Advertisement

Investigational New Drugs

, Volume 25, Issue 2, pp 173–180 | Cite as

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

  • Stefan von DeliusEmail author
  • Florian Eckel
  • Stefan Wagenpfeil
  • Martina Mayr
  • Konrad Stock
  • Frank Kullmann
  • Florian Obermeier
  • Johannes Erdmann
  • Renate Schmelz
  • Stefan Quasthoff
  • Helmuth Adelsberger
  • Rainer Bredenkamp
  • Roland M. Schmid
  • Christian Lersch
PHASE II STUDIES

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.

Keywords

Oxaliplatin Neurotoxicity Carbamazepine Randomised clinical trial Colorectal cancer 

Notes

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.

References

  1. 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 55:10–30PubMedCrossRefGoogle Scholar
  2. 2.
    Meyerhardt JA, Mayer RJ (2005) Systemic therapy for colorectal cancer. N Engl J Med 352(5):476–487PubMedCrossRefGoogle Scholar
  3. 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 350:2343–2351Google Scholar
  4. 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):895–924PubMedCrossRefGoogle Scholar
  5. 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):25–32PubMedCrossRefGoogle Scholar
  6. 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):342–351PubMedCrossRefGoogle Scholar
  7. 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):29–38PubMedCrossRefGoogle Scholar
  8. 8.
    Grothey A (2005) Clinical management of oxaliplatin-associated neurotoxicity. Clin Colorectal Cancer 5 (Suppl 1):S38–S46PubMedCrossRefGoogle Scholar
  9. 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):78–82Google Scholar
  10. 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 69:893–900PubMedCrossRefGoogle Scholar
  11. 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):3478–3483PubMedCrossRefGoogle Scholar
  12. 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):1767–1774PubMedCrossRefGoogle Scholar
  13. 13.
    Schmelz R, Lersch C (2002) Acute oxaliplatin-induced peripheral-nerve hyperexcitability. J Clin Oncol 20(16):3561–3562PubMedCrossRefGoogle Scholar
  14. 14.
    Rougier P, Lepere C (2005) Second-line treatment of patients with metastatic colorectal cancer. Semin Oncol 32(6 Suppl 9):S48–S54PubMedCrossRefGoogle Scholar
  15. 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):421–422PubMedCrossRefGoogle Scholar
  16. 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):3359–3361PubMedCrossRefGoogle Scholar
  17. 17.
    Durand JP, Brezault C, Goldwasser F (2003) Protection against oxaliplatin acute neurosensory toxicity by venlafaxine. Anticancer Drugs 14(6):423–425PubMedCrossRefGoogle Scholar
  18. 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):4055–4061PubMedCrossRefGoogle Scholar
  19. 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 1:1–4Google Scholar
  20. 20.
    Susman E (2006) Xaliproden lessens oxaliplatin-mediated neuropathy. Lancet Oncol 7(4):288PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Stefan von Delius
    • 1
    Email author
  • Florian Eckel
    • 1
  • Stefan Wagenpfeil
    • 2
  • Martina Mayr
    • 1
  • Konrad Stock
    • 1
  • Frank Kullmann
    • 3
  • Florian Obermeier
    • 3
  • Johannes Erdmann
    • 1
  • Renate Schmelz
    • 1
  • Stefan Quasthoff
    • 4
  • Helmuth Adelsberger
    • 5
  • Rainer Bredenkamp
    • 6
  • Roland M. Schmid
    • 1
  • Christian Lersch
    • 1
  1. 1.Department of Internal Medicine IITechnical University of MunichMunichGermany
  2. 2.Institute of Medical Statistics and EpidemiologyTechnical University of MunichMunichGermany
  3. 3.Department of Internal Medicine IUniversity of RegensburgRegensburgGermany
  4. 4.Department of NeurologyKarl Franzens UniversityGrazAustria
  5. 5.Institute of NeuroscienceTechnical University of MunichMunichGermany
  6. 6.Munich Center for Clinical StudiesTechnical University of MunichMunichGermany

Personalised recommendations