Acetyl-l-carnitine (γ-trimethyl-β-acetylbutyrobetaine [ALC]) is the acetyl ester of carnitine. ALC is present throughout the central and peripheral nervous systems, plays an essential role in the oxidation of free fatty acids, and has displayed neuroprotective properties. Carnitine is available without a prescription as a dietary supplement and is found in highest concentrations in red meat and dairy products.
Not Recommended for Practice
Albers, J.W., Chaudhry, V., Cavaletti, G., & Donehower, R.C. (2011). Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database of Systematic Reviews (Online), Feb. 16 (2), CD005228.doi: 10.1002/14651858.CD005228.pub3
Examine the efficacy of purported chemoprotective agents to prevent or limit neurotoxicity of cisplatin and related agents
TYPE OF STUDY: Combined systematic review and meta-analysis
DATABASES USED: Cochrane Neuromuscular Disease Group Specialized Register, Cochrane Central Register of Controlled Clinical Trials, MEDLINE, EMBASE, LILACS, and CINAHL
KEYWORDS: Extensive list provided in article appendix
INCLUSION CRITERIA: Quasi-randomized or randomized clinical trials whose participants received cisplatin (or related compounds) chemotherapy with or without a potential chemoprotectant and were evaluated zero to six months after completing chemotherapy using quantitative sensory testing (primary) or other measures, including nerve conduction studies or neurologic impairment rating using validated scales (secondary)
TOTAL REFERENCES RETRIEVED: Sixteen randomized trials were evaluated in the initial 2006 review. In the 2010 update, 11 additional randomized trials not among the 2006 review were identified.
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Cochrane method of evaluation for risk of bias done by two authors and finalized by consensus
- N (studies) = 6
- SAMPLE RANGE ACROSS STUDIES: 14–242
- TOTAL PATIENTS INCLUDED IN REVIEW: 1,537 participants
- KEY SAMPLE CHARACTERISTICS: Patients who received cisplatin chemotherapy
Cisplatin is considered to have neurotoxic effects, with patients developing sensory neuropathy. Symptoms of pain, numbness, and tingling are observed mostly in the extremities from a distal to proximal distribution. The neuropathy experienced by patients may recover partially or may become permanent. Neuroprotective agents such as acetylcysteine, acetyl-L carnitine, amifostine, calcium and magnesium, growth factors, glutathione, ORG 2766, oxcarbazepine, and vitamin E have been tested. The five newly added randomized controlled trials included three chemoprotective agents not previously described in the 2006 review.
From the data examined in this updated review, inconclusive evidence exists for recommending any neuroprotective agent tested to prevent or limit the neurotoxicity of platinum chemotherapy.
While 1,537 participants were included in the 2010 update, few trials were amenable to meta-analysis. Clinical trials of neuroprotective agents are plagued by issues of study design, including small sample size, unclear randomization and blinding procedures, and lack of quantitative measures, especially conventional QST or electrophysiologic evaluation.
Hershman, D.L., Lacchetti, C., Dworkin, R.H., Lavoie Smith, E.M., Bleeker, J., Cavaletti, G., . . . American Society of Clinical Oncology. (2014). Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. Journal of Clinical Oncology, 32, 1941–1967.doi: 10.1200/JCO.2013.54.0914
STUDY PURPOSE: To provide evidence-based guidance on optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy in adult cancer survivors
TYPE OF STUDY: Systematic review
DATABASES USED: Ovid Medline (1946–April, week 2, 2013); EMBASE (1980–2013, week 16); AMED Allied and Complementary Medicine (1985–April 2013)
KEYWORDS: chemotherapy-induced peripheral neuropathy; adult cancer survivors; randomized clinical trials
INCLUSION CRITERIA: Adult cancer survivors with chemotherapy-induced peripheral neuropathy; randomized trials
EXCLUSION CRITERIA: Phase 1 trials; published in a language other than English; less than 10 patients; focused on radiation or stem cell transplant neuropathy; animal studies
TOTAL REFERENCES RETRIEVED = 1,252
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: An expert panel representing neurology, nursing, medical oncology, community oncology, pain research, and genetics met through teleconference and emails to review and develop the American Society of Clinical Oncology guidelines.
- FINAL NUMBER STUDIES INCLUDED = 48
- TOTAL PATIENTS INCLUDED IN REVIEW: Treatment studies: 780; prevention studies: 3,741
Phase of Care and Clinical Applications:
- PHASE OF CARE: Active antitumor treatment
Forty-two randomized clinical trials involved 19 various interventions for prevention of chemotherapy-induced peripheral neuropathy. These agents included anticonvulsants, antidepressants, vitamins, minerals, and other chemoprotectant drugs. Only six randomized clinical trials discovered six different drugs, such as antidepressants, anticonvulsants, and a topical gel, for the prevention of chemotherapy-induced peripheral neuropathy. The following are not recommended for use: acetyl-l-carnitine, amifostine, amitriptyline, calcium and magnesium, glutathione, nimodipine, ORG 2766, trans retinoic acid, rhuLIF, and vitamin E. Venlafaxine is not recommended for routine use in clinical practice. Although data support potential utility, evidence is not strong enough to suggest use. For treatment of chemotherapy-induced peripheral neuropathy, clinicians can offer duloxetine. No recommendation is made regarding ALC. Tricyclic antidepressants or gabapentin through trial use may be reasonable. The panel felt that trying topical gel containing baclofen, amitriptyline, and ketamine would be reasonable.
No agents were recommended for the prevention of chemotherapy-induced peripheral neuropathy, but duloxetine is moderately recommended for the treatment of chemotherapy-induce peripheral neuropathy. Even though conclusive evidence is lacking to recommend tricyclic antidepressants such as nortriptyline, gabapentin, and a topical gel containing baclofen,amitriptyline, and ketamine for treatment of chemotherapy-induced peripheral neuropathy, the expert panel agreed that offering these agents based on treatment for neuropathic pain is reasonable. The panel also recommended that patients be counseled regarding the lack of evidence in treating chemotherapy-induced peripheral neuropathy with these agents.
- Small, insufficient sample
- Inability to compare studies because of different outcomes
- Measurements and instruments used at different points in treatment
Nurses are at the frontline in assessing patients who are receiving agents with the potential for chemotherapy-induced peripheral neuropathy. Nurses should be aware of the standard of care in treating this population. Many drugs prescribed have no evidence in preventing or treating these patients. However, with these American Society of Clinical Oncology guidelines, a role for duloxetine is clear and a role for tricyclic antidepressants is possible. Nurses need to be knowledgeable about this information to better inform patients.
Research Evidence Summaries
Bianchi, G., Vitali, A., Caraceni, A., Ravaglia, S., Capri, G., Cundari, S., . . . Gianni, L. (2005). Symptomatic and neurophysiological responses of paclitaxel or cisplatin-induced neuropathy to oral acetyl-L-carnitine. European Journal of Cancer, 41(12), 1746–1750.doi: 10.1016/j.ejca.2005.04.028
Intervention Characteristics/Basic Study Process:
Oral acetyl L-carnitine (ALC) was given at 1 g three times per day for eight weeks.
- The total samples consisted of 25 patients (3 men and 22 women) with a mean age of 53 years.
- The patients had greater than grade 3 neuropathy (based on the National Cancer Institute's Common Terminology Criteria for Adverse Events [NCI-CTCAE]) during paclitaxel or cisplatin therapy or greater than grade 2 persistent neuropathy after three months of therapy discontinuance.
- Exclusion criteria included having diabetes mellitus and neuropathy from origins other than paclitaxel or cisplatin.
The study had a non-randomized clinical trial design.
- Physical and neurologic examinations were conducted before and after ALC administration by an independent neurologist using the NCI-CTCAE grading scale.
- Conduction velocity of sensory and motor fibers was measured by electromyography.
- Neuropathy was measured by the Total Neuropathy Score (TNS), with each variable scored on a scale of 0 (none) to 4 (severe), and the sum of these forms the TNS.
- For a general neurologic evaluation, patients were evaluated for bulbar symptoms of muscle weakness sensory disturbances (negative, positive) and autonomic symptoms.
Twenty patients had neuropathy attributed to paclitaxel and five from cisplatin. Six of the 25 were receiving a taxane at enrollment; the remaining 18 patients has persistent neuropathy at enrollment. Sensory neuropathy improved in 15 patients and motor neuropathy improved in 11. In addition, sensory and motor action potentials (SNAP and CMAP) improved significantly in 21 patients and CMAP improved in 12 patients (non-significant). Twenty-three patients had amelioration of the TNS score, and one patient (receiving concomitant vinorelbine) worsened. Patients showed improved bulbar and limb muscle weakness and sensory disturbance scores after eight weeks of ALC. No change in autonomic symptoms was observed. All patients had normalization of motor strength, deep tendon reflexes, and vibration.
- Limitations include a small sample size of 25 patients with differing levels of neuropathy and no statistical control for confounding variables.
- Although the researchers used comprehensive testing for neuropathy, the use of many variables of neuropathy that were assessed by statistical t tests is cause for concern related to galloping alpha effect, making obtaining statistical significance more likely.
- The one-group, non-randomized design and lack of a control group makes it impossible to infer causality. Testing for these patients (clinical, neurophysiological) is time consuming, painful (nerve conduction), and costly.
Hershman, D.L., Unger, J.M., Crew, K.D., Minasian, L.M., Awad, D., Moinpour, C.M., . . . Albain, K.S. (2013). Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. Journal of Clinical Oncology, 31, 2627-2633.doi: 10.1200/JCO.2012.44.8738
To determine if acetyl-L-carnitine (ALC) prevents chemotherapy-induced peripheral neuropathy (CIPN) in women with early stage breast cancer receiving taxane-based treatment
Intervention Characteristics/Basic Study Process:
Patients were randomly assigned to receive either placebo or ALC 3,000 mg (6 capsules) daily for 24 weeks.
- N = 409 (final sample); 208 received ALC and 201 received placebo
- MEDIAN AGE = 51 years
- FEMALES: 100%
- KEY DISEASE CHARACTERISTICS: Women with stage I-II breast cancer who were to receive adjuvant taxane therapy
- SITE: Multi-site
- SETTING TYPE: Outpatient
Phase of Care and Clinical Applications:
PHASE OF CARE: Active antitumor treatment
Randomized, double-blind, placebo-controlled
- Neurotoxicity component of the Functional Assessment of Cancer Therapy–Taxane scale (FACT-NTX)
- Functional Assessment of Cancer Therapy–Taxane Trial Outcome Index (FACT-TOI)
- Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue)
At week 12, patients taking ALC had lower FACT-NTX scores (0.9), indicating more CIPN than those taking placebo (P = .17). After 24 weeks, patients taking ALC had a greater than 5-point decrease in FACT-NTX scores (P = .05). The FACT-TOI scores were lower with ALC (P = .03 ). There was no difference in the FACIT-Fatigue score between arms. Patients reported grade 3-4 neuropathy in the ALC arm versus grade 1 reported in the placebo arm resulting from taxane (P = .46).
At the end of 24 weeks, patients who had been taking ALC reported an increase in CIPN and a decrease in function, compared to those taking placebo.
- Subject withdrawals were ≥ 10%.
- Since this study was done with a taxane-based chemotherapy, it is unknown how other neurotoxic drugs given with ALC would influence CIPN.
- The scores at 24 weeks represented the main secondary endpoint and not the primary endpoint; however, since not all patients had completed the taxane treatment at 12 weeks from when they were registered, 24 weeks may have been the most appropriate endpoint after all.
- Since this trial indicated a detrimental effect with ALC and a taxane, it is recommended that a taxane-based chemotherapy and ALC trial not be repeated.
It has been reported in the literature that many patients take supplements without any evidence of efficacy. Patients often have discussions with nurses and ask questions about the use of supplements. To give patients correct information, including the risks, nurses need to be knowledgeable about the efficacy of nutritional supplements. It is recommended, from the results of this study, that nurses discourage patients from taking ALC since it may be harmful.
Maestri, A., De Pasquale Ceratti, A., Cundari, S., Zanna, C., Cortesi, E., & Crino, L. (2005). A pilot study on the effect of acetyl-L-carnitine in paclitaxel- and cisplatin-induced peripheral neuropathy. Tumori, 91, 135–138.
Intervention Characteristics/Basic Study Process:
Patients were treated with acetyl-L-carnitine (ALC) 1 g per day via IV for at least 10 consecutive days. Cisplatin neuropathy was characterized as numbness, tingling, loss of vibration sensation, and diminished proprioception.
- The sample consisted of 27 patients with paclitaxel- or cisplatin-induced chemotherapy-induced peripheral neuropathy (CIPN) aged 48–75 years.
- Potential participants were excluded if they had a European Cooperative Oncology Group performance status greater than 2 or preexisting neuropathy (not CIPN).
The study was conducted from April 2000 to December 2002.
- CIPN severity was graded using the World Health Organization toxicity grading scale.
- Clinical neurologic assessment was preformed at baseline and at the end of ALC treatment.
Of the 26 patients, 19 (73%) showed at least one grade of CIPN improvement, and all cisplatin-treated patients showed at least one grade of CIPN improvement. In addition, one patient with World Health Organization grade 2 neuropathy had complete resolution of neuropathy after 11 days of treatment. For paclitaxel-treated patients, 8 of 12 (67%) showed one grade improvement, as did 8 of 10 (80%) in the combination paclitaxel and cisplatin treatment group. The remaining patients had stable CIPN.
- Limitations included a small sample size (27 enrolled, 26 with data for analysis); the non-randomized, non-blinded design; and no control group, because of which no causality can be inferred.
- Whether the clinical neurologic examinations were conducted by the same physician using a standard approach or by different practitioners is unclear.
- No information concerning inter- or intrarater reliability was provided.
- The parameters tested and methods used to conduct the clinical neurologic testing was not provided.
- The number of variables used in the statistical tests also are unknown, making it difficult to evaluate the conclusions.