Supportive Care in Cancer

, Volume 19, Issue 6, pp 833–841 | Cite as

A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA

  • Debra L. Barton
  • Edward J. Wos
  • Rui Qin
  • Bassam I. Mattar
  • Nathan Benjamin Green
  • Keith S. Lanier
  • James Dewitt BeardenIII
  • John W. Kugler
  • Kay L. Hoff
  • Pavan S. Reddy
  • Kendrith M. RowlandJr
  • Mike Riepl
  • Bradley Christensen
  • Charles L. Loprinzi
Original Article



Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic symptom that has no proven pharmacologic treatment. The purpose of this double-blind randomized placebo-controlled trial was to evaluate a novel compounded topical gel for this problem.


Patients with CIPN were randomized to baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to determine its effect on numbness, tingling, pain, and function. The primary endpoint was the baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks.


Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO arm over placebo in both the sensory (p = 0.053) and motor subscales (p = 0.021). The greatest improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity.


Topical treatment with BAK-PLO appears to somewhat improve symptoms of CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research is needed with increased doses to better clarify the clinical role of this treatment in CIPN.


CIPN Topical gel BAK-PLO 


  1. 1.
    Cavaletti G, Bogliun G, Marzorati L et al (1995) Peripheral neurotoxicity of Taxol in patients previously treated with cisplatin. Cancer 75:1141–1150PubMedCrossRefGoogle Scholar
  2. 2.
    Cavaletti G, Fabbrica D, Minoia C et al (1998) Carboplatin toxic effects on the peripheral nervous system of the rat. Ann Oncol 9:443–447PubMedCrossRefGoogle Scholar
  3. 3.
    Ocean JA, Vahdat LT (2004) Chemotherapy-induced peripheral neuropathy: pathogenesis and emerging therapies. Support Care Cancer 12:619–625PubMedGoogle Scholar
  4. 4.
    Pace A, Bove L, Aloe A et al (1997) Paclitaxel neurotoxicity: clinical and neurophysiological study of 23 patients. Ital J Neurol Sci 18:73–79PubMedCrossRefGoogle Scholar
  5. 5.
    Rowinsky EK, Chaudry V, Cornblath DR et al (1993) Neurotoxicity of taxol. J Natl Cancer Inst Monogr 15:107–115PubMedGoogle Scholar
  6. 6.
    Verstappen C, Heimans JJ, Hockman K et al (2003) Neurotoxic complications of chemotherapy in patients with cancer. Drugs 63(15):1549–1563PubMedCrossRefGoogle Scholar
  7. 7.
    Windebank AJ (1999) Chemotherapeutic neuropathy. Curr Opin Neurol 5:565–571CrossRefGoogle Scholar
  8. 8.
    Campana WM, Eskeland N, Calcutt NA et al (1998) Prosaptide prevents paclitaxel neurotoxicity. Neurotoxicology 19:237–244PubMedGoogle Scholar
  9. 9.
    Cliffer KD, Siuciak JA, Carson SR et al (1998) Physiological characterization of taxol-induced large-fiber sensory neuropathy in the rat. Ann Neurol 43:46–55PubMedCrossRefGoogle Scholar
  10. 10.
    Guastalla JP, Pujade-Lauraine E, Weber B (1998) Efficacy and safety of paclitaxel and carboplatin combination in patients with previously treated advanced ovarian carcinoma. Ann Oncol 9(9):37–43PubMedCrossRefGoogle Scholar
  11. 11.
    Polomano RC, Bennett GJ (2001) Chemotherapy-evoked peripheral neuropathy. Pain Medicine 2:8–14PubMedCrossRefGoogle Scholar
  12. 12.
    Pujude-Lauraine E, Guastalla JP, Weber B et al (1997) Efficacy and safety of the combination of paclitaxel/carboplatin in patients with previously treated advanced ovarian carcinoma: a multicenter French Groupe des investigateurs Nationauz pour l'etude des cancers ovariens phase II study. Semin Oncol 24:S15-30–S15-35Google Scholar
  13. 13.
    Quasthoff S, Hartung HP (2002) Chemotherapy induced peripheral neuropathy. J Neurol 249:9–17PubMedCrossRefGoogle Scholar
  14. 14.
    Envig AI, Wiernik PH, Wadler S et al (1998) Phase I study of paclitaxel (taxol) and granulocyte colony stimulating factor (g-csf) in patients with unresectable malignany. Invest New Drugs 16:29–36CrossRefGoogle Scholar
  15. 15.
    LoMonaco M, Milone M, Batocchi AP et al (1992) Cisplatin neuropathy: clinical course and neurophysiologic findings. J Neurol 239:199PubMedCrossRefGoogle Scholar
  16. 16.
    Nikcevich DA, Grothey A, Sloan JA, Kugler JW, Silberstein PT, Dentchev T, Wender DB, Novotny PJ, Windschitl HE, Loprinzi CL (2008) Effect of intravenous calcium and magnesium (IV CaMg) on oxaliplatin-induced sensory neurotoxicity (sNT) in adjuvant colon cancer: results of the phase III placebo-controlled, double-blind NCCTG trial N04C7. J Clin Oncol 26:(abstr 4009)Google Scholar
  17. 17.
    Ahmad M, Goucke CR (2002) Management strategies for the treatment of neuropathic pain in the elderly. Drugs Aging 19(12):929–945PubMedCrossRefGoogle Scholar
  18. 18.
    Argoff CE, Katz N, Backonja M (2004) Treatment of postherpetic neuralgia:a review of therapeutic options. J Pain Symptom Manage 28(4):396–411PubMedCrossRefGoogle Scholar
  19. 19.
    Jensen PG, Larson JR (2001) Management of painful diabetic neuropathy. Drugs Aging 18(10):737–749PubMedCrossRefGoogle Scholar
  20. 20.
    Hammack JE et al (2002) Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy. Pain 98(1–2):195–203PubMedCrossRefGoogle Scholar
  21. 21.
    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(9):2110–2118PubMedCrossRefGoogle Scholar
  22. 22.
    Rao RD, Flynn PJ, Sloan J et al (2008) Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double blind, placebo controlled NCCTG trial, N01C3. Cancer 112(21):2802–2808PubMedCrossRefGoogle Scholar
  23. 23.
    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(22):4207–4213PubMedCrossRefGoogle Scholar
  24. 24.
    Vahdat L, Papadopoulos K, Lange D et al (2001) Reduction of paclitaxel-induced peripheral neuropathy with glutamine. Clin Cancer Res 7:1192–1197PubMedGoogle Scholar
  25. 25.
    Baron (2006) Mechanisms of disease: neuropathic pain, a clinical perspective. Nat Clin Pract Neurol 2(2):95–106PubMedCrossRefGoogle Scholar
  26. 26.
    Jones M (2000) Chronic neuropathic pain: pharmacological interventions in the new millennium. Int J Pharm Comp 4(1):6–15Google Scholar
  27. 27.
    Sawynok J (2005) Topical analgesics in neuropathic pain. Curr Pharm Des 11(23):2995–3004PubMedCrossRefGoogle Scholar
  28. 28.
    Sawynok J (2003) Topical and peripherally acting analgesics. Pharmacol Rev 55:1–20PubMedCrossRefGoogle Scholar
  29. 29.
    Lynch ME, Clark AJ, Sawynok J (2003) A pilot study examining topical amitriptyline, ketamine and a combination of both in the treatment of neuropathic pain. Clin J Pain 19:323–328PubMedCrossRefGoogle Scholar
  30. 30.
    Lynch ME, Clark AJ, Sawynok J, Sullivan MJL (2005) Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes. Anesthesiology 103(1):140–146PubMedCrossRefGoogle Scholar
  31. 31.
    Lynch ME, Clark AJ, Sawynok J, Sullivan MJ (2005) Topical amitriptyline and ketamine in neurotopical amitriptyline and ketamine in neuropathic pain syndromes: an open label study. J Pain 6(10):644–649PubMedCrossRefGoogle Scholar
  32. 32.
    Lockhart E (2004) Topical combination of amitriptyline and ketamine for post herpetic neuralgia. J Pain 5:S182CrossRefGoogle Scholar
  33. 33.
    Everton D, Bhagwat D, Damask M (2007) An open-label pharmacokinetic study in humans of a 4% amitriptyline, 2% ketamine topical cream. J Pain 8(4 suppl 1):S48CrossRefGoogle Scholar
  34. 34.
    Ceschel G, Bergamante V, Maffei P et al (2005) Solubility and transdermal permeation properties of dehydroepiandrosterone cyclodextrin complex from hydrophilic and lipophilic vehicles. Drug Delivery 12:275–280PubMedCrossRefGoogle Scholar
  35. 35.
    Franek M, Vaculin S, Rokyta R (2004) GABAB receptor agonist baclofen has non-specific antinociceptive effect in the model of peripheral neuropathy in the rat. Pysiol Res 53:351–355Google Scholar
  36. 36.
    Smith GD, Harrison SM, Birch PJ et al (1994) Increased sensitivity to the antinociceptive activity of ± baclofen in an animal model of chronic neuropathic, but not chronic inflammatory hyperalgesia. Neuropharmacology 33:1103–1108PubMedCrossRefGoogle Scholar
  37. 37.
    Gammaitoni A, Gallagher RM, Welz-Bosna M (2000) Topical ketamine gel: possible role in treating neuropathic pain. Pain Medicine 1(1):97–100PubMedCrossRefGoogle Scholar
  38. 38.
    Pocock SJ, Simon R (1975) Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 31:103–115PubMedCrossRefGoogle Scholar
  39. 39.
    Postma TJ, Aaronson NK, Heimans JJ, EORTC Quality of Life Group et al (2005) The development of an EORTC quality of life questionnaire to assess chemotherapy-induced peripheral neuropathy: the QLQ-CIPN20. Eur J Cancer 41(8):1135–1139PubMedCrossRefGoogle Scholar
  40. 40.
    McNair DM, Loor M, Droppleman LF (2003) Profile of mood states manual. Multi-Health Systems, New YorkGoogle Scholar
  41. 41.
    Cleeland CS, Ryan KM (1994) Pain assessment: global use of the brief pain inventory. Ann Acad Med Singapore 23(2):129–138PubMedGoogle Scholar
  42. 42.
    Sloan JA, O'Fallon JR, Suman VJ et al (1998) Incorporating quality of life measurement into oncology clinical trials. Proc Am Stat Assoc 1998:282–287Google Scholar
  43. 43.
    Grunberg SM, Groshen S, Steingass S (1996) Comparison of conditional quality of life terminology and visual analogue scale measurements. Qual Life Res 5:65–72PubMedCrossRefGoogle Scholar
  44. 44.
    Gudex C, Dolan P, Kind P (1996) Health state valuations from the general public using the visual analogue scale. Qual Life Res 5:521–531PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Debra L. Barton
    • 1
  • Edward J. Wos
    • 2
  • Rui Qin
    • 1
  • Bassam I. Mattar
    • 3
  • Nathan Benjamin Green
    • 4
  • Keith S. Lanier
    • 5
  • James Dewitt BeardenIII
    • 6
  • John W. Kugler
    • 7
  • Kay L. Hoff
    • 8
  • Pavan S. Reddy
    • 3
  • Kendrith M. RowlandJr
    • 9
  • Mike Riepl
    • 10
  • Bradley Christensen
    • 1
  • Charles L. Loprinzi
    • 1
  1. 1.Mayo Clinic College of MedicineRochester55905USA
  2. 2.Medcenter One Health SystemBismarckUSA
  3. 3.Wichita CCOPWichitaUSA
  4. 4.Missouri Valley Cancer Consortium CCOPOmahaUSA
  5. 5.Providence Oncology and Hematology Care ClinicPortlandUSA
  6. 6.Spartanburg Regional Medical CenterSpartanburgUSA
  7. 7.Illinois CancerCarePeoriaUSA
  8. 8.Cancer Resource CenterLincolnUSA
  9. 9.Carle Cancer CenterUrbanaUSA
  10. 10.Gateway Health Mart PharmacyBismarckUSA

Personalised recommendations