Skip to main content

Advertisement

SpringerLink
Log in

Carbamazepine for prevention of oxaliplatin-related neurotoxicity in patients with advanced colorectal cancer: Final results of a randomised, controlled, multicenter phase II study

  • PHASE II STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Background: Oxaliplatin-induced neurotoxicity is a growing, relevant clinical problem. In this study we evaluated the efficacy and safety of carbamazepine for prevention of oxaliplatin-associated neuropathy in patients with advanced colorectal cancer.

Methods: Chemotherapeutic treatment consisted of oxaliplatin 85 mg/m2 given biweekly and weekly folinic acid 500 mg/m2 followed by a 24-h infusion of 5-FU 2000 mg/m2 (FUFOX). One cycle consisted of six consecutive weeks of treatment followed by two weeks of rest (=Treatment B). For Treatment A carbamazepine was added in a dosage for targeted plasma levels of 4–6 mg/L.

Neurotoxicity was regularly assessed using a specific scale. Moreover, an evaluation of chronic sensory symptoms and a neurologic examination including tests for vibrational sense, strength and deep tendon reflexes were added creating a peripheral neuropathy (PNP) score.

Results: The prospectively defined adequate number of patients needed to provide power for the primary outcome could not be achieved. 19 patients were assigned to Treatment A and 17 to Treatment B. At baseline, the distribution of all clinicopathologic variables was comparable between the two groups. Overall response rates were 16% and 24% and overall survival 15.1 months and 17.4 months for Treatment A and Treatment B, respectively. Between Treatment A and Treatment B there were no major differences when considering worst neurotoxicity during the study period (p=0.46). Grade 3/4 neurotoxicity occured in 4 patients with Treatment A vs. 6 patients with Treatment B. There were no major differences between both groups in each category of the PNP score.

Conclusions: Based on the small number of patients and low statistical power of our study definite conclusions regarding efficacy and safety of carbamazepine for prevention of oxaliplatin-associated neuropathy in patients with advanced colorectal cancer cannot be drawn.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ (2005) Cancer statistics, 2005. CA Cancer J Clin 55:10–30

    Article  PubMed  Google Scholar 

  2. Meyerhardt JA, Mayer RJ (2005) Systemic therapy for colorectal cancer. N Engl J Med 352(5):476–487

    Article  PubMed  CAS  Google Scholar 

  3. 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) Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343–2351

    Google Scholar 

  4. Culy CR, Clemett D, Wiseman LR (2000) Oxaliplatin. A review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies. Drugs 60(4):895–924

    Article  PubMed  CAS  Google Scholar 

  5. Adelsberger H, Quasthoff S, Grosskreutz J, Lepier A, Eckel F, Lersch C (2000) The chemotherapeutic oxaliplatin alters voltage-gated Na(+) channel kinetics on rat sensory neurons. Eur J Pharmacol 406(1):25–32

    Article  PubMed  CAS  Google Scholar 

  6. Holmes J, Stanko J, Varchenko M, Ding H, Madden VJ, Bagnell CR, Wyrick SD, Chaney SG (1998) Comparative neurotoxicity of oxaliplatin, cisplatin, and ormaplatin in a Wistar rat model. Toxicol Sci 46(2):342–351

    Article  PubMed  CAS  Google Scholar 

  7. Luo FR, Wyrick SD, Chaney SG (1999) Comparative neurotoxicity of oxaliplatin, ormaplatin, and their biotransformation products utilizing a rat dorsal root ganglia in vitro explant culture model. Cancer Chemother Pharmacol 44(1):29–38

    Article  PubMed  CAS  Google Scholar 

  8. Grothey A (2005) Clinical management of oxaliplatin-associated neurotoxicity. Clin Colorectal Cancer 5 (Suppl 1):S38–S46

    Article  PubMed  CAS  Google Scholar 

  9. Eckel F, Schmelz R, Adelsberger H, Erdmann J, Quasthoff S, Lersch C (2002) [Prevention of oxaliplatin-induced neuropathy by carbamazepine. A pilot study] Dtsch Med Wochenschr 127(3):78–82

  10. Levi F, Misset JL, Brienza S et al (1992) A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid and oxaliplatin using an ambulatori multichannel programmable pump. High antitumor effectiveness against metastatic colorectal cancer. Cancer 69:893–900

    Article  PubMed  CAS  Google Scholar 

  11. Cascinu S, Catalano V, Cordella L, Labianca R, Giordani P, Baldelli AM, Beretta GD, Ubiali E, Catalano G (2002) Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 20(16):3478–3483

    Article  PubMed  CAS  Google Scholar 

  12. Wilson RH, Lehky T, Thomas RR, Quinn MG, Floeter MK, Grem JL (2002) Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol 20(7):1767–1774

    Article  PubMed  CAS  Google Scholar 

  13. Schmelz R, Lersch C (2002) Acute oxaliplatin-induced peripheral-nerve hyperexcitability. J Clin Oncol 20(16):3561–3562

    Article  PubMed  Google Scholar 

  14. Rougier P, Lepere C (2005) Second-line treatment of patients with metastatic colorectal cancer. Semin Oncol 32(6 Suppl 9):S48–S54

    Article  PubMed  CAS  Google Scholar 

  15. Penz M, Kornek GV, Raderer M, Ulrich-Pur H, Fiebiger W, Scheithauer W (2001) Subcutaneous administration of amifostine: a promising therapeutic option in patients with oxaliplatin-related peripheral sensitive neuropathy. Ann Oncol 12(3):421–422

    Article  PubMed  CAS  Google Scholar 

  16. Gedlicka C, Scheithauer W, Schull B, Kornek GV (2002) Effective treatment of oxaliplatin-induced cumulative polyneuropathy with alpha-lipoic acid. J Clin Oncol 20(15):3359–3361

    Article  PubMed  CAS  Google Scholar 

  17. Durand JP, Brezault C, Goldwasser F (2003) Protection against oxaliplatin acute neurosensory toxicity by venlafaxine. Anticancer Drugs 14(6):423–425

    Article  PubMed  CAS  Google Scholar 

  18. Gamelin L, Boisdron-Celle M, Delva R, Guerin-Meyer V, Ifrah N, Morel A, Gamelin E (2004) Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-Fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res 10(12 Pt 1):4055–4061

    Article  PubMed  CAS  Google Scholar 

  19. Lin PC, Lee MY, Wang WS, Yen CC, Chao TC, Hsiao LT, Yang MH, Chen PM, Lin KP, Chiou TJ (2006) N-acetylcysteine has neuroprotective effects against oxaliplatin-based adjuvant chemotherapy in colon cancer patients: preliminary data. Support Care Cancer 1:1–4

    CAS  Google Scholar 

  20. Susman E (2006) Xaliproden lessens oxaliplatin-mediated neuropathy. Lancet Oncol 7(4):288

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Computational assistance of Caterina Riehle, IMSE TU Munich, is gratefully acknowledged. We also thank Nadine Röthling for assistance with documentation. This study was supported by a grant from Sanofi-Aventis.

Author information

Authors and Affiliations

  1. Department of Internal Medicine II, Technical University of Munich, Munich, Germany

    Stefan von Delius, Florian Eckel, Martina Mayr, Konrad Stock, Johannes Erdmann, Renate Schmelz, Roland M. Schmid & Christian Lersch

  2. Institute of Medical Statistics and Epidemiology, Technical University of Munich, Munich, Germany

    Stefan Wagenpfeil

  3. Department of Internal Medicine I, University of Regensburg, Regensburg, Germany

    Frank Kullmann & Florian Obermeier

  4. Department of Neurology, Karl Franzens University, Graz, Austria

    Stefan Quasthoff

  5. Institute of Neuroscience, Technical University of Munich, Munich, Germany

    Helmuth Adelsberger

  6. Munich Center for Clinical Studies, Technical University of Munich, Munich, Germany

    Rainer Bredenkamp

Authors
  1. Stefan von Delius
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Florian Eckel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefan Wagenpfeil
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martina Mayr
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Konrad Stock
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Frank Kullmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Florian Obermeier
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Johannes Erdmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Renate Schmelz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Stefan Quasthoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Helmuth Adelsberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Rainer Bredenkamp
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Roland M. Schmid
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Christian Lersch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefan von Delius.

Rights and permissions

Reprints and permissions

About this article

Cite this article

von Delius, S., Eckel, F., Wagenpfeil, S. et al. Carbamazepine for prevention of oxaliplatin-related neurotoxicity in patients with advanced colorectal cancer: Final results of a randomised, controlled, multicenter phase II study. Invest New Drugs 25, 173–180 (2007). https://doi.org/10.1007/s10637-006-9010-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-006-9010-y

Keywords

Search

Navigation