Zalat et al. (2020): Evaluation of the cardioprotective effects of l-carnitine and silymarin in cancer patients receiving anthracycline-containing chemotherapy

Reference ↗
Title	Evaluation of the cardioprotective effects of l-carnitine and silymarin in cancer patients receiving anthracycline-containing chemotherapy
Topic	Carnitine
Author	Zalat ZA, Elewa HA, Abdel-Latif M, Alm El-Din MA, Kohaf NA
Year	2020
Journal	Journal of Bioscience and Applied Research
DOI	https://doi.org/10.21608/jbaar.2020.119755

Brief summary

This study evaluated data from 83 patients who were randomly divided into 3 arms: one arm received carnitine in addition to chemotherapy, another arm received silymarin (from milk thistle fruits) in addition to chemotherapy, and the third arm received no additional interventions. After 6 months of chemotherapy, the ejection fraction, which is a measure of heart function, was assessed. There was a significant deterioration in the control arm, an improvement in the carnitine arm, and no change in the silymarin arm. At the end of the study, no comparisons between the arms were conducted. The study provides little information about the methodology, procedure, and arm allocation, making it difficult to fully understand.

Diese Studie wertete Daten von 83 Patienten aus. Diese wurden zufällig in 3 Gruppen eingeteilt: eine Gruppe erhielt zusätzlich zu der Chemotherapie Carnitin, eine Gruppe erhielt zusätzlich Sylmarin (aus den Früchten von Mariendistel) und eine Gruppe erhielt keine zusätzlichen Maßnahmen. Nach 6 Monaten Chemotherapie wurde die Ejektionsfraktion gemessen, die ein Bewertungsmaß für die Herzfunktion ist. Es zeigte sich eine deutliche Verschlechterung in der Kontrollgruppe, eine Verbesserung in der Carnitingruppe und keine Änderung in der Sylmaringruppe. Am Ende der Studie wurden keine Vergleiche zwischen den Gruppen durchgeführt. Die Studie gibt wenig Informationen über die Methodik, den Ablauf und die Zuteilung der Gruppen, sodass man diese nicht genau nachvollziehen kann.

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	Monocentric
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	No
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	3

Study characteristics

Inclusion criteria	Cancer patients receiving anthracycline chemotherapy in their protocol alone (without any cardioprotective agent), aged 20-60 years
Exclusion criteria	Patients with a history of heart failure, arrhythmia, history of cardiac catheterizations or, history of angina, uncontrolled hypertension and uncontrolled diabetes, patients with impaired liver function tests, previous anthracycline-containing regimens and any cardiotoxic chemotherapy regimens, previous history of chest wall irradiation. Brain metastasis, pregnant patients, and patients who refused informed consent, patients who could not be sampled serially, or had bypass surgery, which precluded sampling throughout their hospital stay
N randomized	105
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	Data are expressed as the mean value (± standard deviation). One-way analysis of variance test (one-way ANOVA) followed by LSD post hoc test was used to assess any significant difference between the three groups. Paired t-test was used to assess any significant difference within each group at baseline and after chemotherapy. All probability values presented were two-tailed and p ≤ 0.05 was considered statistically significant.
Countries of data collection	Egypt
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: Baseline T1: after 6 months of chemotherapy

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
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer, Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin)
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	Breast adjuvant, Breast neoadjuvant, Breast metastatic, NHL II, NHL III
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Anthracycline-chemotherapy, chemotherapy regime: AC: Adriamycin + cyclophosphamide, FAC: 5-flourouracil + Adriamycin +cyclophosphamide, CHOP: Cyclophosphamide + Adriamycin + Oncovin +Prednisone
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	7.79% male
Age groups	Adults (18+)
Age groups specification	Age Mean ± SD: carnitine arm 45.64 ± 9.941, silymarin arm 44.68 ± 12.44, control arm 44.455 ± 9.47;range 20–60 years

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	25
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	7
Drop-out reasons	Bad compliance to protocol
Intervention	L-Carnitine + chemotherapy
Dosage and regime	Capsules 3g one day before the chemotherapy cycle and 1 g/day for the following 21 days
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.	182
Side effects / Interactions	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Active control
Number of participants (arm) N randomized	25
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	7
Drop-out reasons	Bad adherence
Intervention	Silymarin + chemotherapy
Dosage and regime	In capsules 140 mg daily during the chemotherapy cycle.
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.	182
Side effects / Interactions	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Passive control
Number of participants (arm) N randomized	33
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	8
Drop-out reasons	Marked decline in % EF n=7 Cancer related death n=1
Intervention	No additional intervention
Dosage and regime	NA
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.	182
Side effects / Interactions	NI

Outcomes

Ejection fraction

Outcome type As specificed by the authors	Primary
Outcome specification	Cardiotoxicity
Type of measurement	NI
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 6 months of chemotherapy: Significant deterioration in control arm (p = 0.00) and significant improvement in carnitine arm (p = 0.002), no change in silymarin arm (p = 0.817); At 6 months: No group comparison presented, but the discussion reports that a difference between the carnitine and control arm was found after chemotherapy.
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".	NA

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	According to authors no external funding.
Conflicts of Interest	According to authors no conflict 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

PRO:

• Ethical approval
• Study protocol
• Baseline comparison

CONTRA:

• No blinding
• Simple randomization: Even numbers assigned to carnitine and odd numbers to silymarin arm; unclear how the control group was randomized and no additional details on randomization
• Statistical methods opaque: No group comparison despite planned ANOVA with group comparison
• Unclear process for patient inclusion and unclear timing of randomization (patients were "recruited" after randomization); exclusion reasons in text differ from those in the figure
• High risk of bias as 14 patients in the intervention groups dropped out due to non-compliance with the protocol and no ITT analysis was conducted
• No information on adverse events
• Change in silymarin arm over 6 months from 66.7 ± 0.045 to 68.56 ± 0.031 is highly significant (p = 0.003), despite a very small difference