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Interventions for Preventing Neuropathy Caused by Cisplatin and Related Compounds

Background

Chemotherapy is associated with a variety of side effects, including neuropathy.  Chemotherapy-induced peripheral neuropathy (CIPN) commonly occurs with certain agents, such as taxanes, platinum-based drugs, vinca alkaloids, specific monoclonal antibody agents (bortezomib), and thalidomide.1 These agents can have both short and long term effects. Oxaliplatin, a platinum-based agent, is an integral component of standard chemotherapy approaches in both adjuvant and metastatic colorectal cancer (CRC) treatment. Dose reductions or dose interruption of oxaliplatin may occur due to neuropathy, potentially impacting patient outcomes; improvements in the management of CIPN are greatly needed.  Multiple studies have reported varying success with different agents in an attempt to improve strategies to manage CIPN. A recent Cochrane Review update examined the efficacy of chemoprotective agents intended to reduce or limit the neurotoxicity of cisplatin and related agents.2 Albers and colleagues2 searched several databases, including the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials, EMBASE, LILACS, and CINAHL, for randomized trials evaluating neuroprotective agents for CIPN. Quasi-randomized or randomized controlled trials in which patients received cisplatin or related compounds with or without a potential chemoprotectant. Patients were examined zero to six months after completing chemotherapy using quantitative sensory testing or other measures (such as conduction studies) regarding neurological impairment.2

Sixteen randomized trials were identified in the initial 2006 review; a 2010 update found 11 additional randomized trials consisting of nine possible chemoprotective agents (including acetylcysteine, calcium and magnesium, and oxycarbazepine). The total number of participants included in the trials equaled 1,537, however meta-analysis was possible for very few of these trials.2 

Selected results of the comprehensive review demonstrated: 2

  • Amifostine showed a favorable outcome for neuroprotection in one of four eligible trials using quantitative sensory testing (n= 541 in all four trials), but the vibration perception threshold results was based on data from just 14 participants who completed the post-treatment evaluation; therefore results should be regarded with caution
  • Glutathione, a tripeptide antioxidant, was the active agent studied in six eligible trials of 354 participants; one used quantitative sensory testing but reported only qualitative analysis. Varying doses were reported (1.5 grams/m2 to 5 grams/m2 before chemotherapy); five out of six studies reported a significant protective effect, but variable doses, high drop-out rates, subjective study measures, and limited statistical analyses make results difficult to judge
  • The combination of calcium and magnesium was found in one article fulfilling the selection criteria; however measures of neurotoxicity were subjective or limited and enrollment in the study was terminated early due to interim analysis results of poorer tumor control in Ca/Mg group.  Final analyses did not confirm the interim findings but further research is needed
  • Oxycarbazepine and vitamin E had one trial each fulfilling the selection critieria for the review.  The oxycarbazepine study used a small sample size and no quantitative sensory testing; however results did favor the study drug group. Vitamin E appears encouraging, but small study size, methodology issues, lack of blinding reflect on the study findings and more definitive studies are needed

The authors of the paper noted that at present, data are insufficient to recommend any of the purported chemoprotective agents to prevent or limit neurotoxicity in patients.2

ManageCRC Commentary

It is well documented that certain chemotherapy agents cause dose-limiting or significant neurotoxicity and that improved strategies for management of this common side effect are needed.  It is discouraging that many poorly designed studies serve as the basis for our current management strategies.  Randomized, placebo-controlled trials are needed to definitively answer the question of which neuroprotective strategy to use in controlling CIPN; strategies must also demonstrate a lack of effect on the anti-tumor regimens used to combat CRC and other cancers.  This updated Cochrane review demonstrates that despite a number of studies examining the effects of various strategies for CPIN, a lack of well-designed trial data limits our approach toward management of this common adverse event.  Further research is needed to define the optimal treatment strategies for CIPN, a side effect that occurs with multiple agents, including oxaliplatin.

References

  1. Visovsky, C, Collins, M, Abbot, L et al. Evidence-based interventions for chemotherapy-induced peripheral neuropathy. Clin J Oncol Nurs. 2007; 11(6): 901-13. doi: 10.1188/07.CJON.901-913  Free full text: http://ons.metapress.com/content/38054849w7731327/fulltext.pdf
  2. Albers, JW, Chaudhry, V, Cavaletti, G et al. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev. 2011; Feb 16;2:CD005228.doi:10.1002/14651858.CD005228.pub3  Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/21328275


Article Created On : 3/16/2011 3:06:47 PM             Article Updated On : 3/16/2011 3:06:47 PM