Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 6, pp 1413–1419 | Cite as

Tumor growth modeling from clinical trials reveals synergistic anticancer effect of the capecitabine and docetaxel combination in metastatic breast cancer

  • N. Frances
  • L. Claret
  • R. Bruno
  • A. IliadisEmail author
Original Article



Most of the cancer chemotherapy treatments employ drugs in combination. For combination treatments, it is relevant to assess interaction between two or more anticancer agents used in clinics. Based on clinical data and using modeling techniques, the work analyzes the pharmacodynamic interaction between capecitabine and docetaxel used in combination in metastatic breast cancer.


We developed mathematical models to describe tumor growth inhibition profile under treatment based on Phase II and Phase III clinical data of capecitabine and docetaxel in metastatic breast cancer. Model parameters were estimated by population approach with NONMEM® on single-agent and combination data. Simulations were performed using MATLAB.


Capecitabine and docetaxel combination in metastatic breast cancer results in a synergistic effect as compared with the simple additive effects of single-agent treatments. Docetaxel is more efficient than capecitabine at the start of treatment but develops resistance faster. Modeling revealed no resistance of capecitabine for the combination data.


Modeling could be a powerful tool to design the most advantageous combination regimen for capecitabine and docetaxel in metastatic breast cancer in order to increase the time before regrowth and decrease the tumor size at regrowth.


Modeling Interaction Drug combination Clinical data 



The authors thank Ms. Franziska Schaedeli-Stark of Pharma Research and Early development, Translational Research Sciences, Modeling and Simulation, F. Hoffmann-La Roche, Basel, Switzerland for her helpful comments and suggestions.


  1. 1.
    Frei E (1972) Combination cancer therapy: presidential address. Cancer Res 32(12):2593–2607
  2. 2.
    Koch G, Walz A, Lahu G, Schropp J (2009) Modeling of tumor growth and anticancer effects of combination therapy. J Pharmacokinet Pharmacodyn 36(2):179–187CrossRef
  3. 3.
    Rocchetti M, Bene FD, Germani M, Fiorentini F, Poggesi I, Pesenti E, Magni P, Nicolao GD (2009) Testing additivity of anticancer agents in pre-clinical studies: a PK/PD modelling approach. Eur J Cancer 45(18):3336–3346CrossRef
  4. 4.
    Schicher N, Paulitschke V, Swoboda A, Kunstfeld R, Loewe R, Pilarski P, Pehamberger H, Hoeller C (2009) Erlotinib and bevacizumab have synergistic activity against melanoma. Clin Cancer Res 15(10):3495–3502CrossRef
  5. 5.
    Goteti K, Garner C, Utley L, Dai J, Ashwell S, Moustakas D, Gönen M, Schwartz G, Kern S, Zabludoff S, Brassil P (2010) Preclinical pharmacokinetic/pharmacodynamic models to predict synergistic effects of co-administered anti-cancer agents. Cancer Chemother Pharmacol 66(2):245–254CrossRef
  6. 6.
    Walko C, Lindley C (2005) Capecitabine: a review. Clinical Therapeutics 27(1):23–44CrossRef
  7. 7.
    Sawada N, Ishikawa T, Fukase Y, Nishida M, Yoshikubo T, Ishitsuka H (1998) Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 4(4):1013–1019
  8. 8.
    Blum J, Jones S, Buzdar A, Lorusso P, Kuter L, Vogel C, Osterwalder B, Burger H, Brown C, Griffin T (1999) Multicenter Phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17(2):485–493
  9. 9.
    O’Shaughnessy J, Miles D, Vukelja S, Moieseyenko V, Ayoub J, Cervantes G, Fumoleau P, Jones S, Lui W, Mauriac L, Twelves C, Hazel G, Verma S, Leonard R (2002) Superior survival with capecitabine docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J Clin Oncol 12(12):2812–2823CrossRef
  10. 10.
    Beal S, Sheiner L (1980) The NONMEM system. Am Stat 34(2):118–119CrossRef
  11. 11.
    Jacqmin P, Snoeck E, Schaick EV, Gieschke R, Pillai P, Steimer J, Girard P (2007) modelling response time profiles in the absence of drug concentrations: definition and performance, evaluation of the K–PD model. J Pharmacokinet Pharmacodyn 34(1):57–85CrossRef
  12. 12.
    Mager D, Wyska E, Jusko W (2003) Diversity of mechanism-based pharmacodynamic models. Drug Metab Dispos 31(5):510–518CrossRef
  13. 13.
    Frances N, Claret L, Stark FS, Bruno R, Iliadis A (2008) Modeling of longitudinal tumor size data in clinical oncology studies of drugs in combination. PAGE, Marseille
  14. 14.
    MATLAB (2008) High-performance numeric computation and visualization software. R2008.a edn. The Math Works, Natick MA
  15. 15.
    Pronk L, Vasey P, Sparreboom A, Reigner B, Planting A, Gordon R, Osterwalder B, Verweij J, Twelves C (2000) A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours. Br J Cancer 83(1):22–29CrossRef
  16. 16.
    DeJonge M, Huitema A, Schellens J, Rodenhuis S, Beijnen J (2005) Individualised cancer chemotherapy: strategies and performance of prospective studies on therapeutic drug monitoring with dose adaptation: a review. Clin Pharmacokinet 44(2):147–173CrossRef
  17. 17.
    Tham LS, Wang L, Soo RA, Lee SC, Lee HS, Yong WP, Goh BC, Holford NH (2008) A pharmacodynamic model for the time course of tumor shrinkage by gemcitabine + carboplatin in non-small cell lung cancer patients. Clin Cancer Res 14(13):4213–4218CrossRef
  18. 18.
    Claret L, Girard P, Zuideveld K, Jorga K, Fagerberg J, Bruno R (2006) A longitudinal model for tumor size measurements in clinical oncology studies. PAGE, Bruges, Belgium
  19. 19.
    Durie B, Jacobson J, Barlogie B, Crowley J (2004) Magnitude of response with myeloma frontline therapy does not predict outcome: importance of time to progression in southwest oncology group chemotherapy trials. J Clin Oncol 22(10):1857–1863CrossRef
  20. 20.
    Iliadis A, Barbolosi D (2000) Optimizing drug regimens in cancer chemotherapy by an efficacy-toxicity mathematical model. Comput Biomed Res 33(3):211–226CrossRef

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Pharmacokinetics, UMR-MD3, Faculty of PharmacyUniversity of MéditerranéeMarseille cedex 5France
  2. 2.Pharsight, A Certara™ CompanyMarseilleFrance

Personalised recommendations