Cohen et al. (2018): Favorable Effects of a Ketogenic Diet on Physical Function, Perceived Energy, and Food Cravings in Women with Ovarian or Endometrial Cancer: A Randomized, Controlled Trial

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Title	Favorable Effects of a Ketogenic Diet on Physical Function, Perceived Energy, and Food Cravings in Women with Ovarian or Endometrial Cancer: A Randomized, Controlled Trial
Topic	Low-carbohydrate or ketogenic diet
Author	Cohen, C, W., Fontaine, K R, Arend, R C, Soleymani, T, Gower, B A
Year	2018
Journal	Nutrients
DOI	https://doi.org/10.3390/nu10091187

Brief summary

In this study, 73 patients with ovarian and uterine cancer, 45 of whom completed the study, were randomly divided into 2 groups. They followed a ketogenic diet (high fat, low carbohydrate) or the American Cancer Society recommendations (high fiber, low fat) for 12 weeks. Quality of life was assessed. After 12 weeks, there were no differences in mental function and energy level/fatigue. However, there was better physical function in the ketogenic diet group compared to the other group. However, the effect seems to be influenced by the decrease in body fat at the end of the study, as the effect of the ketogenic diet on physical function disappears when body fat loss is taken into account. Overall, the study is very clearly presented, but important contextual and demographic variables of the subjects are not reported. Statistically, the credibility of the results is questionable, as statistically significant differences may have arisen due to imprecise statistics.

In dieser Studie wurden 73 Patientinnen mit Eierstock- und Gebärmutterkrebs, von denen 45 die Studie beendeten, zufällig in 2 Gruppen eingeteilt. Diese hielten sich für 12 Wochen an eine ketogene Diät (viel Fett, wenig Kohlenhydrate) oder an die Empfehlungen der Amerikanischen Krebsgesellschaft (ballastoffreich, wenig Fett). Untersucht wurde die Lebensqualität. Nach 12 Wochen zeigten sich keine Unterschiede bezüglich seelischer Funktionen und dem Energielevel/ Fatigue. Es zeigte sich jedoch eine bessere körperliche Funktion in der Gruppe mit der ketogenen Diät im Vergleich zur anderen Gruppe. Der Effekt scheint allerdings von der Abnahme des Körperfettes zum Ende der Studie mitbeeinflusst, da der Effekt von ketogener Diät auf die physische Funktionalität unter Berücksichtigung der Körperfettabnahme verschwindet. Insgesamt ist die Studie sehr übersichtlich dargestellt, jedoch werden dabei wichtige Rahmenbedingungen und demographische Variablen der Probanden nicht gegeben. Statistisch gesehen ist die Glaubwürdigkeit der Ergebnisse jedoch anzuzweifeln, da statistisch bedeutsamen Unterschiede durch die ungenaue Statistik entstanden sein können.

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	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	Women diagnosed with ovarian or endometrial cancer; BMI ≥ 18.5 kg/m2; age ≥ 19 years; no medical condition affecting body weight (other than cancer and its associated treatment); not attempting diet modification; women with type 2 diabetes eligible to participate with additional medical supervision from the study physician
Exclusion criteria	NI
N randomized	73
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	Analysis of covariance (ANCOVA) was used to assess between-group differences. Baseline values, chemotherapy status, and/or change in fat mass were used as covariates where appropriate. To assess differences in perceived energy between diet groups, sub-group analyses were conducted on the basis of chemotherapy status due to the prevalence of chemotherapy-related fatigue. Paired t-tests were used to assess within-group differences. Pearson correlation analyses were used to estimate associations between questionnaire results and serum β-hydroxybutyrate concentration, a biomarker of circulating ketones. The statistical analysis plan included an investigation for outliers, and the final analyses excluded them in order to lessen the influence of extreme observations on the overall results. One outlier (>3 standard deviations above the mean) was excluded from food craving analyses involving starches and high-fat foods. In addition, two participants in the KD group only partially completed the SF-12 at the follow-up visit; two participants in the KD group also did not complete all items on the VAS. Accordingly, these participants’ responses have been excluded from the corresponding analyses.
Countries of data collection	United States
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: after 12 weeks

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.	NI
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Gynecologic Cancers - Ovarian Cancer, Gynecologic Cancers - Endometrial 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	NI
Specifications on cancer stages	NI
Comorbidities	Four women with type 2 diabetes completed the study
Current cancer therapies	Chemotherapy, No therapy
Specifications on cancer therapies	n = 11 (24%) patients received concurrent chemotherapy
Previous cancer therapies	NI
Gender	Female
Gender specifications	Female n (%): 73 (100)
Age groups	Adults (18+)
Age groups specification	Age in years (n = 45), mean (range): 60.2 (31-79)

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	37
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	12
Drop-out reasons	Withdrew due to scheduling conflicts (n=6); not separated by arm: no longer wishing to comply with dietary requirements (n=3); cancer recurrence (n=3); death (n=2)
Intervention	Ketogenic diet (KD) + all participants received individual dietary advice, e-mails, and one personal meeting
Dosage and regime	Approximately 5% of energy from carbohydrate (≤20 g/day), 25% from protein (≤100 g/day) and 70% from fat (≥125 g/day) + all participants received individual dietary advice from certified dieticians, weekly e-mails, and one-time personal meeting after baseline survey
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.	84
Side effects / Interactions	NI Weight loss unclear

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	36
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	16
Drop-out reasons	Withdrew due to scheduling conflicts (n=6); not separated by arm: no longer wishing to comply with dietary requirements (n=3); cancer recurrence (n=3); death (n=2)
Intervention	American Cancer Society (ACS) diet + all participants received individual dietary advice, e-mails, and one personal meeting
Dosage and regime	High fiber, low fat every day + all participants received individual dietary advice from certified dieticians, weekly e-mails, and one-time personal meeting after baseline survey
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.	84
Side effects / Interactions	NI Weight loss unclear

Outcomes

Quality of life

Outcome type As specificed by the authors	NI
Outcome specification	Quality of life via mental and physical functionality, including energy level/fatigue
Type of measurement	MOS SF-12 (Medical Outcomes Study/ 12-Item Short Form Health Survey)
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".	NI
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 difference for adjusted physical functionality between KD arm and ACS arm (p=0.04), but not for mental functionality; no significant arm differences for energy level/fatigue Taking into account the decrease in body fat associated with diet, effect on physical functionality no longer significant (p=0.064); decrease in body fat appears to significantly moderate physical functionality

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	?

Appetite

Outcome type As specificed by the authors	NI
Outcome specification	Hunger/appetite and craving for sweets and starchy products
Type of measurement	VAS (Visual Analogue Scale)
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".	NI
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".	At 12 weeks significant between-arm difference in the desire to eat something salty, the KD arm craved salt to a greater extent than the ACS arm; difference remained after adjusting for baseline values and chemotherapy status (p = 0.03, significant); no other significant between-arm differences; no significant within-arm differences from baseline to week 12

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	This research was funded by the American Institute for Cancer Research, UAB Comprehensive Cancer Center, Nutrition Obesity Research Center P30DK56336, and Diabetes Research Center P60DK079626.
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	?