Methodological Approaches to Ketogenic Dietary Treatments in Glioma Patients from a Nutritional Point of View

Figures & data

Table 1. Description of ketogenic dietary therapies commonly used in combination with standard treatment among glioma patients.

	CKD	MAD	MCT diet
Dietary composition	3–4:1 ratio Fat 80% Carbohydrate 8% Protein 12%	1–2:1 ratio Fat 50% Carbohydrate 24% Protein 35%	Fat 60% (>30% MCT) Protein 16%
Primary populations	Adults diagnosed with epilepsy	Adults diagnosed with epilepsy not tolerating classical ketogenic diet. Adolescents and young adults diagnosed with epilepsy.	Patients with indication for ketogenic diet, but difficulties to follow a classical ketogenic diet
Opportunities	Reported efficient results in ketosis	Allowed a free intake of protein, fluids, and calories. Preferable for patients who found the CKD difficult	Allowed adjustments in dietary composition

CKD, classical ketogenic diet; MAD, modified Atkins diet; MCT, medium-chain triglyceride.

Table 2. Overview of the study on the type of ketogenic diet, study design, diagnosis, ketone measurement and target levels.

Author, year, reference	Diet	Study design	Diagnosis	Ketone measurement	Target levels
Artzi et al. (2017) (36)	CKD	Clinical trial	GBM glioma grade 2	Urine ketone levels	>2 ketone level
Foppiani et al. (2021) (37)	MAD/CKD	Single-arm study	GBM, glioma grade 3	Blood ketone levels	>1mmol/l
Klein et al. (2020) (35)	CKD	Open label study	GBM	Urine- and blood ketone levels	Not specified
Martin-McGill et al. (2018) (38)	MAD	Single-arm study	GBM, glioma grade 3	Urine ketone levels	>4 mmol/l
Martin-McGill et al. (2020) (39)	MAD/MCT	Two-arm study	GBM	Urine ketone levels	>4 mmol/l
Panhans et al. (2020) (40)	CKD	Case series	GBM, glioma grade 2, 3	Blood ketone levels	>0.5 mM
Porper et al. (2020) (41)	MAD	Clinical trial	GBM, glioma grade 3	Urine- and blood ketone levels	Not specified
Rieger et al. (2014) (42)	MAD	Clinical trial	GBM	Urine ketone levels	>5mmol/l
Santos et al. (2018) (43)	MAD	Two-arm study	GBM	Urine ketone levels	5–15 mg/dl
Schreck et al. (2021) (44)	MAD	Single-arm study	GBM, glioma grade 2, 3	Urine ketone levels	>40mg/dL
Van der Louw et al. (2019) (45)	CKD/MAD	Single-arm study	GBM	Blood ketone levels	>3 mmol/l
Voss et al. (2020) (46)	MAD	Clinical trial	GBM, lower grade glioma	Blood ketone levels	Not specified
Woodhouse et al. (2019) (47)	MAD	Cohort study	GBM, glioma grade 2, 3	Blood ketone levels	>2 results>0.5 mmol/L

CKD, classical ketogenic diet; GBM, glioblastoma; MAD, modified Atkins diet; MCT, medium-chain triglyceride ketogenic diet; RD, registered dietitian.

Figure 1. Overview of literature search and inclusion of eligible articles.

Table 3. Overview of the study regarding their type of ketogenic diet, number of participants, duration of intervention, diet restriction, follow-up, consultation with a registered dietitian, and other dietary aspects.

Author, year, reference	Diet	N	Duration^a	Restriction	Follow up	RD	Other
Artzi et al. (2017) (36)	CKD	5	2–>31 mo	–	–	–	Individual diet plan, KetoCal
Foppiani et al. (2021) (37)	MAD/CKD	6	1–4 mo	<30g	Weekly	–	–
Klein et al. (2020) (35)	CKD	8	6 mo	1600 kcal/d	Monthly	–	Vitamin supplement
Martin-McGill et al. (2018) (38)	MAD	6	1–1.5 mo	<20 g	3rd week	Yes	–
Martin-McGill et al. (2020) (39)	MAD/MCT	12	3 mo	–	3rd week	Yes	–
Panhans et al. (2020) (40)	CKD	12	4 mo	<20g	–	Yes	Meal plan, prepared meals
Porper et al. (2020) (41)	MAD	13	20 mo	–	–	Yes	MCT coconut oil
Rieger et al. (2014) (42)	MAD	20	1.5 mo	<60 g	6–8 week	–	Fermented yoghurt and oils
Santos et al. (2018) (43)	MAD	17	3 mo	25% carb	By phone	–	–
Schreck et al. (2021) (44)	MAD	25	2 mo	<20g carb 2d <20% RDI	–	Yes	KetoCal
Van der Louw et al. (2019) (45)	CKD/MAD	9	3.5 mo	–	Daily/monthly	Yes	MCT supplements
Voss et al. (2020) (46)	MAD	25	9 day	<50g 3d 21–23 g kcal/kg/d	–	Yes
Woodhouse et al. (2019) (47)	MAD	29	1.5 mo	–	Weekly	Yes	–

Carb, carbohydrates; CKD, classical ketogenic diet; ER, energy-restricted; MAD, modified Atkins diet; MCT, medium-chain triglyceride ketogenic diet; RD, registered dietitian; RDI, recommended daily intake.

a Duration of intervention.

Table 4. Overview of the study results on adverse events, adherence, and metabolic outcomes.

Author, year, reference	Adverse events	Adherence	Metabolic outcomes
Artzi et al. (2017) (36) CKD, N = 5	Not measured	2 dropout at 2 mo 3 dropout at 8–31 mo	Not measured
Foppiani et al. (2021) (37) MAD/CKD, N = 6	No adverse events were reported	1 dropout at 1 mo 4 dropout at 2 mo	↓ BW, WC, FM, FFM
Klein et al. (2020) (35) CKD, N = 8	GI problems (n = 1), nausea (n = 3), fatigue/dizziness (n = 3)	3 dropout	↓ BW
Martin-McGill et al. (2018) (38) MAD, N = 6	GI problems (n = 2)	2 dropout	No sig. change in BW, BMI, FM,
Martin-McGill et al. (2020) (39) MAD/MCT, N = 12	Partial seizure (n = 1)	3 dropout (MAD) 4 dropout (MCT)	↑ HDL ratio (all participants) No sig. change in BW
Panhans et al. (2020) (40) CKD, N = 12	Not measured	No dropout	↓ BW
Porper et al. (2020) (41) MAD, N = 13	Nausea/vomiting (n = 8), anorexia (n = 6), GI problems (n = 4), hiccups (n = 1)	5 dropout	↓ BW (n = 1)
Rieger et al. (2014) (42) MAD, N = 20	No adverse events reported	3 dropout	↓ BW
Santos et al. (2018) (43) MAD, N = 17	No adverse event reported	8 dropout	↓ Total cholesterol, LDL-C, TG
Schreck et al. (2021) (44) MAD, N = 25	Leukopenia, nausea, diarrhea, fatigue, seizure (numbers not specified)	4 dropout	↑ FFM, LDL-C ↓ BW, BMI, FM
Van der Louw et al. (2019) (45) CKD/MAD, N = 9	GI problems (n = 8), nausea/vomiting (n = 2), hypoglycemia (n = 1), hallucinations (n = 1), allergic reaction (n = 1), wound infection (n = 1)	3 dropout	No sig. change
Voss et al. (2020) (46) MAD, N = 25	Headache, nausea (numbers not specified)	3 dropout	↓ BW
Woodhouse et al. (2019) (47) MAD, N = 29	GI problems (n = 1), fatigue, nausea (numbers not specified)	1 dropout	↑ BMI (n = 3) ↓ BMI (n = 25)

BW, body weight; CKD, classical ketogenic diet; FFM, fat-free mass; FM; fat mass; LDL-C, Low-density lipoprotein-cholesterol; MAD, modified Atkins diet; MCT, medium-chain triglyceride ketogenic diet; TG, triglyceride; WC, waist circumference.

Table 5. Overview of the study results on clinical outcomes, diet tolerance, and quality of life.

Author, year, reference	Clinical outcomes	Diet tolerance	Quality of life
Artzi et al. (2017) (36) CKD, N = 5	Not measured	Tolerated diet (n = 4)	Not measured
Foppiani et al. (2021) (37) MAD/CKD, N = 6	Not measured	No malnutrition was observed	Not measured
Klein et al. (2020) (35) CKD, N = 8	OS: 11–38.7 mo	Increased hunger (n = 6), diet restrictiveness (n = 4)	Not measured
Martin-McGill et al. (2018) (38) MAD, N = 6	Not measured	Positive experience, would recommend others (n = 6)	Not measured
Martin-McGill et al. (2020) (39) MAD/MCT, N = 12	OS: 7.9–16.8 mo PFS: 1.3–16.1 mo	Reduced food acceptability (all participants)	↓ Quality of life (MCT) ↑ Quality of life (MKD)
Panhans et al. (2020) (40) CKD, N = 12	OS: 4–56 mo PFS: 2–22	Increased energy, mood, headache (n = 2), appetite (n = 4). Reduced appetite (n = 5)	Not measured
Porper et al. (2020) (41) MAD, N = 13	OS: 21/8 (median) PFS: 10/4 mo (median)	Not measured	Not measured
Rieger et al. (2014) (42) MAD, N = 20	OS: 8 mo (median) PFS 6/3 w (median)	Slight hunger presented at first week of diet	↓ QoL (n = 3)
Santos et al. (2018) (43) MAD, N = 17	PR (n = 7), SD (n = 1), PD (n = 1)	Not measured	Not measured
Schreck et al. (2021) (44) MAD, N = 25	Not measured	Not measured	Not measured
Van der Louw et al. (2019) (45) CKD/MAD, N = 9	OS: 9.8–19.0 mo	Increased fatigue. Nausea/vomiting decreased over time, GI problems reported throughout the study.	Normal values in QoL
Voss et al. (2020) (46) MAD, N = 25	OS: 250–485 day PFS: 50–261 day SC (no specific numbers)	Dietary challenges, hunger and craving for sugar pronounced at day 6	Not measured
Woodhouse et al. (2019) (47) MAD, N = 29	OS: 26.7% >24 mo	Not measured	Not measured

CKD, classical ketogenic diet; MAD, modified Atkins diet; MCT, medium-chain triglyceride ketogenic diet; PR, partial response; PD, progressive disease; SD, stable disease; SC; seizure control; QoL, quality of life.

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