Hershman, D.L., Unger, J.M., Crew, K.D., Till, C., Greenlee, H., Minasian, L.M., . . . Albain, K.S. (2018). Two-year trends of taxane-induced neuropathy in women enrolled in a randomized trial of acetyl-l-carnitine (SWOG S0715). Journal of the National Cancer Institute, 110, 669–676.
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)
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.