Académique Documents
Professionnel Documents
Culture Documents
Original article
a r t i c l e i n f o s u m m a r y
Article history: Background: We have found that a ketogenic diet (KD) during the course of radiotherapy (RT) was
Received 26 August 2015 feasible and led to a preservation or favorable changes of body composition. Based on these observations
Accepted 9 November 2015 and theoretical considerations, we initiated a study to investigate the impact of a KD or a ketogenic
breakfast intervention in patients undergoing RT.
Keywords: Methods: All patients presenting for curative RT with age between 18 and 75, body mass index between
Cancer
18 and 34 kg/m2 and a histologically confirmed cancer of the breast, colorectum or head and neck region
Ketogenic diet
are considered for inclusion. Exclusion criteria are Karnofsky index <70, pregnancy, metallic body parts
Radiotherapy
that interfere with bioimpedance analysis (BIA), type I diabetes, known enzyme defects that contradict a
KD and renal insufficiency. Randomization is achieved by all consecutive patients first entering the
control group and then an intervention group 1 until both groups contain 15 breast, 15 colorectal and 5
head and neck cancer patients. Intervention group 1 will receive each radiotherapy fraction after an
overnight fast and subsequently ingest a ketogenic breakfast consisting of (i) 50e250 ml of a medium-
chain triglyceride drink (betaquick®, vitaflo, Bad Homburg, Germany) plus (ii) 5e15 g amino acids (MAP,
dr. reinwald healthcare gmbhþco kg, Schwarzenbruck, Germany). If willing to undertake a complete KD
for the duration of RT, patients are entered into intervention group 2. Intervention group 2 does not have
to fast prior to RT fractions but will be supplemented with MAP analogous to intervention group 1. The
control group will not receive dietary advice to follow a KD or reduce carbohydrate intake. The objective
is twofold: (i) to test whether the ketogenic interventions are feasibly, as measured by the number of
dropouts; (ii) to see whether intervention groups 1 and 2 attain a better preservation of BIA phase angle
than the control group.
Endpoints: Primary endpoints are the feasibility of the interventions (measured through dropout rates),
and changes in body weight and composition (measured through BIA). Secondary endpoints are changes
in quality of life (EORTC questionnaires) and blood parameters as well as the occurrence and grade of
toxicities and grade of regression after surgery in case of colorectal carcinomas.
Trial registration: Registered under ClinicalTrials.gov Identifier no. NCT00123456.
© 2015 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights
reserved.
http://dx.doi.org/10.1016/j.clnesp.2015.11.001
2405-4577/© 2015 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Klement RJ, Sweeney RA, Impact of a ketogenic diet intervention during radiotherapy on body composition: II.
Protocol of a randomised phase I study (KETOCOMP), Clinical Nutrition ESPEN (2016), http://dx.doi.org/10.1016/j.clnesp.2015.11.001
e2 R.J. Klement, R.A. Sweeney / Clinical Nutrition ESPEN xxx (2016) e1ee6
protect normal tissue from ionizing radiation [1,3]. In a series of these changes are different from those observed when no dietary
preclinical studies and human cases the research group of Valter intervention is made. According to the preclinical data, pro-
Longo was able to show that fasting prior to chemo- and radio- longing the nocturnal postabsorptive state until the RT fraction
therapy has opposite effects on normal and tumor tissue, such on the morning could induce a differential stress response be-
that the former gets protected while the latter sensitized to tween normal and tumor tissue such that only the former ex-
therapy-induced damage [4e6]. The fasting patients mainly periences protection against radiation. If radiation is then
profited from substantially reduced side-effects. Since a “fasting followed by a ketogenic breakfast this would minimize the
metabolism” is to a large part based on the de facto reduction in postprandial rise of blood glucose levels, promote ketogenesis,
carbohydrates (CHOs) [7], CHO restriction could be considered an and sustain or mimic a fasting metabolism for some time. By
alternative to food abstention in oncological patients [8]. From the substituting with MAP, maintenance of muscle mass could be
supply of exogenous amino acids and fat a better preservation of supported without producing excessive glucose through gluco-
muscle mass would be expected without completely giving up the neogenesis. If this intervention (RT after an overnight fast fol-
positive effects of fasting which are based on molecular mecha- lowed by a ketogenic breakfast with MAP) is feasible and has
nisms that can partly be activated by CHO restriction [3]. comparable effects on body composition as a complete KD, the
Furthermore it has been shown that the ketone bodies acetoace- ketogenic breakfast could provide a practicable option for pa-
tate and b-hydroxybutyrate, whose concentrations rise with tients not willing or able to undergo a complete KD.
increasing fasting duration, have anti-tumor [9] and anti-
cachectic [10] properties. While ketogenesis is classically pro-
moted by fasting or a KD, recent data have shown that intake of 2. Materials and methods
medium-chain triglycerides (MCTs) can even then induce elevated
ketone body levels when given within the context of a not 2.1. Objectives and endpoints
necessarily CHO-restricted diet [11]. The reason is that due to their
water solubility, after absorption in the gut MCTs are directly The study hypothesis is that morning irradiation after an over-
transported to the liver via the portal vein where they stimulate night fast with subsequent ketogenic breakfast consisting of an
ketogenesis. Several studies on a KD in tumor patients have MCT drink (10e50 g MCTs per serving) and 5e15 g MAP diminishes
therefore specifically substituted with MCTs [12e14]. The the expected decrease of PA during the course of RT. The exclusive
administration of non-glucogenic amino acids could further make ingestion of a KD plus MAP should have a similar or stronger effect.
a valuable contribution to the diet of tumor patients without The primary goal is the assessment of the feasibility of both
leading to increased hepatic glucose production and nitrogen ketogenic interventions (breakfast and complete KD) during RT.
waste. With a net nitrogen utilization of 99%, the Master Amino Furthermore it should be investigated whether these interventions
Acid Pattern (MAP) supplement fulfills these properties [15]. In have a positive influence on body composition.
theory, one gram of MAP should therefore only provide 0.04 kcal if Secondary goals are the recording of quality of life, relevant
the constituting amino acids are almost entirely used for building blood parameters and regression grade after surgery in case of
bodily proteins and not as substrates for gluconeogenesis. Indeed colorectal carcinoma. A detailed description of all study endpoints
some institutions use MAP as part of a KD in the treatment of is given in Table 1.
cancer patients, in particular to maintain the amount of muscle
mass [16]. 2.2. Study collective
The effects of a dietary intervention during RT can be followed
with bioimpedance analysis (BIA) measurements [17,18]. BIA pro- 2.2.1. Patient accrual
vides an easy and fast method for assessing body composition; its Eligible patients are those that present for primary RT with
results have been validated as prognostic factors for life expectancy curative intent in our institution which is located within a com-
of cancer and other critically ill patients. Already in 2004 the ESPEN munity hospital. Of special interest in connection to CHO limitation
considered BIA as a suitable and reproducible method for assessing
fat free mass and total body water except in cases with extreme
body weight or hydration status [17,18]. Reproducibly mainly seems Table 1
to depend on whether the patient has eaten or is in a fasted state. Primary and secondary endpoints of the study.
By keeping to certain standards, the method therefore seems to Primary Dropout rates as a measure of feasibility/tolerability in
have a high reproducibility [18]. endpoints intervention groups 1 and 2
The phase angle (PA) is a directly measurable parameter and Phase angle from BIA (measured at 1, 1.5, 2, 3, 5, 7.5, 10, 15,
appears because the voltage lags behind the current due the 20, 30, 50, 75, 100, 150, 200, 300, 500, 1000 kHz; main
interest is in 5 and 50 kHz)
behavior of the cell membranes as capacities. Therefore, PA is
Body composition, a composite measure of several
established as a good indicator of cell wall integrity as well as body parameters obtained from the BIA scale (body weight, fat
composition, particularly muscularity [19]. In oncological patients mass, fat free mass, total body water, extracellular water,
there was a significant correlation between low PA and poor intracellular water)
prognosis [20,21]. A recently published prospective study has Secondary Quality of life (assessed using EORTC QLQ-C30 and site-
endpoints specific questionnaires)
shown that a RT in the head and neck, abdominal and thoracic area Blood parameters (composite measure including small
was associated with a significant reduction of PA [22]. blood count, glucose, albumin, urea, HbA1c, b-
In a pilot case study of six patients, we have found that a KD hydroxybutyrate, triglycerides, HDL and LDL cholesterol,
during RT resulted in a preservation of PA in all but one patient. creatinine, liver enzymes, insulin, IGF-1, TSH, free T3 and
T4)
The KD was tolerated well, but some patients reported diffi-
Regression grade after surgery (only for colorectal patients
culties with its everyday practicability. Therefore we initiated a undergoing neoadjuvant RT: cTN status prior to and ypTN
phase I study to investigate whether a strategic abstinence from status after surgery)
CHOs only before and shortly after each RT fraction induces Normal tissue toxicity after RT (evaluated according to
similar changes in PA and body composition measures as a National Cancer Institute Common Terminology Criteria
for Adverse Events (NCI-CTCAE) version 4.0
complete KD conducted over the whole RT period, and whether
Please cite this article in press as: Klement RJ, Sweeney RA, Impact of a ketogenic diet intervention during radiotherapy on body composition: II.
Protocol of a randomised phase I study (KETOCOMP), Clinical Nutrition ESPEN (2016), http://dx.doi.org/10.1016/j.clnesp.2015.11.001
R.J. Klement, R.A. Sweeney / Clinical Nutrition ESPEN xxx (2016) e1ee6 e3
Please cite this article in press as: Klement RJ, Sweeney RA, Impact of a ketogenic diet intervention during radiotherapy on body composition: II.
Protocol of a randomised phase I study (KETOCOMP), Clinical Nutrition ESPEN (2016), http://dx.doi.org/10.1016/j.clnesp.2015.11.001
e4 R.J. Klement, R.A. Sweeney / Clinical Nutrition ESPEN xxx (2016) e1ee6
large interest in a KD during the initial consultation, started a KD from mBCA results and those obtained by gold standard reference
their own initiative or those considered for intervention group 1 but methods [26]. To further optimize the reproducibility of BIA results,
who agreed to try a complete KD during the study consultation. all measurements are performed after an overnight fast, without
This recruitment procedure can be considered as randomized in having drunk for at least 10 h, and with an empty bladder as rec-
so far as the individual groups are filled by consecutive patients ommended by the ESPEN guidelines [18]. The mBCA device has a
without preselection. In this way we mainly try to prevent the standing platform with an integrated scale and a handrail system,
interaction between patients from intervention group 1 and the with one pair of electrodes for each hand and foot (eight-electrode
control group in order to not influence the diet of the latter. BIA). A current of 100 mA and a total of 19 frequencies between
1 kHz and 1000 kHz are used to obtain impedance measurements.
2.3.3. Bioimpedance measurements Instrumental precision is specified as 100 g for BW between 50 kg
BIA and body weight measurements are made on a seca 515/514 and 200 kg and 5 U for impedance of the left and right half of the
medical Body Composition Analyzer (mBCA; seca Deutschland, body. Following the manufacturer's instructions, body height is
Hamburg, Germany), a combination between scale and BIA device. measured to within the closest 5 mm with a seca 231 stadiometer
The device has a CE certificate and complies with the 93/42/EWG before each BIA measurement.
guidelines about medical devices. Its construction allows a high The first BIA measurement serves to define the baseline status
reproducibility of patient positioning which was partly made and is performed in the week prior to the first RT fraction. All
responsible for the good individual agreement between the seca consecutive measurements take place at least once weekly, in
Please cite this article in press as: Klement RJ, Sweeney RA, Impact of a ketogenic diet intervention during radiotherapy on body composition: II.
Protocol of a randomised phase I study (KETOCOMP), Clinical Nutrition ESPEN (2016), http://dx.doi.org/10.1016/j.clnesp.2015.11.001
R.J. Klement, R.A. Sweeney / Clinical Nutrition ESPEN xxx (2016) e1ee6 e5
general in the morning prior to irradiation. Patient appointments breakfast will be provided immediately after each RT fraction by
will be preferentially scheduled in the morning between 7:30 and our staff, ensuring adherence to the prescription. However, dietary
9:30. The final measurement takes place in the last week of RT. intake in intervention group 2 will be much less controlled, with
ketone monitoring being the main indicator of whether the diet is
2.3.4. Blood withdrawals ketogenic or not. However, we are planning to employ an registered
The first blood withdrawal is performed together with the first dietician for this study in order to ensure compliance to the KD.
BIA measurement in the week prior to the first RT session. Further The risk associated with both dietary interventions is judged as
blood withdrawals are scheduled according to the treating physi- small. Hypoglycemia could occur in both intervention groups with
cian's decision, but at least once during RT (after an expected time associated symptoms such as lightheadedness. In intervention
of three weeks into treatment). The final blood withdrawal is taken group 2, the first 2e3 weeks of the KD could induce some adaption
within the last week of RT. A regular control of ketone body and symptoms such as headache, nausea, anorexia and digestive
blood glucose levels in the intervention groups is performed once problems. In general such symptoms improve during a few weeks.
weekly on days of BIA measurements, either by the clinical labo- Intestinal problems can also occur after consuming the MCT drink,
ratory or through finger-pricktests with a FreeStyle Precision device but by increasing the doses carefully we hope to minimize these
(Abbott Diabetes Care Ltd., Range Road, Witney, UK). problems. Due to the restriction of the intervention period to a
maximum of approximately 6 weeks RT, no long term negative
effects are expected.
2.3.5. Questionnaires
In summary, this study is going to collect data on the feasibility
QoL will be assessed before, once during and at the end of RT using
of a ketogenic diet intervention in the form of a MCT and amino
the EORTC QLC-C30 questionnaire version 3.0 together with its
acid-rich ketogenic breakfast. The effects of the intervention on
disease-specific modules [27]. At termination of RT, each patient in
body composition, as well as blood parameters and quality of life,
intervention group 2 will receive a short non-validated questionnaire
will be evaluated against those on a complete KD or an unspecified
addressing several aspects of their subjective feeling with regard to
non-ketogenic control diet. If the ketogenic breakfast intervention
the KD that we used in an initial case study.
shows its feasibility and efficacy this would provide a good and less
restrictive alternative to a complete KD as a supportive option
3. Discussion
during RT.
Please cite this article in press as: Klement RJ, Sweeney RA, Impact of a ketogenic diet intervention during radiotherapy on body composition: II.
Protocol of a randomised phase I study (KETOCOMP), Clinical Nutrition ESPEN (2016), http://dx.doi.org/10.1016/j.clnesp.2015.11.001
e6 R.J. Klement, R.A. Sweeney / Clinical Nutrition ESPEN xxx (2016) e1ee6
[5] Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, [18] Kyle UG, Bosaeus I, De Lorenzo AD, Deurenberg P, Elia M, Manuel Go mez J,
et al. Fasting cycles retard growth of tumors and sensitize a range of cancer et al. Bioelectrical impedance analysis-part II: utilization in clinical practice.
cell types to chemotherapy. Sci Transl Med 2012;4:124ra27. Clin Nutr 2004;23:1430e53.
[6] Safdie F, Brandhorst S, Wei M, Wang W, Lee C, Hwang S, et al. Fasting en- [19] Selberg O, Selberg D. Norms and correlates of bioimpedance phase angle in
hances the response of glioma to chemo- and radiotherapy. PLoS One 2012;7: healthy human subjects, hospitalized patients, and patients with liver
e44603. cirrhosis. Eur J Appl Physiol 2002;86:509e16.
[7] Klein S, Wolfe RR. Carbohydrate restriction regulates the adaptive response to [20] Toso S, Piccoli A, Gusella M, Menon D, Bononi A, Crepaldi G, et al. Altered
fasting. Am J Physiol 1992;262:E631e6. tissue electric properties in lung cancer patients as detected by bioelectric
[8] Klement RJ. Mimicking caloric restriction: what about macronutrient impedance vector analysis. Nutrition 2000;16:120e4.
manipulation? A response to Meynet and Ricci. Trends Mol Med 2014;20: [21] Gupta D, Lammersfeld CA, Burrows JL, Dahlk SL, Vashi PG, Grutsch JF,
471e2. et al. Bioelectrical impedance phase angle in clinical practice: implications
[9] Fine EJ, Miller A, Quadros EV, Sequeira JM, Feinman RD. Acetoacetate reduces for prognosis in advanced colorectal cancer. Am J Clin Nutr 2004;80:
growth and ATP concentration in cancer cell lines which over-express 1634e8.
uncoupling protein 2. Cancer Cell Int 2009;9:14. [22] Da Silva Paixao EM, Gonzalez MC, Ito MK. A prospective study on the radiation
[10] Shukla SK, Gebregiworgis T, Purohit V, Chaika NV, Gunda V, Radhakrishnan P, therapy associated changes in body weight and bioelectrical standardized
et al. Metabolic reprogramming induced by ketone bodies diminishes phase angle. Clin Nutr 2014;34(3):496e500.
pancreatic cancer cachexia. Cancer Metab 2014;2:18. [23] Peine S, Knabe S, Carrero I, Brundert M, Wilhelm J, Ewert A, et al. Generation
[11] Courchesne-Loyer A, Fortier M, Tremblay-Mercier J, Chouinard- of normal ranges for measures of body composition in adults based on
Watkins Raphael, Roy M, Nugent S, et al. Stimulation of mild, sustained bioelectrical impedance analysis using the seca mBCA. Int J Body Comp Res
ketonemia by medium-chain triacylglycerols in healthy humans: estimated 2013;11:67e76.
potential contribution to brain energy metabolism. Nutrition 2013;29: [24] Hedderich J, Sachs L. Angewandte Statistik. 14th ed. Springer-Verlag Berlin
635e40. Heidelberg; 2012.
[12] Fearon KC, Borland W, Preston T, Tisdale MJ, Shenkin A, Calman KC. Cancer [25] Ka€mmerer U, Schlatterer C, Knoll G. Krebszellen lieben Zucker - Patienten
cachexia: influence of systemic ketosis on substrate levels and nitrogen brauchen Fett. 1st ed. 2012. Systemed.
metabolism. Am J Clin Nutr 1988;47:42e8. [26] Bosy-Westphal A, Schautz B, Later W, Kehaylas J, Gallagher D, Müller M. What
[13] Nebeling LC, Lerner E. Implementing a ketogenic diet based on medium-chain makes a BIA equation unique? validity of eight-electrode multifrequency BIA
triglyceride oil in pediatric patients with cancer. J Am Diet Assoc 1995;95: to estimate body composition in a healthy adult population. Eur J Clin Nutr
693e7. 2013;67(Suppl. 1):S14e21.
[14] Schmidt M, Pfetzer N, Schwab M, Strauss I, K€ammerer U. Effects of a ketogenic [27] Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The
diet on the quality of life in 16 patients with advanced cancer: a pilot trial. European Organization for Research and Treatment of Cancer QLC-C30: a
Nutr Metab 2011;8:54. quality-of-life instrument for use in international clinical trials in oncology.
[15] Luca-Moretti M. Discovery of the master amino acid pattern. Ann R Acad Med J Natl Cancer Inst 1993;85:365e76.
Spain 1998;CXV:397e416. [28] Buse MG, Biggers JF, Friderici KH, Buse JF. Oxidation of branched chain amino
[16] Ruggiero M, Ward E, Smith R, Branca JJV, Noakes D, Morucci G, et al. Oleic acid, acids by isolated hearts and diaphragms of the rat. The effect of fatty acids,
deglycosylated vitamin D-binding protein, nitric oxide: a molecular triad glucose, and pyruvate respiration. J Biol Chem 1972;247:8085e96.
made lethal to cancer. Anticancer Res 2014;34:3569e78. [29] Palaiologos G, Felig P. Effects of ketone bodies on amino acid metabolism in
[17] Kyle UG, Bosaeus I, De Lorenzo AD, Deurenberg P, Elia M, Go mez JM, et al. isolated rat diaphragm. Biochem J 1976;154:709e16.
Bioelectrical impedance analysisepart I: review of principles and methods. [30] Sherwin RS, Hendler RG, Felig P. Effect of ketone infusions on amino acid and
Clin Nutr 2004;23:1226e43. nitrogen metabolism in man. J Clin Invest 1975;55:1382e90.
Please cite this article in press as: Klement RJ, Sweeney RA, Impact of a ketogenic diet intervention during radiotherapy on body composition: II.
Protocol of a randomised phase I study (KETOCOMP), Clinical Nutrition ESPEN (2016), http://dx.doi.org/10.1016/j.clnesp.2015.11.001