Hershman et al. (2018): Two-Year Trends of Taxane-Induced Neuropathy in Women Enrolled in a Randomized Trial of Acetyl-L Carnitine

Reference ↗
Title	Two-Year Trends of Taxane-Induced Neuropathy in Women Enrolled in a Randomized Trial of Acetyl-L Carnitine
Topic	Carnitine
Author	Hershman, DL, Unger, JM, Crew, KD, Till, C, Greenlee, H, Minasian, LM, Moinpour, CM, Lew, DL, Fehrenbacher, L, Wade, JL III, Wong, SF, Fisch, MJ, Henry, NL, Albain, KS
Year	2018
Journal	Journal of the National Cancer
DOI	https://doi.org/10.1093/jnci/djx259

Brief summary

This study is a follow-up study of the 2013 study Hershman et al. (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, in which the data of the patients are reported after 2 years. In the study, breast cancer patients were randomly divided into 2 arms. One arm received an additional 3000mg of carnitine daily for 24 weeks during (taxane-based) chemotherapy and the other arm received a placebo. The results show that the neuropathy occurs significantly more in the carnitine arm on average. This effect is still visible after 1 year, i.e. long after the carnitine has been discontinued. After 2 years, the values of the patients no longer differ significantly from each other. The study was methodologically well conducted and shows only a few weaknesses. It is characterized by a large sample and detailed and clear reporting quality.

Diese Studie ist eine Folgestudie der Studie von 2013 Hershman et al. (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, in der die Daten der Patienten nach 2 Jahren berichtet werden. In der Studie wurden Brustkrebspatientinnen zufällig in 2 Gruppen eingeteilt. Eine Gruppe erhielt während der (taxanbasierten-) Chemotherapie über 24 Wochen zusätzlich täglich 3000mg Carnitin und die andere Gruppe erhielt ein Placebo. Die Ergebnisse zeigen, dass die Neuropathie im Mittel bedeutend stärker in der Carnitingruppe auftritt. Dieser Effekt ist auch noch nach 1 Jahr sichtbar, also lange nach Absetzen des Carnitins. Nach 2 Jahren unterscheiden sich die Werte der Patienten nicht mehr bedeutsam voneinander. Die Studie ist methodisch gut durchgeführt und zeigt nur wenige Schwächen. Sie zeichnet sich durch eine große Stichprobe und detaillierte sowie klare Berichtsqualität aus.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	2

Study characteristics

Inclusion criteria	Women with a history of stage I to III breast cancer, scheduled to undergo adjuvant taxane-based chemotherapy with one of the following standard regimens were included: paclitaxel 80 mg/m2 once per week for 12 cycles, paclitaxel 175 mg/m2 once every 2 weeks for four cycles, paclitaxel 175 mg/m2 once every 2 weeks for six cycles, docetaxel 75 mg/m2 once every 3 weeks for four cycles, or docetaxel 75 mg/m2 once every 3 weeks for six cycles; Zubrod performance status of 0 to 2
Exclusion criteria	History of diabetes, history of peripheral neuropathy resulting from other causes, or seizure disorder; receiving any of the following medications used to treat CIPN were excluded: vitamin E, glutamine, gabapentin, nortriptyline, amitriptyline or duloxetine hydrochloride (HCL), and other nutritional supplements used to treat CIPN
N randomized	409
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	PP Analysis
Specifications on analyses	?
Countries of data collection	NI
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: Baseline T1: 12th week T2: 24th week T3: 36th week T4: 52nd week T5: 104th week

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Curative, Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Early Stage, Advanced Stage
Specifications on cancer stages	?
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Taxan-based chemotherapy; paclitaxel 80 mg/m2 once per week for 12 cycles, paclitaxel 175 mg/m2 once every 2 weeks for four cycles, paclitaxel 175 mg/m2 once every 2 weeks for six cycles, docetaxel 75 mg/m2 once every 3 weeks for four cycles, or docetaxel 75 mg/m2 once every 3 weeks for six cycles
Previous cancer therapies	NI
Gender	Female
Gender specifications	100% female
Age groups	Adults (18+)
Age groups specification	?

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	208
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	n= 41 Analyzed at Baseline n=208, week 12 n=192, week 24 n=180, week 36 n=175, 1 year n=179, 2 year n=167
Drop-out reasons	NI
Intervention	Acetyl-L-carnitine (ALC)
Dosage and regime	3g (6 capsules each (hydrochloride, cellulose, 500mg ALC)) daily for 24 weeks
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	168
Side effects / Interactions	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	201
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	n=41 Analyzed at baseline n=201, week 12 n=182, week 24 n=176, week 36 n=173, 1 year n=171, 2 years n=160
Drop-out reasons	NI
Intervention	Placebo
Dosage and regime	6x capsules (cellulose) daily for 24 weeks
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	168
Side effects / Interactions	NI

Outcomes

CINV (Chemotherapy-Induced Nausea and Vomiting)

Outcome type As specificed by the authors	Primary
Outcome specification	11-item neurotoxicity component (NTX) of the FACT-Taxane scale
Type of measurement	FACT (Functional Assessment of Cancer Therapy)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Baseline to week 104: Intervention arm sign. Reduction in NTX (more severe neuropathy) compared to placebo arm (mean difference -1.39 points, 95% CI = -2.48, -0.30; p=0.01); particularly strong at week 24 (end of intervention) (-1.68, 95% CI = -3.02, -0.33) Further results see study Hershman et al. (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
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Baseline to week 104: Intervention arm sign. Reduction in NTX (more severe neuropathy) compared to placebo arm (mean difference -1.39 points, 95% CI = -2.48, -0.30; p=0.01); particularly strong at week 24 (end of intervention) (-1.68, 95% CI = -3.02, -0.33), week 36 (-1.37, 95% CI = -2.69, -0.04) and week 52 (-1.83, 95% CI = -3.35, -0.32), but no difference at week 104 At 104 weeks, 39.5% on the ALC arm and 34.4% on the placebo arm reported a five-point (10%) decrease from baseline; in both arms, 104-week NTX scores were statistically significantly different compared with baseline (p<0.001) Addition: Predictors: A 5-point reduction on the scale from baseline: Women aged ≥60 had an increased risk of worse neuropathy symptoms compared to those under 60 in year 1 (both arms). In arm A, weight was significantly associated with a 14% increased risk of worsening neuropathy for every 5 kg weight gain in year 1, and a 16% increased risk of worsening neuropathy per 5 kg weight in year 2. No further associations with baseline values were observed.

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Functionality

Outcome type As specificed by the authors	Secondary
Outcome specification	With With FACT–Trial Outcome Index (TOI)
Type of measurement	FACT (Functional Assessment of Cancer Therapy)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Baseline to week 104 showed no differences between arms (p>0.05)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Baseline to week 104 showed no differences between arms (p>0.05)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Fatigue

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	FACIT (Functional Assessment of Chronic Illness Therapy)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Baseline to week 104 showed no differences between arms (p>0.05)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Baseline to week 104 showed no differences between arms (p>0.05)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Funding and Conflicts of Interest

Funding	?
Conflicts of Interest	?

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis	?
- Reasons for insufficient sample size based on power analysis	?
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention	?
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	?
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	?
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

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