Advertisement

Supportive Care in Cancer

, Volume 19, Issue 11, pp 1769–1777 | Cite as

The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: results of a randomized phase III clinical trial

  • Lisa A. Kottschade
  • Jeff A. Sloan
  • Miroslaw A. Mazurczak
  • David B. Johnson
  • Bronagh P. Murphy
  • Kendrith M. Rowland
  • DeAnne A. Smith
  • Alan R. Berg
  • Philip J. Stella
  • Charles L. Loprinzi
Original Article

Abstract

Background

Chemotherapy-induced peripheral neuropathy (CIPN) continues to be a substantial problem for many cancer patients. Pursuant to promising appearing pilot data, the current study evaluated the use of vitamin E for the prevention of CIPN.

Methods

A phase III, randomized, double-blind, placebo-controlled study was conducted in patients undergoing therapy with neurotoxic chemotherapy, utilizing twice daily dosing of vitamin E (400 mg)/placebo. The primary endpoint was the incidence of grade 2+ sensory neuropathy (SN) toxicity (CTCAE v 3.0) in each treatment arm, analyzed by chi-square testing. Planned sample size was 100 patients per arm to provide 80% power to detect a difference in incidence of grade 2+ SN toxicity from 25% in the placebo group to 10% in the vitamin E group.

Results

Two-hundred seven patients were enrolled between December 1, 2006 and December 14, 2007, producing 189 evaluable cases for analysis. Cytotoxic agents included taxanes (109), cisplatin (8), carboplatin (2), oxaliplatin (50), or combination (20). There was no difference in the incidence of grade 2+ SN between the two arms (34%—vitamin E, 29%—placebo; P = 0.43). There were no significant differences between treatment arms for time to onset of neuropathy (P = 0.58), for chemotherapy dose reductions due to neuropathy (P = 0.21), or for secondary endpoints derived from patient-reported neuropathy symptom assessments. The treatment was well tolerated overall.

Conclusions

Vitamin E did not appear to reduce the incidence of sensory neuropathy in the studied group of patients receiving neurotoxic chemotherapy.

Keywords

Chemotherapy-induced peripheral neuropathy Sensory neuropathy toxicity Vitamin E 

Notes

Acknowledgments

This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-35113, and 124477.

Conflict of interest

None.

References

  1. 1.
    Verstappen CC, Heimans JJ, Hoekman K et al (2003) Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management. Drugs 63:1549–1563PubMedCrossRefGoogle Scholar
  2. 2.
    Ocean AJ, Vahdat LT (2004) Chemotherapy-induced peripheral neuropathy: pathogenesis and emerging therapies. Support Care Cancer 12:619–625PubMedGoogle Scholar
  3. 3.
    Polomano RC, Bennett GJ (2001) Chemotherapy-evoked painful peripheral neuropathy. Pain Med 2:8–14PubMedCrossRefGoogle Scholar
  4. 4.
    Flatters SJ, Bennett GJ (2004) Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain 109:150–161PubMedCrossRefGoogle Scholar
  5. 5.
    Chaudhary UB, Haldas JR (2003) Long-term complications of chemotherapy for germ cell tumours. Drugs 63:1565–1577PubMedCrossRefGoogle Scholar
  6. 6.
    Hammack JE, Michalak JC, Loprinzi CL et al (2002) Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy. Pain 98:195–203PubMedCrossRefGoogle Scholar
  7. 7.
    Quasthoff S, Hartung HP (2002) Chemotherapy-induced peripheral neuropathy. J Neurol 249:9–17PubMedCrossRefGoogle Scholar
  8. 8.
    Argoff CE, Katz N, Backonja M (2004) Treatment of postherpetic neuralgia: a review of therapeutic options. J Pain Symptom Manage 28:396–411PubMedCrossRefGoogle Scholar
  9. 9.
    Jensen PG, Larson JR (2001) Management of painful diabetic neuropathy. Drugs Aging 18:737–749PubMedCrossRefGoogle Scholar
  10. 10.
    Ahmad M, Goucke CR (2002) Management strategies for the treatment of neuropathic pain in the elderly. Drugs Aging 19:929–945PubMedCrossRefGoogle Scholar
  11. 11.
    Raja SN, Haythornthwaite JA, Pappagallo M et al (2002) Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 59:1015–1021PubMedGoogle Scholar
  12. 12.
    Kautio A-L, Haanpaa M, Saarto T et al (2008) Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms. J Pain Symptom Manage 35:31–39PubMedCrossRefGoogle Scholar
  13. 13.
    Backonja M, Glanzman RL (2003) Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther 25:81–104PubMedCrossRefGoogle Scholar
  14. 14.
    Pappagallo M (2003) Newer antiepileptic drugs: possible uses in the treatment of neuropathic pain and migraine. Clin Ther 25:2506–2538PubMedCrossRefGoogle Scholar
  15. 15.
    Rao RD, Flynn PJ, Sloan JA et al (2008) The efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase III randomized, double blind, placebo-controlled trial, N01C3. Cancer 112(12):2802–2808PubMedCrossRefGoogle Scholar
  16. 16.
    Rao RD, Michalak JC, Sloan JA et al (2007) Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3). Cancer 110:2110–2118PubMedCrossRefGoogle Scholar
  17. 17.
    Moore DH, Donnelly J, McGuire WP et al (2003) Limited access trial using amifostine for protection against cisplatin- and three-hour paclitaxel-induced neurotoxicity: a phase II study of the Gynecologic Oncology Group. J Clin Oncol 21:4207–4213PubMedCrossRefGoogle Scholar
  18. 18.
    Openshaw H, Beamon K, Synold TW et al (2004) Neurophysiological study of peripheral neuropathy after high-dose Paclitaxel: lack of neuroprotective effect of amifostine. Clin Cancer Res 10:461–467PubMedCrossRefGoogle Scholar
  19. 19.
    Vahdat L, Papadopoulos K, Lange D et al (2001) Reduction of paclitaxel-induced peripheral neuropathy with glutamine. Clin Cancer Res 7:1192–1197PubMedGoogle Scholar
  20. 20.
    Stubblefield MD, Vahdat LT, Balmaceda CM et al (2005) Glutamine as a neuroprotective agent in high-dose paclitaxel-induced peripheral neuropathy: a clinical and electrophysiologic study. Clinical Oncology (Royal College of Radiologists) 17:271–276CrossRefGoogle Scholar
  21. 21.
    Wang WS, Lin JK, Lin TC et al (2007) Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients. Oncologist 12:312–319PubMedCrossRefGoogle Scholar
  22. 22.
    Cascinu S, Catalano V, Cordella L et al (2002) Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 20:3478–3483PubMedCrossRefGoogle Scholar
  23. 23.
    Cascinu S, Cordella L, Del Ferro E et al (1995) Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial. J Clin Oncol 13:26–32PubMedGoogle Scholar
  24. 24.
    Smyth JF, Bowman A, Perren T et al (1997) Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomised trial. Ann Oncol 8:569–573PubMedCrossRefGoogle Scholar
  25. 25.
    Weijl NI, Cleton FJ, Osanto S (1997) Free radicals and antioxidants in chemotherapy-induced toxicity. Cancer Treat Rev 23:209–240PubMedCrossRefGoogle Scholar
  26. 26.
    Bove L, Picardo M, Maresca V et al (2001) A pilot study on the relation between cisplatin neuropathy and vitamin E. J Exp Clin Cancer Res 20:277–280PubMedGoogle Scholar
  27. 27.
    Pace A, Savarese A, Picardo M et al (2003) Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. J Clin Oncol 21:927–931PubMedCrossRefGoogle Scholar
  28. 28.
    Argyriou AA, Chroni E, Koutras A et al (2005) Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial. Neurology 64:26–31PubMedCrossRefGoogle Scholar
  29. 29.
    Pace A, Carpano S, Galiè E et al (2007) Vitamin E in the neuroprotection of cisplatin induced peripheral neurotoxicity and ototoxicity. J Clin Oncol 25(18S):Abstract 9114Google Scholar
  30. 30.
    Argyriou AA, Chroni E, Koutras A et al (2006) Preventing paclitaxel-induced peripheral neuropathy: a phase II trial of vitamin E supplementation. J Pain Symptom Manage 32:237–244PubMedCrossRefGoogle Scholar
  31. 31.
    Therneau TM (1993) How many stratification factors are “too many” to use in a randomization plan? Control Clin Trials 14:98–108PubMedCrossRefGoogle Scholar
  32. 32.
    Sloan JA, Berk L, Roscoe J et al (2007) Integrating patient-reported outcomes into cancer symptom management clinical trials supported by the National Cancer Institute-sponsored clinical trials networks. J Clin Oncol 25:5070–5077PubMedCrossRefGoogle Scholar
  33. 33.
    Sloan JA, Dueck A (2004) Issues for statisticians in conducting analyses and translating results for quality of life end points in clinical trials. J Biopharm Stat 14:73–96PubMedCrossRefGoogle Scholar
  34. 34.
    Cohen J (1988) Statistical power analysis for the behavioral sciences. Lawrence Erlbaum Associates, HillsdaleGoogle Scholar
  35. 35.
    Argyriou AA, Chroni E, Koutras A et al (2006) A randomized controlled trial evaluating the efficacy and safety of vitamin E supplementation for protection against cisplatin-induced peripheral neuropathy: final results. Support Care Cancer 14:1134–1140PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Lisa A. Kottschade
    • 1
  • Jeff A. Sloan
    • 1
  • Miroslaw A. Mazurczak
    • 2
  • David B. Johnson
    • 3
  • Bronagh P. Murphy
    • 4
  • Kendrith M. Rowland
    • 5
  • DeAnne A. Smith
    • 1
  • Alan R. Berg
    • 6
  • Philip J. Stella
    • 7
  • Charles L. Loprinzi
    • 1
  1. 1.Mayo ClinicRochesterUSA
  2. 2.Siouxland Hematology-Oncology AssociatesSioux CityUSA
  3. 3.Wichita Community Clinical OncologyWichitaUSA
  4. 4.Metro-Minnesota Community Clinical Oncology ProgramSt. Louis ParkUSA
  5. 5.Carle Cancer Center CCOPUrbanaUSA
  6. 6.Missouri Valley Cancer ConsortiumOmahaUSA
  7. 7.Michigan Cancer Research ConsortiumAnn ArborUSA

Personalised recommendations