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.