A Nutritional Perspective of Ketogenic Diet in Cancer: A ......narrative review on this topic, we...

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668 JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS

Narrative Review

A Nutritional Perspective of Ketogenic Diet inCancer: A Narrative Review
Camila L. P. Oliveira, MSc; Stephanie Mattingly, PhD; Ralf Schirrmacher, MD; Michael B. Sawyer, MD; Eugene J. Fine, MD;Carla M. Prado, PhD, RD*
ARTICLE INFORMATION

Article history:Submitted 29 June 2016Accepted 2 February 2017Available online 30 March 2017

Keywords:Ketogenic dietCancerMetabolismTreatmentNutrition

2212-2672/Copyright ª 2018 by the Academy ofNutrition and Dietetics.http://dx.doi.org/10.1016/j.jand.2017.02.003

*Certified in Canada.

ABSTRACTThe predominant use of glucose anaerobically by cancer cells (Warburg effect) may bethe most important characteristic the majority of these cells have in common and,therefore, a potential metabolic pathway to be targeted during cancer treatment.Because this effect relates to fuel oxidation, dietary manipulation has been hypothesizedas an important strategy during cancer treatment. As such, the concept of a ketogenicdiet (KD) in cancer emerged as a metabolic therapy (ie, targeting cancer cell meta-bolism) rather than a dietary approach. The therapeutic mechanisms of action of thishigh-fat, moderate-to-low protein, and very-low-carbohydrate diet may potentiallyinfluence cancer treatment and prognosis. Considering the lack of a dietetics-focusednarrative review on this topic, we compiled the evidence related to the use of thisdiet in humans with diverse cancer types and stages, also focusing on the nutritionand health perspective. The use of KD in cancer shows potentially promising, butinconsistent, results. The limited number of studies and differences in study designand characteristics contribute to overall poor quality evidence, limiting the ability todraw evidence-based conclusions. However, the potential positive influences a KD mayhave on cancer treatment justify the need for well-designed clinical trials to betterelucidate the mechanisms by which this dietary approach affects nutritional status,cancer prognosis, and overall health. The role of registered dietitian nutritionists isdemonstrated to be crucial in planning and implementing KD protocols in oncologyresearch settings, while also ensuring patients’ adherence and optimal nutritionalstatus.J Acad Nutr Diet. 2018;118:668-688.

DURING THE 1920S, OTTO WARBURG OBSERVEDthat most cancer cells, regardless of oxygen avail-ability and functional mitochondria, capture andmetabolize large amounts of glucose and convert it

to lactate rather than fully oxidizing it (as in the case ofhealthy respiring cells) to carbon dioxide. This phenomenon,now termed theWarburg effect,1 represents an inefficient useof glucose because the theoretical yield of adenosinetriphosphate (ATP) generated by aerobic glycolysis (2 ATP/mol glucose) is lower than that theoretically obtainedthrough mitochondrial respiration (36 ATP/mol glucose). Thisinefficient use of glucose may be countered by an increasedrate of glucose uptake, which alters levels of the in-termediates and substrates associated with glycolysis, andconsequently promotes growth, survival, proliferation, andmaintenance of tumor cells.2,3 This distinctive metabolicfeature of cancer cells is the basis for the imaging of tumortissue by positron emission tomography using the radio-labeled glucose analogue 18F-fluorodeoxyglucose (18F-FDG).4

Considering that cancer is a highly heterogeneous diseasebecause of its distinct genotypes, the Warburg effect is animportant characteristic that the majority of cancer cells havein common, representing a susceptible metabolic pathway

that could be targeted during cancer treatment. Despite beingknown for several decades for its broad applicability todiverse cancers, there have been few systematic clinical in-vestigations of the phenomenon,5 and the development oftreatment strategies based on an understanding of the im-plications of the Warburg effect have likewise been limited.The Warburg effect relates to fuel oxidation, so dietary

manipulations have been hypothesized as important strate-gies to prevent and treat cancer. As such, the ketogenic diet(KD) has emerged as a potential metabolic therapy (asopposed to simply a dietary approach) with the aim ofexploiting the aforementioned metabolic vulnerability ofcancer cells; that is, overreliance on glycolysis.6 Although theevidence of its influence on cancer is limited, a KD approachhas been extensively studied for the treatment of epilepticseizures.7 The initial application of KD to epilepsy stemmedfrom the observation that seizures were reduced or absentwhen affected individuals were fasting.8 A KD dietary patterncan simulate a fasted state because reliance on fat meta-bolism is a key characteristic under both dietary condi-tions.9,10 Although the mechanisms of action are not fullyunderstood, metabolic consequences of a KD as they relate tocancer include its influence on cancer cell epigenetics and on

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growth-factor signaling pathways, including insulin, reactiveoxygen species production, and angiogenic factors, and theinflammatory state,6,11 as described by Klement and Kam-merer.6 Its use has been extensively studied in cell and ani-mal models,12 and a few clinical trials in human beings haveaimed to establish feasibility and safety and to assessefficacy.13,14

In general, the KD is characterized by high-fat, moderate-to-low protein, and very-low carbohydrate content. Theconventional fat to carbohydrate and protein ratio of this dietis 4:1 and 3:1, respectively, which gives a macronutrientdistribution of approximately 90% fat, 2% carbohydrate, and8% protein.11 However, alternative macronutrient distribu-tions have been recently developed to increase flexibility andpalatability (eg, lower fat to carbohydrate and protein ratio,medium-chain triglyceride KD, and low glycemic indextreatment).11,15 The increased fat metabolism and limitedcarbohydrate metabolism of a KD induce a state of physio-logic ketosis with increased production of ketone bodies inthe blood (18 to 90 mg/dL [1 to 5 mmol/L]),13 decreasedglucose (65 to 80 mg/dL [3.6 to 4.4 mmol/L])11,16 and insulin(6.6 to 9.4 mU/L [45.8 to 65.2 pmol/L]),11,16 and maintenance ofblood pH levels (pH¼7.4).11,16

The macronutrient distribution range of KD is not ideal formaintenance and promotion of health and prevention ofchronic diseases according to the Acceptable MacronutrientDistribution Range recently published in the Dietary Guide-lines for Americans (10% to 35% of protein, 45% to 65% ofcarbohydrate, and 20% to 35% fat).17 However, its therapeuticmechanisms of action may transcend this concern in clinicalsettings. In fact, beneficial effects of KD have been observedin the context of conditions such as epilepsy18 and otherneurologic diseases,19 obesity,20-27 diabetes,28-31 polycysticovary syndrome,32 cancer,11 respiratory conditions,33 andcardiovascular disease.26,34-38 In these and other contexts,decreased morbidity and mortality may exceed potentialacute or chronic side effects observed with a KD dietarypattern.11 In view of the potential influence of a KD on cancertreatment or prognosis and the lack of a dietetics-focusednarrative review on this topic, this review describes the evi-dence related to the use of this diet in cancer therapyresearch, either as a standalone treatment or in conjunctionwith other therapies, focusing on the nutrition and healthperspective.

METHODSThe focus of this review is to describe original human studiesconducted in individuals diagnosed with cancer who areconsuming a KD. A literature search was performed inPubMed/MEDLINE from its inception until May 2016. Thesearch strategy consisted of two separate components, eachinvolving key words related to “cancer” and “ketogenic diet”individually. The key words in each component were linkedusing “OR” as a Boolean function, and the results of the twosections were combined by utilizing the “AND” Boolean infinal search. Nonoriginal articles, in vitro studies, studies withanimal models, studies with children, studies in which canceroriginated because of a previously diagnosed disease, andstudies in languages other than English were excluded. Allstudies meeting the inclusion criteria were reviewed—fromcase studies to randomized controlled trials—despite

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statistical approach. Titles and abstracts of retrieved studieswere screened to select potentially relevant articles. Full textof the remaining studies was then analyzed independently todetermine whether they met the established criteria. Refer-ences of eligible articles were then searched manually foradditional articles that could have been missed by the elec-tronic search. A flow chart of the literature selection processis shown in the Figure.

Studies Investigating KD in CancerA total of 14 studies published between 1988 and 2016 thatincluded 206 individuals (94 women, 106 men, and 6 notdefined) assessed effects of the KD in cancer patients (see theTable). The age and sex of participants were not mentioned inone study.39 The mean sample size was 15 participants(range¼1 to 78 participants). Study designs included 2 clin-ical trials,40,41 1 controlled clinical trial,42 1 randomizedcontrolled trial,43 5 case reports,44-48 1 retrospective study,39

1 prospective single-arm pilot study,14 1 pilot clinical study,13

1 systematic prospective cohort study,49 and 1 prospectiveobservational pilot study.50

Cancer types varied substantially among studies. The use ofconcurrent standard cancer treatments were not mentionedin four studies.40,41,44,49 Concurrent treatment includedchemotherapy (one study)43 and radiationþchemotherapy(four studies).14,39,46,47 Five studies used KD as the soletherapy.13,42,45,48,50 The duration of the dietary interventionsranged from 5 days to 12 months, and consisted of oralKD,13,39,43,47,48 oral KD plus supplements (vitamins, minerals,carnitine, arginine, highly fermented yogurt drinks, vitaminD-3, and/or n-3 fatty acid),14,40,44-46,50 and parenteral KDfeeding.42,44 No details of diet administration were providedin two studies.41,49

Nine studies assessed the effects of KD on tumor meta-bolism and/or disease progression.13,14,41,42,44,46,48-50 Amongthem, 2 reported negative results,46,48 2 showed diverse re-sults among participants,13,49 4 did not report any differencebetween treatments,14,42,44,50 and 1 demonstrated an alter-ation in cancer cell metabolism (not related to 18F-FDG)associated with the KD intervention.41 The remaining fivestudies assessed effects of the KD on metabolic and healthoutcomes as well as its safety and feasibility.39,40,43,45,47

KD and Disease ProgressionThe two studies reporting negative results were case studiesconducted in patients with glioblastoma (World HealthOrganization grade IV).46,48 In the first study, an older womanfollowed a KD for 14 days,46 compared with a 12-weekintervention in two adult men.48 Despite discrepancies inthe length of the dietary intervention, cohort, and dietcharacteristics, both studies failed to demonstrate efficacy,which could be explained by the aggressiveness of the tumortype being studied (1.5-year median survival).51,52 In addi-tion, Schwartz and colleagues48 reported a positive expres-sion of ketolytic enzymes in participants’ tumor cells,suggesting an ability to metabolize ketone bodies to produceenergy. These findings are supported by a recent study inhuman beings reporting that malignant glioma cells aregenetically heterogeneous, and have different ketolytic andglycolytic enzyme expression.53 Therefore, as concluded bythe authors, expression of ketolytic enzymes may also

JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS 669

Articles identified through database

searching in Pubmed

(n=1,353)

Screening

Included

Eligibility

Identification Additional articles searched

manually

(n=3)

Articles screened (title and abstract)

(n=1,356)

Articles excluded (n=1,342)

Reason:

Irrelevant articles (n=1,206)

Animal studies (n=59)

In vitro studies (n=15)

Studies with children (n=3)

Studies in which cancer was

originated because of a previous

diagnosed disease (n=1)

Review articles (n=51)

Letters (n=6)

Articles in other languages (n=1)

Full-text articles

assessed for eligibility

(n=14)

Articles included in the

review

(n=14)

Figure. Flow chart of the literature selection process assessing the effects of the ketogenic diet in cancer.

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determine the response or success of a KD approach. Thiscould help explain some of the inconsistencies in theliterature.53

Two studies demonstrated variable disease responseamong participants.13,49 Fine and colleagues13 conducted a 4-week pilot study to evaluate safety and feasibility of a KD insubjects diagnosed with different cancer types. They foundthat for those participants whose disease remained stable orpartially remitted, their ketotic response (measured by serumbeta-hydroxybutyrate concentration) was, on average,threefold higher when compared with those with progressivedisease (P¼0.018). This variation in disease response may beexplained by the observed difference in the degree of ketosisachieved. The second study reporting mixed findings relatingto the influence of a KD on disease progression had thelargest sample size of all human studies conducted to date49;however, very poor dietary adherence (17%) and the omissionof several relevant factors (diet access, diet composition,participants’ energy and nutrient intake, metabolicmeasurements, level of ketosis, and tumor size) limit theconclusions that may be drawn from the study. Despitethese limitations, transketolase-like-1 (TKTL1) levels were


assessed, which have been associated with aerobic glycolysisin cancer cells, and reduced levels were reported in in-dividuals ingesting a KD compared with increased levelsduring active disease. High levels of TKTL1 are associatedwith worse prognosis and development of end-stage disease.The authors concluded that TKTL1 may be a useful marker ofaerobic glycolysis and disease progression. Furthermore, theKD interventionwas found to be feasible and likely beneficial,reinforcing the need for further investigation of the uniquemetabolic characteristics of tumor cells and their response tolow-carbohydrate and high fat-diets.49

Among four studies14,42,44,50 showing no difference indisease progression with a KD intervention, two adminis-tered the KD via parenteral nutrition.42,44 The provision ofreadily available nutrients through parenteral nutrition andtheir potential influence on increasing tumor growth hasbeen an unresolved concern for more than 30 years.54 Asshown in the Table, despite similar feeding access, thesestudies differed on design, sample size, cancer type, lengthof intervention, protein content of the diet, and medicationsused by participants. Both of these studies failed to show apositive influence on disease progression. Similar to studies


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previously mentioned, Schmidt and colleagues50 could notdemonstrate a positive effect of a KD, but noted a higherprevalence of stable disease among participants whoadhered to the KD intervention compared with the observeddisease progression among dropouts. The authors indicatedthat a statistical evaluation of the effect of the diet ontumor characteristics was not feasible due to the smallsample size and participant heterogeneity. Lastly, Rieger andcolleagues14 observed that when a KD was consumed, someparticipants presented with stable disease, and the oneswith stable ketosis experienced a trend for longerprogression-free survival (6 vs 3 weeks; P¼0.069). The trendtoward significance may infer a potential clinical benefit tobe explored in larger future studies investigating synergisticeffects of a KD and chemotherapy on disease progression.Another interesting finding reported by these authors wasthat two participants did not achieve a ketotic state despiteadherence to the dietary intervention, which could beexplained by genetic or other unknown factors affecting theinfluence of a KD, also an important factor to be explored infuture studies.14

Considering that some studies have shown that KDs lead todecreased blood glucose levels and insulin secretion, glucoseuptake is altered, making 18F-FDG a suboptimal positronemission tomography tracer to evaluate the influence of thisdiet on cancer cell metabolism.4 As such, to better under-stand cancer cell metabolism and the inconsistent findings inthe literature regarding KD interventions, the authors aredeveloping positron-emitting fluorine-18 labeled ketonebody radiotracers (similar to existing carbon-11 versions)55 toinvestigate the uptake of ketone bodies by tumor tissuethrough positron emission tomography imaging.

Alterations in Cancer Cell MetabolismSchroeder and colleagues41 reported decreased lactate levelsin tumor tissue when compared with tumor-free mucosaafter 5 days of following a KD. Considering that high lactatelevels in tumor cells are related to worse prognosis inpatients with head and neck squamous cell carcinoma, thisfinding highlights one way in which nutrition can influencecancer cell metabolism, and that KD may be a promisingtherapeutic dietary approach for this cancer type. However,important limitations of the study included sample size;length of intervention; absence of a control group; and lack ofinformation regarding diet adherence, composition, feedingaccess, participant nutrient intake, level of ketosis, and effecton disease progression.

Metabolic OutcomesKD interventions were associated with blood glucose levelsthat decreased in 4 studies,39,40,44,46 did not change in 6studies,13,14,41,42,47,50 were unstable in 1 study,48 and were notmeasured in 3 studies.43,45,49 It is expected that individualsconsuming a KD would experience decreased blood glucoselevels that, nevertheless, are maintained within physiologi-cally safe levels (65 to 80 mg/dL [3.6 to 4.4 mmol/L]) becausegluconeogenesis can provide sufficient glucose for normalfunction, including nervous system requirements.16 Frequentuse of steroid medication may alter glucose metabolism, andalso gluconeogenesis, potentially explaining the conflicting


results. In addition, low adherence to the dietary interventionis another factor to be considered.In regard to lipid profile, blood lipid levels were not

measured in 8 studies,13,39-41,43,45,46,49 worsened in 2studies,44,48 improved in 1 study,50 and were unaltered in 3studies.14,42,47 Considering the high fat content of a KD,adverse effects on blood lipid levels might be expected;however, a considerable number of studies showedimprovements in blood lipid profile during KD adherence.This includes elevated high-density lipoprotein blood levels,decreased triglyceride levels, and unchanged or slightlyelevated low-density lipoprotein levels along with reductionin low-density lipoprotein density.26,34-38,56,57 Moreover,improvements of participants’ cholesterol and low-densitylipoprotein and high-density lipoprotein values observed inthe study conducted by Schmidt and colleagues50 could bepartially explained by the inclusion of n-3 fatty acids in thediet, as supported by another study.58

No differences in liver or kidney function were observed inthree studies assessing these variables,40,44,50 with lengths ofintervention ranging from 13 days to 5 months. Nitrogenbalance remained stable among participants in one study40

and was increased in another,44 with 13 and 150 days of KDintervention, respectively.

Anthropometrics and Body CompositionChanges in body weight were not measured in 2 studies,41,45

not reported in 1 study,49 unchanged in 2 studies,42,44

decreased in 7 studies,13,14,39,46-48,50 and increased in 2studies.40,43 Only two studies assessed the influence offollowing a KD on body composition, both using bioelectricalimpedance analysis (BIA).43,47 Breitkreutz and colleagues43

demonstrated that the group that received the interventionincreased body weight, body mass index, fat-free mass, andpreserved body cell mass, when compared with the controlgroup. Total body fat and extracellular mass did not differbetween groups and the extracellular mass/body cell massquotient was lower in the group that received the KD.43

However, the most recent study showed that two out of sixpatients following the KD lost weight (although all partici-pants lost weight, the loss was only significant in these twoindividuals).47 Among patients who presented with weightloss, body composition analysis showed this loss was mainlyof fat mass, with a significant decrease observed in threepatients.47 Fat-free mass increased in three patients and wasstable in the remaining.47 As measured by BIA, no significantchanges were observed in patients’ extracellular water, totalbody water, and hydration; however, intracellular waterdecreased in three patients and increased in one.47 Moreover,phase angle was decreased in one patient.47 Although theamount of protein offered is considered adequate for cancerpatients59 and positive results were demonstrated by theauthors, the body composition measurement technique usedwas BIA, which is not a gold-standard method and of ques-tionable accuracy in cancer patients.60 Furthermore, changesin hydration status are known to directly influence BIAmeasurements.61,62 Because the KD may decrease glycogenstores, altered hydration and changes in electrolyte concen-trations might have occurred (diuretic effect), consideringeach gram of glycogen is bound to 2 to 4 g water and 0.45mmol potassium.63,64


Table. Literature search of human studies investigating use of the ketogenic diet in cancer

Author(s),reference,year

Studydesign

Samplecharacteristics

Cancertype

Cancertreatment Interventiona Measurements Results

Fearon andcolleagues,40

1988

Clinical trial CachecticN¼53 women,2 men

Women: ovarian,gastric, andlung

Men: gastric andlung

NMb 13 d of interventionNasogastric feeding at aconstant rate over 24 h

Day 1-6 (normal diet):44 kcal/kg/d1.5 g protein/kg/d (wheyprotein)

4 mmol arginine/kg/d55% carbohydrate21% fatDay 7-13 (ketogenic diet):44 kcal/kg/d1.5 g protein/kg/d (wheyprotein)

4 mmol arginine/kg/d70% fat (MCTf)

Body weight Day 6: NSc

Day 13: Sd (increased)Performance score Day 6: No changee

Day 13: Increasede

Serum sodiumconcentration

Day 6: NSDay 13: S (increased)

Serum potassiumconcentration

Day 6: NSDay 13: NS

Serum chlorideconcentration

Day 6: NSDay 13: NS

Serum bicarbonateconcentration

Day 6: S (decreased)Day 13: S (increased)

Urea concentration Day 6: NSDay 13: NS

Creatinineconcentration

Day 6: NSDay 13: NS

Serum phosphateconcentration


Liver function Day 6: NSDay 13: NS

Serum albuminconcentration


Ketone bodies Day 6: NSDay 8, 10, and 13: S(increased)

Glucose Day 6: NSDay 8, 10 and 13: S(Decreased)

Lactate Day 6: NSDay 13: S (decreased)

Pyruvate Day 6: NSDay 13: S (decreased)

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Table. Literature search of human studies investigating use of the ketogenic diet in cancer (continued)


Studydesign


Cancertype


FFAg Day 6: NSDay 13: NS

Alanine Day 6: NSDay 13: NS

Glutamine Day 6: NSDay 13: NS

Insulin Day 6: NSDay 13: NS

Nitrogen balance:Whole-bodyprotein synthesis,degradation andturnover ratio

Day 6: NSDay 13: NS

Urinary creatinineexcretion

Day 6: NSDay 13: NS

Diet toleration Well tolerated

Rossi-Fanelliandcolleagues,42

1991

Controlledclinical trial

N¼2713 women14 menn¼9 in each group

Esophageal(n¼9), gastric(n¼9), andcolorectal(n¼9)

None of the patientshad previouslyreceived anti-neoplastic therapy

14-d interventionArm A (parenteral diet):Total calorie requiremententirely met bydextrose.

0.24 g/kg/d amino-acidsVitamins and mineralsArm B (parenteral diet):80% fat20% dextrose0.24 g/kg/d amino-acidsVitamins and mineralsArm C (oral diet control):isocaloricisonitrogenous

Cancer cellreplication rate

Within: NSBetween: NS

Total lymphocytescount

Within: S (decreased inArms A and B)

Between: NSBlood glucose Within: NS

Between: NSTriglyceride levels Within: NS

Between: NSBody weight Within: NS

Between: NSTriceps skinfold Within: NS

Between: NSMidarmcircumference



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Studydesign


Cancertype


Serum albumin Within: NSBetween: NS

Prealbumin Within: NSBetween: NS

Transferrin Within: NSBetween: NS

Retinol-bindingprotein


Bozzetti andcolleagues,44

1996

Case report N¼1Adult man

Desmoid tumor NM 5 moTotal parenteral nutrition28 nonprotein lipid kcal/kg/d (70% as

LCTh and 30% MCTf)1.5 g amino acid/kg/dApproximately 40 g/dglucose (oral)

4 g/d carnitine for 1 moVitamins andelectrolytes provided.Hydrazine sulfate for 2mo

Body weight No changee

Total protein Decreased, butmaintained withinnormal rangese

Serum albumin Increased, butmaintained withinnormal rangese

Cholinesterase Increased, butmaintained withinnormal rangese

Lymphocytes Decreased, butmaintained withinnormal rangese

Hemoglobin Decreased andmaintained belownormal rangese

Cholesterol Increased, butmaintained withinnormal rangese

Triglycerides Increased andmaintained abovenormal rangese

Total bilirubin Decreased andmaintained belownormal rangese


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Studydesign


Cancertype


ASTi Increased, butmaintained withinnormal rangese

ALTj Decreased andmaintained withinnormal rangese

GGTk Increased andmaintained abovenormal rangese

Alkalinephosphatase

Decreased andmaintained withinnormal rangese

Prothrombin time Increased, butmaintained withinnormal rangese

Glucose Decreased, butmaintained withinnormal rangese

Serum urea Increased, butmaintained withinnormal rangese

Serum creatinine No changee

Urine ketonebodies

Increasede

Respiratoryquotient

Decreasede

Lactate No changee

Tolerance to diet Diet well toleratedNitrogen balance Increasede

Tumor size NS


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Studydesign


Cancertype


Breitkreutz andcolleagues,43

2005

Randomizedcontrolledtrial

Moderatelymalnourishedpatients

N¼23Group A (n¼11)Group B (n¼12)

Gastrointestinaladenocarcinoma(colorectal andgastric)

Patients receivedchemotherapy

56-d interventionGroup A (conventionalnatural diet):

35 nonprotein kcal/kg/d1.1 g protein/kg/dGroup B (commercial fat-enriched drinkþnaturaldiet):

35 nonprotein kcal/kg/d1.1 g protein/kg/dDrink supplied at least 20nonprotein kcal/kg/d (9.3 g fat/100 mL)

Nutrition counseling wasprovided to bothpatient groups every14 d

Body weight Within: S (increased inGroup B)

Between: S (increased inGroup B after 4 and 8wk)

FFMl Within: NSBetween: S (increased inGroup B)

TBFm Within: NSBetween: NS

BCMn Within: S (decreased inGroup A)

Between: S (increased inGroup B after 4 and 8wk)

ECMo Within: NSBetween: NS

Quotient ECMo/BCMn

Within: S (increased inGroup A)

Between: S (decreased inGroup B)

Serum albuminconcentration

Within: S (decreased inGroup A)

Between: NSSerumcholinesteraseconcentration

Within: S (decreased inGroup A)

Between: S (increased inGroup B)

Total lymphocytecount

Within: S (decreased inGroup B)

Between: S (decreased inGroup B)


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Studydesign


Cancertype


Quality of life Within: S (decreased inGroup A, and increasedin Group B)

Between: NS

Zuccoli andcolleagues,46

2010

Case report 65-y woman Glioblastomamultiforme

Radiation andchemotherapy

14-d interventionCalorie-restrictedketogenic diet: 600kcal/d

42 g fat/dVitamins and mineralssupplementation

Body weight 8 wk after intervention:Decreasede

Blood glucoselevels

8 wk after intervention:Decreasede

Urinary ketones 8 wk after intervention:Increasede

Tumor 10 wk after suspension ofthe intervention: tumorrecurrencee

Diet-relatedadverse events

Not found

Tolerance to diet Well tolerated

Schmidt andcolleagues,50

2011

Prospectiveobservationalpilot study

N¼1612 women4 men

Advanced/metastatictumor stage ofsolid malignanttumors ofdifferent origins

No establishedtherapeuticoption available

(no chemo- orradiotherapy)

90-d interventionKetogenic diet:<70 g carbohydrate/d2.6 g/d n-3 fatty acid3 T/d olive, flaxseed, andhempseed oils with theprinciple meals

Patients were instructedin the principals andpractical realization ofthe diet

Dropout Did not tolerate the diet:2 patients

Died early: 2 patientsUnable to stick to thediet: 1 patient

Stopped due to progressof the disease: 4patients

Stopped due totreatment: 1 patient

Stopped due to weightloss and weakness: 1patient

Adherence to diet 31% of patientsEmotionalfunctioning andinsomnia

Improvede


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Studydesign


Cancertype



Not found

Ketonuria Reached in 3 patientse

Global healthstatus andfunctional score

No changee

Physical and rolefunctioning

Decreasede

Appetite loss,constipation ordiarrhea

Increasede

Fatigue and pain Increasede

Blood cholesterol S (decreased)HDLp S (decreased)LDLq S (decreased)LDL/HDL relation S (decreased)Serum triglycerides NSBlood glucoselevels

NS

Creatinine NSAlbumin NSBlood ureanitrogen

S (increased, but stillwithin normal range)

Liver parameters S (decreased, but stillwithin normal range)

Total leukocytecount

S (increased)

Body weight S (decreased)Diseaseprogression

Stable diseasee


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Studydesign


Cancertype


Fine andcolleagues,13

2012

Pilot clinicalstudy

N¼107 women3 men

Incurable,advancedcancer (varioustypes), withprogressivedisease after atleast 2conventionalanticancertreatments

Chemotherapy wasdiscontinued forat least 2 wkbefore trialinitiation

26-to 28-d interventionThe carbohydrate intakewas targeted at nohigher than 5% of totalenergy

Increased fat and proteiningestion wasencouraged to attemptto maintain stablecalorie intake andweight

Investigators instructedparticipants on how toconsume the diet

Mean caloric intake S (decreased whencompared withbaseline)

Body weight S (decreased)Diseaseprogression

Progressive disease in 4patientse

Stable disease in 5patientse

Partial remission in 1patiente

Dietary ketosis S (increased in patientswith stable disease orpartial remission)

Ketosis and seruminsulin levels

S (inverse relationbetween insulinsecretion andb-hydroxybutyrate)

Blood glucoselevels

NS


Short-term reversiblefatigue, constipation,and leg cramps

Schroeder andcolleagues,41

2013

Clinical trial N¼111 woman9 men

Advanced-stagecancer (stagesIII and IV)

NM 5-d interventionKetogenic diet

Urea Increased in tumor tissuecompared with tumor-free mucosae

Glucose Increased in tumor tissuecompared to tumor-free mucosae

Serum glucose No changee

Lactate Decreased in tumortissue compared withtumor-free mucosae


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Studydesign


Cancertype


Pyruvate Increased in tumor tissuecompared to tumor-free mucosae

Circadian rhythm ofthe tumormetabolism

No changee

Champ andcolleagues,39

2014

Retrospectivestudy

N¼6 Glioblastomamultiforme(stages III-IV)

Treatment withconcurrentchemoradiotherapyand adjuvantchemotherapy

Intervention periodvaried between 3 and12 mo

Ketogenic diet:30-50 g carbohydrate/d77% of total energyintake of fat, 8% ofcarbohydrate, and 15%of protein

Serum glucoselevels

S (decreased)


Grade I constipation andfatigue, grade II fatigue

Diet tolerance Well tolerated in allpatients

Survival 4 patients alive at amedian follow-up of 14moe

Body weight Decreasede

Ketosis Confirmed 4 out of 6patientse

Rieger andcolleagues,14

2014

Prospective,Single-ArmPilot Study

N¼2013 women7 men

Recurrentglioblastoma

Treatment withradio andchemotherapy

6- to 18-wk interventionmedian time

Ketogenic diet:60 g carbohydrate/d500 mL highly fermentedyogurt/d provided

2 different plant oils perday provided

No calorie restriction(patients instructed toeat to satiety)

Patients were instructed

Body weight S (decreased)Detectable ketosis At least once in 92% of

patients evaluatede

Blood glucose NSHbA1cr NSLipid profile NSDiet-relatedadverse events

Not found

Leukocytopenia Present in 2 patientse

Diseaseprogression

Stable disease in 3patientse


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on how to preparetheir diet

Median overallsurvival

32 wk after start of theinterventione

Adherence to diet 85% of patientsDiet toxicity Not observed

Branca andcolleagues,45

2015

Case report N¼11 woman

Recurrent breastcancer

No treatment 3-wk interventionOral vitamin D-3 (10,000IU/d)þketogenic dietrich in olive oil

Human epidermalgrowth factorreceptor

Decreased expressione

Progesteronereceptor

Increased expressione

Schwartz andcolleagues,48

2015

Case report N¼22 men

Glioblastomamultiforme

No treatment 12-wk interventionEnergy-restrictedketogenic diet:

Commercial formula toprovide a 3:1 ratio offat grams to the gramssupplied by proteinand carbohydrate

0.6 g protein/kg/d20-25 kcal/kg/dþ20%calories restriction/d

Patients were trained byan experiencedregistered dietitiannutritionist

Diseaseprogression

Tumor progressionduring the interventionin both patientse

Body weight Decreasede

Blood glucose Unstable (did notdecreased enough todesired values)e

Ketone bodies Increased in bothpatientse

Serum cholesterol Increased in 1 patiente

LDLq Increased in 1 patiente


Headache reportedbetween Week 6 and 8

Jansen andcolleagues,49

2016

Systematic,prospectivecohort study

N¼7835 women43 men

Any type oftumor, orrecurrence of atumor ormetastasizingdisease duringthe 10 yprevious to the

NM 10-mo interventionKetogenic diet

Adherence to diet 17%(partially ketogenic diet:8% and fully ketogenicdiet: 9%)

Diseaseprogression inpatients who

Improvement: 3 patientse

Stable disease: 7patientse


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initiation of thestudy

adhere toketogenic diet

Progressive disease: 1patiente

TKTL1s levels S (increased in activedisease)

S (increased in patientswho adhered toketogenic diet)

Klement andcolleagues,47

2016

Case report N¼62 women4 men

Various cancertypes Women(breast andrectum) Men(prostate,rectum, andlung)

Treatment withradio and/orchemotherapy

32- to 73-d interventionSelf-administeredketogenic diet:

<50 g carbohydrate/d (ratio <2:1, fat tocarbohydrateþprotein)

Patients were instructedabout the diet onceper week

General subjectivefeeling on thediet

“Good” for all patientse

Diet-related sideeffects

Not reported

Overall quality oflife

No change in all patientse

Body weight S (decreased in 2patients)

Fat mass S (decreased in 3patients)

FFMl S (increased in 3 patients)Hydration status NS (no change in all

patients)Phase angle S (decreased in 1 patient)Biochemical bloodparameters(complete bloodcount, lipidpanel, IGF-1t, andTSHu)

NS

b-hydroxybutyrateblood levels

S (increased in allpatients)


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Correlationbetween b-hydroxybutyrateand glucoseblood levels

S (negative correlation)

aUnless otherwise specified, a registered dietitian nutritionist was not involved, or the information was missing from the study.bNM¼not mentioned.cNS¼not statistically significant (P>0.05).dS¼statistically significant (P<0.05).eNo statistical analysis conducted.fMCT¼medium-chain triglyceride.gFFA¼free fatty acids.hLCT¼long-chain triglyceride.iAST¼aspartate aminotransferase.jALT¼alanine transaminase.kGGT¼gamma-glutamyl transpeptidase.lFFM¼fat-free mass.mTBF¼total body fat.nBCM¼body cell mass.oECM¼extracellular mass.pHDL¼high-density lipoprotein.qLDL¼low-density lipoprotein.rHbA1c¼glycated hemoglobin.sTKTL1¼transketolase-like-1.tIGF-1¼insulin-like growth factor 1.uTSH¼thyroid-stimulating hormone.

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RESEARCH

Quality of LifeQuality of life was evaluated in three studies.43,47,50 Althoughthe randomized controlled trial did not demonstrate differ-ences in quality of life between groups, within-group analysisshowed improvement in the group receiving the KD, andworsening in the control group.43 Klement and colleagues47

did not observe any differences in patients’ overall qualityof life in a single-arm pilot study. Although Schmidt andcolleagues50 reported that emotional functioning andinsomnia were improved in some participants receiving theKD, other quality-of-life parameters (global health status,functional score, global symptom score, digestive functions,fatigue, and pain) remained stable or worsened. The lattercould be reflected by the advanced stage of the disease (mostpresented with progressive disease).50 The authors hypoth-esized that some of the improvements observed amongpatients receiving the diet may have been related to theirmotivation, and the increased levels of the ketone bodybeta-hydroxybutyrate,50 which was shown to cause mildeuphoria.65

Adverse Events and Diet ToleranceDiet-related adverse events were assessed in 7studies,13,14,39,46-48,50 but were reported in only 3 studies,which included one episode of grade II fatigue39 and headachebetween weeks 6 and 8 of cancer treatment48 and short-termreversible fatigue, constipation, and leg cramps.13 Further-more, the diet was well tolerated by participants in 5studies,39,40,44,46,47 whereas in 3 studies tolerance was vari-able14,49,50 and was not mentioned in 6 studies.13,41-43,45,48

DISCUSSIONNutrition-Based PerspectiveDietary manipulations or the use of food as medicine hasbeen practiced since Hippocrates to prevent or treat manyconditions. With modern advances in science and technology,the field of nutrition has increasingly become an evidence-based therapeutic approach that develops alongside thegrowing knowledge base of biochemistry. The possibility ofsupplementing or even replacing pharmacologic treatmentswith dietary manipulation in pathologic conditions may bepromising. Moreover, using nutrition as an adjuvant thera-peutic approach has the potential to enhance drug effects in asynergistic way that could lead to decreased side effects anddependency.The recommended contribution of carbohydrate, protein,

and fat to total calorie intake of, respectively, 45% to 65%, 10%to 35%, and 20% to 35% has been associated with reduced riskof developing chronic disease and provision of adequate in-takes of essential nutrients.15 Macronutrient distributionsoutside this recommendation have been shown nonethelessto benefit health in many pathologic conditions.11,18-38

Although the therapeutic application of KD is not novel, asmentioned previously with regard to epilepsy, emergingevidence suggests its potential benefits in numerous diseases,including cancer.11 The interest in the influence of KDs incancer is growing, and a list of relevant, ongoing KD trials canbe found in a recent review article.66

The physiologic response achieved by the KD (character-ized by high-fat, moderate-to-low protein, and very-lowcarbohydrate content) includes increased fat and limited


carbohydrate metabolism with consequential influence ofnormal blood pH levels, elevated levels of ketone bodies, anddecreased levels of glucose and insulin (ketosis).7,11

In obesity, the KD has been shown to positively modifyappetite sensations through diverse mechanisms,20-22 regu-late adipose tissue metabolism,23,24 and improve metabolicfunction.25-27 In cardiovascular diseases, this diet has beenshown to improve blood lipid profiles26,34-38 and in type 2diabetes it has been shown to improve insulin sensitivity,glycemic control, and to stimulate weight loss.28-31 Asmentioned earlier, KDs may also positively influence otherconditions, but further research is needed to better elucidatethe physiologic mechanisms conferring its benefit in differentclinical scenarios.16,67 Whether a KD can prevent certaindisease states, especially metabolic-driven ones is currentlyunknown.Studies described in this review assessed the effects of a KD

in cancer patients. Potentially promising, but inconsistentresults were shown. The limited number of studies and dif-ferences in study designs and characteristics (ie, length ofintervention, sample size and characteristics, lack of a controlgroup, diet composition, feeding access, cancer type, stageand therapy, methodologies, and techniques used to assessthe results) contribute to a poor overall quality of evidenceand limit the ability to draw evidence-based conclusions.However, the positive influence KDs might have on cancertreatment justifies the need for well-designed randomizedcontrolled trials investigating its physiologic mechanism ofaction. Additional considerations to test the therapeuticinfluence of KD in cancer include the following:

� Length of intervention no shorter than 3 weeksto allow for ketoadaptation (ie, depletion ofglycogen stores,63,64 increased ketone body levels,initial increase followed by eventual decrease ingluconeogenesis—paralleling the reduction in physio-logic requirement for glucose, blood glucose levelreaching a low-normal range, and decreased triglyc-eride levels) and detectable differences in tumor sizeand metabolism.

� Assessment of ketosis state by measuring ketone bodylevels, which is also an indicator of adherence to thedietary intervention.

� In studies in which the primary purpose is cancertreatment, a measure of tumor size and/or metabolismis essential.

� Ideally, the KD intervention should be the only treat-ment being tested to determine the unique contribu-tion of ketosis and insulin inhibition. Whereaswithholding standard treatment may pose ethicalconcerns and also would serve as an impediment toaccrual, in the presurgical setting or among cancerpatients in which active surveillance is an option (ie,women diagnosed with ductal carcinoma in situ ormen diagnosed with nonaggressive prostate cancer),such protocols could be instituted.

� In studies where a KD is employed as a sole therapy,inclusion and exclusion criteria should include failureto respond to standard therapies and end organ failure,respectively.13

The macronutrient distribution characteristics of KDs couldcause unfavorable short-term side effects (eg, gastrointestinal


RESEARCH

discomfort, including constipation, lethargy, and hypoglyce-mia) or chronic adverse effects (eg, worsening lipid profile insusceptible populations, kidney stones, and renal damage).11

Acute effects are observed during the transition phase,which lasts for approximately 1 to 3 weeks, as the bodyadapts to the higher fat and lower carbohydrate content ofthe diet. Moreover, prophylactic approaches can be adoptedto counteract these side effects (eg, potassium citrate sup-plementation for kidney stones68 and gout69 and magnesiumcitrate for constipation70). Long-term adverse effects may beavoided in cases where the diet is offered to patients onlyduring the anticancer therapy (to explore its synergisticeffects).71 Certainly, researchers should bear in mind theinteraction of ketotic metabolism with the presumed mech-anism of action of a chemotherapeutic agent to judgecompatibility before prescribing this diet. As studiesevolve, the benefits and side effects of this dietary manipu-lation must be weighed in view of its potential treatmentadvantages in research populations for whom the therapeuticactions may transcend the side effects. As in any scenario, thepotential benefits and risks should be clearly discussedamong health care teams and disclosed to patients.

Body CompositionThe potential of KDs to lead to favorable changes in bodycomposition is an emerging area of interest. As mentionedpreviously, two studies reported an increase in fat-freemass.43,47 Despite methodological limitations, this is apromising finding because high fat-free mass is associatedwith better response to therapy and survival.72 In addition toproviding an adequate amount of protein (1.0 to 1.5 g protein/kg body weight/day, as recommended for cancer patients),59

a KD elicits changes in fuel oxidation. Through its influenceon nutrient partitioning, the replacement of energy sourcesfrom dietary carbohydrate with fat may ultimately influencebody composition by preserving fat-free mass and reducingfat mass. This body composition phenotype is associated withbetter treatment response, physical function, and quality oflife.72 Importantly, at a eucaloric level the increase in energyexpenditure would be unlikely to lead to substantial weightloss.73 The influence of this diet on body composition shouldbe further studied using state-of-the-art body compositiontechniques such as dual energy x-ray absorptiometry orcomputed tomography analysis.74

It is important to note that the protein content ofKDs offered to cancer patients needs to be further explored.Protein intake guidelines for oncology patients are notevidence-based, and are provided as a range adjusted basedon kilograms of body weight. The large variability of bodycomposition (amounts of fat-free vs fat mass) in this popu-lation,75,76 as well as the metabolic alterations induced by theKD (amino acids enter in the citric acid cycle, generatingglucose and nicotinamide adenine dinucleotide phosphatethrough gluconeogenesis) may influence protein re-quirements in this population. It is worth mentioning thatthe protein content of a KD is different from the Atkins diet,which is higher (w30% of total calorie intake),15 and may notconfer the same potential benefits to cancer, considering thatthe higher amino acid content may contribute to glucose andnicotinamide adenine dinucleotide phosphate generation.


Practical Considerations for Implementing a KDProtocolIf KDs are shown to confer benefits to the care of cancerpatients, its implementation will require close supervision byregistered dietitian nutritionists (RDNs). As an example,guidelines have been published to provide support for RDNswhen implementing KDs in the context of epilepsy.77-80

However, only 6 out of 14 studies reviewed here describedthe provision of nutrition counseling,13,14,43,47,50 with only 1specifically mentioning such counseling was done by RDNs.48

Before implementation of this dietary manipulation, ablood and/or urine analysis for disorders of fatty acid meta-bolism and organic acidurias will be needed, considering thatfat is the primary source of energy in this diet. These disor-ders include carnitine deficiency (primary), carnitine palmi-toyltransferase I or II deficiency, carnitine translocasedeficiency, beta-oxidation defects, pyruvate carboxylasedeficiency, and porphyria. Furthermore, complicating factors,such as presence of kidney stones, dyslipidemia, liver disease,failure to thrive, gastroesophageal reflux, poor oral intake,constipation, cardiomyopathy, and chronic metabolic acidosismust also be evaluated.A comprehensive assessment of nutritional status should

be done, including anthropometric measurements, bodycomposition, and record of food intake (online tools and appscan be used and are reviewed elsewhere).81-83 The recom-mended ketogenic ratio (or percentage of medium-chaintriglyceride oil) individualized based on participants’ prefer-ences increases diet adherence.78,80 Due to the complexity ofthe dietary regimen and potential low palatability, patientadherence depends on their commitment, motivation, andsupport throughout diet implementation and follow-up.Considering that the KD has limited amounts of fruit,

vegetables, enriched grains, and calcium-rich foods, micro-nutrient and fiber ingestion are often below recom-mendations.78,84 Although the American Cancer Societyrecommends an intake of at least 2.5 cups of vegetables andfruits per day for cancer survivors,85 the shortcoming inthese necessary food groups may be met, at least in theshort term, by multivitamin supplementation with minerals(and trace minerals) and calcium with vitamin D, as rec-ommended by the International Ketogenic Diet StudyGroup78 and a practical guide80 for epilepsy. As mentionedearlier, once implemented, patient adherence has to bemonitored to ensure that they have reached and maintaineda state of ketosis. Some of the studies included in thisreview periodically monitored blood glucose and ketonebodies in both urine and blood. These markers can be usedto evaluate the metabolic alterations required to inhibitdisease progression.13,14,39,40,44,46,48,50 Although commonlyused, urinary ketone body measurement is inferior to serumanalysis because the latter is measured quantitatively and isa better general measure of ketosis.86 With ketoadaptation,urinary excretion of ketone bodies falls and the ratio ofbeta-hydroxybutyrate to acetoacetate increases, whereasacetoacetate is the only ketone body detected in certainurine tests. Additional blood parameters such as serumelectrolyte levels and creatinine and liver function tests mayalso be used to determine hepatic and renal effects of thediet as reported in the protocol originally developed by Fineand colleagues.87


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CONCLUSIONSConsidering the prevalence of the Warburg effect across awide range of human cancers, it would seem sensible totarget this distinctive and general feature of cancer meta-bolism with a metabolic therapy. It is surprising that thisreview shows a relative lack of well-designed rigorous trialstesting the influence of specific nutrition interventions totreat cancer or optimize its treatment. Evidence-basedresearch is needed to better elucidate the effects of the KDon nutritional status, as well as its influence on cancerprognosis and overall health. Research themes should alsoinclude its mechanisms of action, doseeresponse effects,types of cancer on which there is an effect, required length ofintervention, and prognostic effect. RDNs play an importantrole in planning and implementing ketogenic protocols inoncology research settings, as well as ensuring patients’adherence and optimal nutritional status.

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RESEARCH

AUTHOR INFORMATIONC. L. P. Oliveira is a doctoral degree student, Nutrition and Metabolism, and C. M. Prado is a registered dietitian, an assistant professor, and CAIPChair in Nutrition, Food, and Health, Department of Agricultural, Food, and Nutritional Science, S. Mattingly is a postdoctoral fellow and M. B.Sawyer is an associate professor, both in the Department of Oncology, Cross Cancer Institute, and R. Schirrmacher is an associate professor,Department of Oncology, Medical Isotope Cyclotron Facility, all at the University of Alberta, Edmonton, Alberta, Canada. E. J. Fine is a clinicalprofessor, Department of Radiology (Nuclear Medicine), Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY.

Address correspondence to: Carla M. Prado, PhD, RD, Division of Human Nutrition, Department of Agricultural, Food, and Nutritional Science,University of Alberta, 4-002 Li Ka Shing Center for Health Research Innovation, Edmonton, AB, Canada T6G 2E1. E-mail: [email protected]

STATEMENT OF POTENTIAL CONFLICT OF INTERESTNo potential conflict of interest was reported by the authors.

FUNDING/SUPPORTNone to report.

688 JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS April 2018 Volume 118 Number 4

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