Khodabakhshi et al. (2019): Feasibility, Safety, and Beneficial Effects of MCT-Based Ketogenic Diet for Breast Cancer Treatment: A Randomized Controlled Trial Study

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Title	Feasibility, Safety, and Beneficial Effects of MCT-Based Ketogenic Diet for Breast Cancer Treatment: A Randomized Controlled Trial Study
Topic	Low-carbohydrate or ketogenic diet
Author	Khodabakhshi, A, Akbari, M E, Mirzaei, H R, Mehrad-Majd, H, Kalamian, M, Davoodi, S H
Year	2019
Journal	Nutrition and Cancer
DOI	https://doi.org/10.1080/01635581.2019.1650942

Brief summary

In the study, data of 77 neoadjuvant patients or patients with metastatic breast cancer were analyzed. They were previously randomly divided into two groups, so that 40 patients followed an MKT-based ketogenic diet (high fat, low carbohydrate and additional intake of medium-chain triglyceride oil) for 3 months and 37 patients followed a standard diet (low fat) for 3 months. After 3 months, the patients on the ketogenic diet showed a reduced body weight, a reduced BMI and a greater reduction in body fat than the subjects in the standard diet group. The study also showed a higher overall survival time for the neoadjuvant patients (44). No results are given for the entire sample. Overall, the results provide few generalizable findings, particularly due to a very crude description of the underlying conditions.

In der Studie wurden die Daten von 77 neoadjuvanten Patienten oder Patienten mit metastasierendem Brustkrebs ausgewertet. Diese wurden zuvor zufällig in zwei Gruppen eingeteilt, so dass 40 Patientinnen über 3 Monate eine MKT basierte ketogene Diät (viel Fett, wenig Kohlenhydrate und zusätzliche Einnahme von mittelkettigem Triglycerid-Öl) und 37 Patientinnen eine Standarddiät (wenig Fett) über 3 Monate anwandten. Nach 3 Monaten zeigten die Patienten in der ketogenen Diät ein verringertes Körpergewicht, einen verringerten BMI und eine höhere Abnahme im Körperfett als die Probanden in der Standarddiätgruppe. Die Studie zeigt auch eine höhere Gesamtüberlebenszeit für die neoadjuvanten Patienten (44). Es werden keine Ergebnisse für die gesamte Stichprobe gegeben. Insgesamt liefern die Ergebnisse wenig verallgemeinerbare Ergebnisse, insbesondere aufgrund einer sehr groben Beschreibung der Rahmenbedingungen.

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	2

Study characteristics

Inclusion criteria	Patients with locally advanced (neo-adjuvant) and metastatic breast cancer refereed to a medical oncology clinic in Shohada-e-Tajrish hospital in Tehran, Iran, from July 2017 to October 2018; proven malignant biopsy; chemotherapy for at least 3 months
Exclusion criteria	Patients with significant cardiac, renal or neurologic comorbidities, or an active state of malnutrition, diabetes, pregnancy, and Karnofsky index less than 70
N randomized	77
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.	ITT Analysis
Specifications on analyses	Statistical analysis was carried out according to the intention to treat protocol. Continuous variables were tested for normal distribution by the Kolmogorov-Smirnov test, then reported as mean (SD) or median as appropriate. Student t-test or Mann–Whitney U test was used to compare continuous variables between groups. Categorical data were summarized as percentages and analyzed with the chi-square test. A repeated measures ANOVA was used to evaluate differences at baseline, middle, and endpoints in time-dependent variables within patient groups. ITT analysis specified, but unclear because demographic information from only 60 patients
Countries of data collection	Iran
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: 3rd visit (after about 9 weeks) T2: after 3 months

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.	Neo-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	Advanced Stage
Specifications on cancer stages	Locally advanced or metastatic breast cancer Cancer stage, n (%) per arm: Neo-adjuvant: intervention: 25 (83.3), comparison: 19 (63.3) Metastasizing: intervention: 5 (16.7), comparison: 11 (36.7)
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	NI
Previous cancer therapies	No therapy
Gender	Female
Gender specifications	Female n (%): 77 (100)
Age groups	Adults (18+)
Age groups specification	Age in years, mean (SD) per arm: intervention arm: 44.8 (8.4) comparison arm 45.2 (15.0)

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	40
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	10
Drop-out reasons	Nausea and hypoglysemia; weakness and hunger; refusal to participate; unable to stick to diet; lack of energy and oiliness of the diet
Intervention	Ketogenic diet
Dosage and regime	Medium-chain triglycerides (MCT) based ketogenic diet (6% calories from carbohydrates, 19% protein, 20% MCT, 55% fat); patients were given 500ml MCT oil from “Nutricia Company” every 2 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.	90
Side effects / Interactions	Significant weight loss; according to authors, no serious complications observed

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	37
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	Frequent blood sampling; surgery; diabetes
Intervention	Standard diet
Dosage and regime	Standard diet (55% carbohydrates, 15% protein, and 30% fat)
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.	90
Side effects / Interactions	According to authors, no serious complications observed

Outcomes

OS (Overall Survival)

Outcome type As specificed by the authors	NI
Outcome specification	Overall survival rate
Type of measurement	Observation
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".	No arm difference in survival rate after 9 weeks
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".	Significant effect only for subgroup: overall survival was higher in intervention arm compared to comparison arm for patients undergoing neoadjuvant treatment (p=0.04) after 3 months n = 25 (intervention) + 19 (comparison)

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	?

Body composition

Outcome type As specificed by the authors	NI
Outcome specification	BMI, body weight, fat (%)
Type of measurement	BIA (Bioelectrical impedance analysis)
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".	No significant differences in body weight, BMI, fat (%) between intervention arm compared to comparison arm (p>0.05, p>0.05, p>0.05) after 9 weeks
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".	Body weight, BMI, fat (%) significantly lower in intervention arm compared to comparison arm (p<0.001, p<0.001, p=0.03) after 3 months

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	NI
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	NI
- Reasons for insufficient sample size based on power analysis	NI
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	NI
- 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	NI
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	NI
- 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	?