Le Rol A, Walter S, Adam R, Misset JL, Lévi F (2000) Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136–147

    PubMed  CAS  Google Scholar 

  3. Grothey A, Sargent D, Goldberg RM, Schmoll HJ (2004) Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22:1209–1214

    Article  PubMed  CAS  Google Scholar 

  4. Link BK, Budd GT, Scott S, Oncology Practice Pattern Study Working Group (2001) Delivering adjuvant chemotherapy to women with early-stage breast carcinoma: current patterns of care. Cancer 92:1354–1367

    Article  PubMed  CAS  Google Scholar 

  5. Hryniuk WM (1988) The importance of dose intensity in the outcome of chemotherapy. Important Adv Oncol 121-141

  6. Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C (1995) Adjuvant cyclophosphamide, methotrexate and fluorouracil in node positive breast cancer. New Engl J Med 14:901–916

    Article  Google Scholar 

  7. Loibl S, Skacel T, Nekljudova V, Lück HJ, Schwenkglenks M, Brodowicz T, Zielinski C, von Minckwitz G (2011) Evaluating the impact of relative total dose intensity (RTDI) on patients’ short and long-term outcome in taxane- and anthracycline-based chemotherapy of metastatic breast cancer- a pooled analysis. BMC Cancer 11:131

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  8. Epelbaum R, Haim N, Ben-Shahar M, Ron Y, Cohen Y (1988) Dose-intensity analysis for CHOP chemotherapy in diffuse aggressive large cell lymphoma. Isr J Med Sci 24:533–538

    PubMed  CAS  Google Scholar 

  9. Kwak LW, Halpern J, Olshen RA, Horning SJ (1990) Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis. J Clin Oncol 8:963–977

    PubMed  CAS  Google Scholar 

  10. Luciani A, Bertuzzi C, Ascione G, Di Gennaro E, Bozzoni S, Zonato S, Ferrari D, Foa P (2009) Dose intensity correlate with survival in elderly patients treated with chemotherapy for advanced non-small cell lung cancer. L Cancer 66:94–96

    Article  CAS  Google Scholar 

  11. Repetto L, Pace M, Mammoliti S, Bruzzone M, Chiara S, Oliva C, Guido T, Conte PF, Campora E, Rubagotti A et al (1993) The impact of received dose intensity on the outcome of advanced ovarian cancer. Eur J Cancer 29:181–184

    Article  Google Scholar 

  12. Fauci JM, Whitworth JM, Schneider KE, Subramaniam A, Zhang B, Frederick PJ, Kilgore LC, Straughn JM Jr (2011) Prognostic significance of the relative dose intensity of chemotherapy in primary treatment of epithelial ovarian cancer. Gynecol Oncol 122:532–535

    Article  PubMed  Google Scholar 

  13. Hryniuk WM, Figueredo A, Goodyear M (1987) Applications of dose intensity to problems in chemotherapy of breast and colorectal cancer. Semin Oncol 14:3–11

    PubMed  CAS  Google Scholar 

  14. Cascinu S, Fedeli A, Luzi FS, Catalano G (1991) 5-Fluorouracil dose intensity increase in 5-fluorouracil and leucovorin combination: results of a phase II study. J Chemother 3:51–54

    PubMed  CAS  Google Scholar 

  15. Maindrault-Goebel F, de Gramont A, Louvet C, André T, Carola E, Gilles V, Lotz JP, Tournigand C, Mabro M, Molitor JL, Artru P, Izrael V, Krulik M (2000) Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-h 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Oncology multidisciplinary research group (GERCOR). Ann Oncol 11:1477–1483

    Article  PubMed  CAS  Google Scholar 

  16. Nakayama G, Kodera Y, Yokoyama H, Okuda N, Watanabe T, Tanaka C, Iwata N, Ohashi N, Koike M, Fujiwara M, Nakao A (2011) Modified FOLFOX6 with oxaliplatin stop-and-go strategy and oral S-1 maintenance therapy in advanced colorectal cancer: CCOG-0704 study. Int J Clin Oncol 16:506–511

    Article  PubMed  CAS  Google Scholar 

  17. Coldman AJ, Goldie JH (1987) Impact of dose-intense chemotherapy on the development of permanent drug resistance. Semin Oncol 14:29–33

    PubMed  CAS  Google Scholar 

  18. Norton L (1997) Evolving concepts in the systemic drug therapy of breast cancer. Semin Oncol 24:S10-3–S10-10

    Google Scholar 

  19. Raymond E, Lawrence R, Izbicka E, Faivre S, Von Hoff DD (1998) Activity of oxaliplatin against human tumor colony-forming units. Clin Cancer Res 4:1021–1029

    PubMed  CAS  Google Scholar 

  20. Yamashita K, Nagashima F, Fujita K, Yamamoto W, Endo H, Miya T, Narabayashi M, Kawara K, Akiyama Y, Ando Y, Ando M, Sasaki Y (2011) Phase I/II study of FOLFIRI in Japanese patients with advanced colorectal cancer. Jpn J Clin Oncol 41:204–209

    Article  PubMed  Google Scholar 

  21. Sunakawa Y, Ichikawa W, Fujita K, Nagashima F, Ishida H, Yamashita K, Mizuno K, Miwa K, Kawara K, Akiyama Y, Araki K, Yamamoto W, Miya T, Narabayashi M, Ando Y, Hirose T, Saji S, Sasaki Y (2011) UGT1A1*1/*28 and *1/*6 genotypes have no effects on the efficacy and toxicity of FOLFIRI in Japanese patients with advanced colorectal cancer. Cancer Chemother Pharmacol 68:279–284

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Goro Nakayama.

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Trial registration: These trials, CCOG-0502 Study (A multicenter, single-arm phase II clinical trial to evaluate the efficacy and toxicity of FOLFIRI in metastatic colorectal cancer patients with UGT1A1*28 wild-type gene) and CCOG-0704 Study (A multicenter, single-arm phase II clinical trial to evaluate the efficacy and safety of mFOLFOX6 with oxaliplatin stop-and-go strategy and oral S-1 maintenance therapy in advanced colorectal cancer), were conducted by Chube Clinical Oncology Group (CCOG). CCOG had not registered a trial at the time the current trials were designed (years 2005 and 2006), although we did begin to register all trials by the year 2008.

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Nakayama, G., Tanaka, C., Uehara, K. et al. The impact of dose/time modification in irinotecan- and oxaliplatin-based chemotherapies on outcomes in metastatic colorectal cancer. Cancer Chemother Pharmacol 73, 847–855 (2014).

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