Carnitine/L-Carnitine

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.

STUDY PURPOSE: To provide a review of best evidence for chemotherapy-induced peripheral neuropathy (CIPN) treatments

TYPE OF STUDY: Systematic review

• FINAL NUMBER STUDIES INCLUDED = 13 
• TOTAL PATIENTS INCLUDED IN REVIEW = 685
• SAMPLE RANGE ACROSS STUDIES: 16–201

PHASE OF CARE: Active antitumor treatment

Interventions included were vitamin E, glutamine, goshajinkigan, alpha-lipoic acid, omega-3 fatty acids, acupuncture, massage therapy, acetyl L carnitine, and physical activity. All interventions showed mixed findings, with findings suggesting that acetyl L carnitine may worsen symptoms in patients receiving chemotherapy.

Limited evidence exists to show the effectiveness of integrative therapies for the prevention or treatment of CIPN.

• Limited number of studies included
• No quality evaluation
• Low sample sizes

Very limited evidence exists for effective interventions to prevent or manage CIPN. More research is needed in this area.

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: 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.

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 grade 3 or greater neuropathy (based on the National Cancer Institute's Common Terminology Criteria for Adverse Events [NCI-CTCAE]) during paclitaxel or cisplatin therapy or grade 2 or greater 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.

To investigate if the addition of acetyl-L-carnitine (ALC) to sagopilone (SAG) in patients with ovarian cancer (OC) and castration-resistant prostate cancer (CRPC) reduced the overall incidence of SAG-induced peripheral neuropathy (PN) compared to SAG and placebo, and to evaluate the safety and efficacy of ALC-SAG compared to SAG-placebo

Patients were randomized to treatment and placebo-controlled arms. All patients received a three-hour infusion every three weeks of SAG 16 mg/m² either with oral ALC (1000 mg) three times a day or oral placebo three times a day for six treatment cycles. ALC or placebo was continued for 30–33 days after the last SAG treatment. Patients with CRPC received oral prednisone 5 mg every two days as standard of care for quality of life.

• N = 111 completed study (n = 53 [ALC-SAG arm], n = 58 [SAG-placebo arm]) 
• MEDIAN AGE = 62 years
• AGE RANGE = 29–82 years
• MALES 35%, FEMALES 65% (out of total N = 150 enrolled) 
• KEY DISEASE CHARACTERISTICS: Metastatic/advanced Disease; OC and CRPC patients had no evidence of PN at enrollment.
• OTHER KEY SAMPLE CHARACTERISTICS: Ovarian cancer International Federation of Gynecology and Obstetrics (FIGO) grades IV (18%), III (69%), II (6%), I (7%); the CRPC median Gleason total score was 8; patients with CRPC taking prednisone 5 mg

• SITE: Multi-site    
• SETTING TYPE: Unknown  
• LOCATION: Europe

• PHASE OF CARE: Active treatment
• APPLICATIONS: Elder care, palliative care

Phase-II, prospective, placebo-controlled, double-blind, randomized trial

• PN was evaluated for time to incidence, time to recovery, and grade of neuropathy within six or fewer cycles.
• Measurement tools/instruments for evaluation of PN not described
• Modified Response Evaluation Criteria in Solid Tumors was used to evaluate tumor size.
• CA-125 blood test
• Prostate-specific antigen (PSA) blood test

No difference in the incidence or median duration of PN existed in either arm. No difference existed in best overall response, tumor markers, time-to-event variables (progression free survival or time to progression), or discontinuations because of adverse events in either arm. Slightly more serious adverse events and grade 3–4 adverse events were reported in the SAG-placebo arm. ALC reduced the incidence of grade 3–4 PN in patients in the SAG-ALC arm compared to patients in the the SAG-placebo arm; however, actual statistical results were not reported.

ALC given concurrently with SAG in patients with advanced OC was reported to reduce the incidence of grade 3–4 PN after six cycles of treatment; however, no results showing statistical significance were provided.

• Risk of bias (sample characteristics)
• Unintended interventions or applicable interventions not described that would influence results
• Key sample group differences that could influence results
• Measurement/methods not well described
• Measurement validity/reliability questionable
• Subject withdrawals ≥ 10% (26%)
• Study methods poorly described
• PN evaluation tool not provided
• Number of cycles and types of prior regimens in sample not described
• Inclusion/exclusion criteria not described
• Statistical methods for analysis of data and significance not described but depicted in tables
• Patient with CRPC on prednisone could potentially confound results
• No report of grades or types/frequencies of adverse events in either group
• No information on what was used as the placebo

ALC concurrently with SAG after six cycles reduced the incidence of grade 3–4 PN in patients with advanced OC. No benefit was observed in patients with CRPC or in reducing the incidence of grade 1–2 for either patients with OC or CRPC. Further randomized, controlled trials are needed to determine the benefits, duration of benefits, and quality of life for ALC-SAG or other neurotoxic regimens in diverse tumor types.

To determine if acetyl-L-carnitine (ALC) prevents chemotherapy-induced peripheral neuropathy (CIPN) in women with early stage breast cancer receiving taxane-based treatment

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: 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.

To investigate the clinical phenotype of CIPN and longitudinal patterns of CIPN over 24 month period in patients on the SWOG S0715 trial (double-blind RCT of stage I-III patients with breast cancer who received an adjuvant taxane-based regimen and compared CIPN between those in the treatment group - acetyl-L-carnitine (ALC) versus the placebo control group x 24 weeks)

• SWOG S0715 post-trial statistical analysis evaluating two-year trends for effect of ALC on peripheral neuropathy using baseline demographics factors and longitudinal data (24 months) of neurotoxicity scores (NTX) scores collected at study baseline, 12, 24, 36, 52, and 104 weeks (see SWOG S0715 trial below). Neurotoxicity scores were analyzed using linear mixed models. Linear regression analyzed individual time points. Baseline neurotoxicity scores and stratification factors were considered in the regression analysis.
• SWOG S0715 trial: A double-blind RCT of women older than age 18 years and with a diagnosis of stage I-III breast cancer receiving an adjuvant taxane-based chemotherapy regimen with a stratified random assignment (by taxane-based chemotherapy regimen and age younger than 60 or older than 60) to either the study drug group: Acetyl-L-carnitine (ALC) 3,000 mg per day divided into six tablets (1,000 mg three times a day) versus control group: matching placebo cellulose 3,600 mg per day divided into six tablets,(1,200 mg three times a day). Treatment with either ALC versus placebo control started at the beginning of chemotherapy and continued daily for a duration of 24 weeks. Peripheral neuropathy was measured at baseline and at 12, 24, 36, 52, and 104 weeks. 
• Taxane-based chemotherapy regimens: weekly paclitaxel 80 mg/m² for 12 cycles, biweekly paclitaxel 175 mg/m² for 4 or 6 cycles, every-three-week docetaxel 75 mg/m² for 4 or 6 cycles

• N = 409 at baseline; 327 at two years   
• MEAN AGE: Combined, 52.5 years; ALC, 53.3; placebo, 51.9
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Stage I-III breast cancer starting adjuvant treatment with a taxane-based regimen
• OTHER KEY SAMPLE CHARACTERISTICS: Age, race, ethnicity, weight, prior mastectomy, planned treatment regimen, performance status, and receipt of G-CSF; patients with diabetes, prior CIPN, and kidney disease, and those taking vitamin E, glutamine, gabapentin, nortriptyline, amitriptyline, duloxetine, or other potentially CIPN-treating supplements were excluded.

• SITE: Multi-site   
• SETTING TYPE: Outpatient    
• LOCATION: Unknown

• PHASE OF CARE: Active anti-tumor treatment
• APPLICATIONS: Elder care

Multi-site double-blind randomized-controlled trial

Peripheral neuropathy measured by the 11-item neurotoxicity section of the Functional Assessment of Cancer Therapy-Taxane (FACT-NTX). A lower score indicates worse CIPN and more than 10% (or 5 points) is considered clinically significant. Sensitivity analysis done to evaluate a 10-point decrease in the FACT-NTX scores from baseline; other measurements were secondary outcomes: FACT-Taxane Trial Outcome Index; fatigue measured by 13-item Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale. All patient measurements taken at baseline and weeks 12, 24, 36, 52, and 104.

Linear mixed model results showed the average difference of NTX between the ALC group and placebo control group was statistically significant (p = 0.01) with worsened CIPN in the ALC group, at 24 weeks (p = 0.02); 36 weeks (p = 0.04); and 52 weeks (p = 0.02) compared to the placebo control group. Functional status (FACT TOI) scores worsened at weeks 24 (p = 0.04) and week 52 (p = 0.05), but was not significantly different at week 104 (p = 0.09). No difference between ALC group and placebo control group for FACIT-Fatigue. No differences observed between groups for medications taken to treat CIPN. At one year, women aged 60 or older had a higher risk of worsening peripheral neuropathy compared with women 60 years or younger at one year (OR = 1.74, p = 0.02) and at two years (OR = 1.67, p = 0.04).

In women receiving a taxane-based chemotherapy, 24 weeks of ALC therapy to reduce symptoms of CIPN caused a statistically significant worsening of short- and long-term CIPN over two years compared to placebo. Age was a risk factor for long-term CIPN. Women 60 years or older were 1.5 times more likely to have clinically significant long-term CIPN.

Exploratory statistical plots showed a non-linear relationship requiring statistical transformation procedures; no quantifiable neuro-diagnostic tests, such as balance/nerve conduction/TNS; no differentiation between sensory, motor, or autonomic neuropathy; no reports of comorbidities developing over course of study; no cumulative taxane dose or number of cycles received

Acetyl-L-carnitine (ALC) has previously been identified as a potential pharmacotherapeutic option for CIPN; however, based on the study results, ALC is not recommended as therapy for CIPN because it can cause harm in worsening CIPN. This study points to the necessity for further research into the mechanisms of CIPN, toxicities, and preventive interventions.

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.

4,900 references were identified that were published between January 1, 1990 and December 31, 2013. 203 articles were included in the final review although only 174 were referenced. Grades used and reported here were A: recommended, high certainty of benefit, B: recommended, high certainty of moderate to substantial benefit, D: recommends against use, moderate to high certainty of no net benefit, and H: recommends against use, moderate to high certainty that harms outweigh benefits.

Interventions for specific symptoms that had strong recommendations for or against use were:

• Anxiety: Music therapy during RT and chemotherapy sessions, meditation, and yoga for patients undergoing therapy (B-level recommendation)
• Depression: Mindfulness-based stress reduction for patients undergoing radiotherapy, relaxation, and yoga (level A recommendation); massage and music therapy (level B)
• Fatigue: Energy conservation (level B)
• CINV: Acupressure and electroacupuncture in addition to antiemetics (B level)
• Neuropathy: Acetyl L carnitine was not recommended because of harm (H level).
• Radiodermatitis: Aloe vera and hyaluronic acid cream were not recommended as standard therapy because of lack of effect (D level).

It appears that only specific types of interventions were included, and there are numerous types of integrative or complementary interventions that were not considered in this review. The findings considered were limited to women with breast cancer. Quality rating of evidence was not discussed individually.

These guidelines provided an evidence-based evaluation of various integrative therapies in women with breast cancer. This set of interventions is not all-inclusive; however, it does provide some guidance to clinicians and others regarding evidence strength in these areas as assessed by this specific study group.