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Effect of Perioperative Immuno-Enhanced EnteralNutrition on Inflammatory Response, NutritionalStatus, and Outcomes in Head and Neck CancerPatients Undergoing Major SurgeryDimitrios Felekis a , Anna Eleftheriadou b , Georgios Papadakos c , Irini Bosinakou d , ElizaFerekidou e , Dimitrios Kandiloros e , Stylianos Katsaragakis e , Konstantinos Charalabopoulosf & Leonidas Manolopoulos ea Medical School, University of Athens, Hippokration Hospital, Athens, Greeceb General Hospital of Rethymnon, Crete, Greecec National Technical University of Athens, Greeced Hippokration Hospital, Athens, Greecee Medical School, University of Athens, and Hippokration Hospital, Athens, Greecef Medical School, University of Ioannina, Ioannina, GreecePublished online: 06 Nov 2010.

To cite this article: Dimitrios Felekis , Anna Eleftheriadou , Georgios Papadakos , Irini Bosinakou , Eliza Ferekidou , DimitriosKandiloros , Stylianos Katsaragakis , Konstantinos Charalabopoulos & Leonidas Manolopoulos (2010): Effect of PerioperativeImmuno-Enhanced Enteral Nutrition on Inflammatory Response, Nutritional Status, and Outcomes in Head and Neck CancerPatients Undergoing Major Surgery, Nutrition and Cancer, 62:8, 1105-1112

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Nutrition and Cancer, 62(8), 1105–1112Copyright C© 2010, Taylor & Francis Group, LLCISSN: 0163-5581 print / 1532-7914 onlineDOI: 10.1080/01635581.2010.494336

Effect of Perioperative Immuno-Enhanced Enteral Nutritionon Inflammatory Response, Nutritional Status, andOutcomes in Head and Neck Cancer PatientsUndergoing Major Surgery

Dimitrios FelekisMedical School, University of Athens, Hippokration Hospital, Athens, Greece

Anna EleftheriadouGeneral Hospital of Rethymnon, Crete, Greece

Georgios PapadakosNational Technical University of Athens, Greece

Irini BosinakouHippokration Hospital, Athens, Greece

Eliza Ferekidou, Dimitrios Kandiloros, and Stylianos KatsaragakisMedical School, University of Athens, and Hippokration Hospital, Athens, Greece

Konstantinos CharalabopoulosMedical School, University of Ioannina, Ioannina, Greece

Leonidas ManolopoulosMedical School, University of Athens, and Hippokration Hospital, Athens, Greece

Administration of imunno-enhanced nutritional support maydecrease postoperative morbidity, mortality, and infectious com-plications in cancer patients. The aim of this study was to verify thatperioperative enteral diet, enriched with the nutrients arginine, ri-bonucleic acid (RNA), and ω-3 fatty acids improves outcomes ofhead and neck cancer patients undergoing major surgery. Fortypatients with squamous cell carcinoma of the head and neck werestudied. Group 1 received no preoperative nutritional support,whereas Group 2 received an oral formula with nutrients argi-nine, RNA, and ω-3 fatty acids. After surgery, Group 1 received astandard enteral formula, whereas Group 2 received an enrichedenteral formula. Albumin (g/dl), prealbumin, fibrinogen, CRP, Il-6,and TNFa were measured 5 days before and 8 days after surgery. Nostatistically significant difference was observed for all the evaluatedmarkers between postoperative and preoperative levels for both

Submitted 2 October 2009; accepted in final form 13 January 2010.Address correspondence to Konstantinos Charalabopoulos Depart-

ment of Physiology, Clinical Unit, Medical School, University of Ioan-nina, 13 Solomou Street, 45221 Ioannina, Greece. Phone: ++30 2651097574. Fax: ++30 26510 97850. E-mail: kcharala@cc.uoi.gr

groups. The rate of complications was significantly reduced in thetotal number of patients receiving immunonutrition and in the par-ticular subgroup of well-nourished patients receiving an immuno-enhanced diet. Perioperative enteral immuno-enhanced feeding inhead and neck cancer patients undergoing major surgery may in-fluence the postoperative outcomes by reducing the frequency rateof infections and wound complications.

INTRODUCTIONMajor surgery frequently causes postoperative complications

based on dysfunction of host homeostasis, defense mechanisms,and inflammatory response. Although immune impairment inthese cases is multifactorial, the immune system may be modu-lated by specific nutritional substrates such as arginine, ribonu-cleic acid (RNA), and ω-3 fatty acids (1). Hence, nutritionalsupport is a potentially beneficial strategy to improve postoper-ative morbidity (2).

Malnutrition is reported in approximately 34% of all head andneck patients (3). It is favored by catabolic factors secreted bythe tumor, such the cytokines tumor necrosis factor-α (TNF-α),

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1106 D. FELEKIS ET AL.

interleukins (IL), and gamma-interferon (4). Other reasons arethe reduced dietary intake due to dysphagia and odynophagiaand the poor dietary habits together with excessive alcohol con-sumption.

Arginine is a semiessential amino acid that may becomeessential in catabolic states. It is a precursor for synthesis ofpolyamines and nucleic acids, both of which are indispens-able substances for cell proliferation and differentiation (5).Beneficial effects on wound healing have been reported, mak-ing arginine a potential therapeutic agent. Arginine is knownto promote T-cell proliferation and generation of lymphokine-activated killer cells (6). Moreover, it has a direct enhancingeffect on phagocytosis of neutrophils and adhesion of polymor-phonuclear cells (7). Arginine is able to reduce the production ofinflammatory mediators such as IL-1 beta, IL-6, and TNF-α atthe site of injury in rat septic models (8) and can accelerate tis-sue growth after trauma or infection (9). RNA supplementationis essential for the proliferation of immune cells or cells in-volved in wound healing and greatly increases the survival rateof infected animals (10). Dietary nucleotides, particularly thepyrimidine uracil, also appear to be essential to the normal lym-phocytes maturation (11). Omega-3 fatty acids are long-chainpolyunsaturated acids that appear to have anti-inflammatory ef-fects, possibly by interference with macrophage eicosanoid pro-duction (12). They play a role on the structural and functionalintegrity of the cell membrane, intercellular signal transduction,and synthesis of eicosanoids. In particular, they influence theproduction of prostanoids from the dienoic to the trienoic vari-ety, the later of which are much less immunosuppressive (13).By replacing other fatty acids with omega 3 fatty acids, mem-brane flexibility is enhanced, which is essential for phagocytes(14). Decrease of proinflamatory cytokines, such as Il-1β, IL-6,IL-8, and TNF-α has been found in patients with sepsis (15).

It is reported that cancer patients receiving immunonutritionperioperatively tended to have fewer postoperative complica-tions (16).

The aim of this study was to evaluate if perioperative enteraldiet rich in arginine, RNA, and ω-3 fatty acids may reduce thepostoperative complications in head and neck patients undergo-ing major surgery. In addition, an effort was made to correlatesuch supplementation with the nutritional status of these patientsand with the inflammatory response after surgery.

Postoperative complications were followed up until dis-charge (median = 12 days).

MATERIALS AND METHODSThe study was a randomized, double-blinded, prospective

trial that was carried out between 2004 and 2008. Written, in-formed consent was obtained from each patient prior to thestudy. The study was approved by the medical ethics committeeof the University of Athens Medical School, Greece.

Patients from the First Department of Otolaryngology, Uni-versity of Athens, Greece, were recruited for this study. In all

cases, there was a histologically proven diagnosis of squamouscell carcinoma of head and neck eligible for surgical treatment.No previous radiotherapy or chemotherapy was applied. Patientsdid not receive immunoglobulin before the study. Exclusion cri-teria included severely impaired renal and hepatic function andautoimmune disorders. We conducted a randomization for theselection of nutritional solution that was introduced to eachstudy patient. The randomization was based on known tech-niques (using a randomization generator). At first we decidedupon the target number for the population of patients enteringthe study. That number was decided to be up to 40 patients.This number was, also, decided to be distributed for cases ofpatients operated for larynx- or hypopharynx-sited tumors in aproportion of 80% (n = 32) and the rest 20% (n = 8) for pa-tients that were operated for oral cavity or tongue-sited tumors.We generated a series of random numbers that ranged from 1to 32 for operated patients for the larynx- or hypopharynx-sitedtumors and 1 to 8 for operated patients for the oral cavity ortongue-sited tumors. We then tabulated the two series accordingto their randomization rating. We assigned the solution for eachnumber, following the randomized sequence, using an alternat-ing mode. Patients were numbered from 1 to 32 if they were inthe first category according to the site of the tumor, and from1 to 8 for the second category, following the sequence of theirarrival, and they were introduced to the solution according to therandomization table. During the execution of the trial, we kept asight on the parameters of gender and age. It was preferable, bythe beginning of the study, that those parameters be distributedas normally as possible between the two groups. There wasno need for interruption of the randomization procedure thatwas originally scheduled because it was noticed that, followingthat procedure, no significant differences in the gender and agedistribution were observed between the two groups.

As it is described above, patients were randomly assigned to2 different treatment groups, each one containing 20 patients.Patients in Group 1 received no preoperative nutritional support,and they were asked to take a standard intake of the estimatedenergy requirements orally during the last 5 days before surgery.These requirements were calculated based on the Harris andBenedict equations for men and women, which take in to accountthe patient’s weight (kg), height (cm), and age (yr) and estimatetheir basal metabolic rate (in kcal). The current body weightwas used in the calculations if the patient had a normal oroverweight body mass index and had not lost weight during thelast time period; however, in case the patient had experienceda weight loss, the preferred weight for the energy expenditureestimation was the patient’s usual weight before the weight loss.If the patient presented obese, we calculated his adjusted bodyweight, using an appropriate equation (which takes into accounthis current and ideal weight). In order to calculate patients’ totaldaily energy expenditure, we used as physical activity Level1, 2 if the patient was sedentary or Level 1, 3 in case he wasambulatory. The abundance of the oral diet was in the form ofcomplex carbohydrates (about 50% of total kcal), an important

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EFFECTS OF PERIOPERATIVE IMMUNO-ENHANCED NUTRITION 1107

contribution derived from protein, and about 30% of the totalcalories originated from fat.

Enteral feeding was started within 24 h of surgery at a rateof 70 ml/h, via a nasogastric tube. Every 24 h the infusionrate increased until 100% of calculated requirements on Day4 after surgery. Postoperatively, Group 1 received tube feed-ing with a standard enteral formula (Nutrison, Nutricia) for 8days. Patients in Group 2 received an equivalent diet to thosein Group 1 during the last 5 days before surgery, adding an oralimmunonutrition formula supplemented with nutrients arginine,RNA, and ω-3 fatty acids (Impact, Novartis). Postoperatively,Group 2 received tube feeding with the enteral formula of Im-pact, Novartis for 8 days The immuno-enhanced formula wasincorporated in a way that caloric equivalence between Groups1 and 2 was preserved. Among the 40 patients, 30 were de-fined as well-nourished (weight loss <10% during the last 6 mobefore admission in the clinic), and 10 were characterized asmalnourished (weight loss >10% during the last 6 mo beforeadmission in the clinic). Group 1 and Group 2 were formed,respectively, from the first and the second nutritional status [15patients among the members of each group were observed to bewell-nourished, and they were signed as Group 1a and Group2a; and the rest (5) that were proven to be malnourished weresigned as Group 1b and Group 2b].

Five days before and 8 days after surgery the following pa-rameters were evaluated: Albumin (g/dl), prealbumin (mg/dl),fibrinogen (mg/dl), and C-reactive protein (CRP; mg/dl) bynephelometry (Dade Behring, Marburg, Germany), Il-6 (pg/ml),and TNF-α (pg/ml) by ELISA (ELISA Kits R&D Systems, Inc.,Minneapolis, MN).

Statistical AnalysisTo assess the response of the preceding concentration mea-

surements before and after the surgical operation we (17)

1. Calculated the mean values and the 95% uncertainty (assum-ing a t distribution) measured in preoperative and postoper-ative time.

2. Calculated the mean difference between every patient’s post-operative and preoperative measured value. We conducted a2-sided t-test on a 95% confidence level to compare thosemeans with the value of zero difference. The null hypothesisof zero difference corresponds to no significant perioperativechange in the measured value.

3. For the differences described in the previous point, we con-ducted a 2-sided t-test to compare those results between thecorresponding groups that received the two different nutri-tional solutions and between their subgroups (well nourishedand malnourished). The null hypothesis of equal periopera-tive differences, comparing the two groups, corresponds tono difference as for the impact of the selection for the nutri-tional solution for the emerging perioperative differences inmeasured concentrations.

4. We assessed the relation between the postoperative and thepreoperative measured value for each variable using a linearregression model (ordinary least squares analysis) and bycalculating the corresponding correlation coefficient.

All P values <0.05 were accepted as statistically significant.In order to compare the postoperative complications that

emerged within the groups of patients, we used the exact bi-nomial method for single sample closed cohort data (18). Thismethod uses the binomial distribution and calculates the corre-sponding tail probability for that side of the binomial distributionthat is closer to the tested result.

The probability that corresponds to the P value in Table 1is the minimum between the two values given by the followingformulas:

P (x ≤ a|π0) =∑a

x=0

(n

x

)πx

0 (1 − π0)n−x

= 1 −∑n

x=a+1

(n

x

)πx

0 (1 − π0)n−x

P (x ≥ a|π0) = 1 −∑a−1

x=0

(n

x

)πx

0 (1 − π0)n−x

=∑n

x=a

(n

x

)πx

0 (1 − π0)n−x

For the 1-sided test, we calculated p1−sided = min(P (A ≥a|π0), P (A ≥ a|π0)), and for the 2-sided test, p2−sided = 2 ∗p1−sided (doubling method), where x is the number of operatedpatients who, finally, had postoperative complications; n is thetotal number of operated patients who participated in the cohort;and π0 is the control value for the proportion of the operatedpatients who are expected to have a postoperative complication.

Due to this calculation, we added the probabilities of havinga result of up to x = a cases (e.g., postsurgery complications)within a group of n tested patients. That means we added theprobabilities of having 0, 1, and up to a cases out of n patients,which forms the nearest to the number a tail probability for thebinomial distribution with parameters (π0, n). The probabilitythat is calculated by that summation is considered as the P valuefor a corresponding statistical test, with a null hypothesis ofπ = π0.

In this particular trial, we used as a control value the pro-portion that was observed in the opposite group in comparisonwith the one examined each time. This assumption, essentially,means that we consider one of the groups as not having beenaffected at all by the treatment that was provided. In this way,the observed proportion of complications in this group is con-sidered as an estimation of the general case of not receiving anytreatment at all. Nevertheless, this imposes a weakness for thecalculation that the control value is based on a single observationand not on a precise statistical estimation.

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1108 D. FELEKIS ET AL.

TABLE 1Cases observed in respect for the complications that emerged postoperatively among the patients under study and the results of

the test based on the exact binomial methoda

Group π0 P Value

Complications Code Complications Probability 95% CI 2-Sided 1-Sided

Minor 1 3/20 .10 (= 2/20) 0.01–0.32 0.65 0.322 2/20 .15 (= 3/20) 0.03–0.38 0.81 0.40

1a 2/15 .07 (= 1/15) 0.00–0.32 0.57 0.282a 1/15 .13 (= 2/15) 0.02–0.40 0.80 0.401b 1/5 .20 (= 1/5) 0.00–0.72 1.00 >0.502b 1/5 .20 (= 1/5) 0.00–0.72 1.00 >0.50

Major 1 5/20 .05 (= 1/20) 0.00–0.25 <0.01 <0.012 1/20 .25 (= 5/20) 0.09–0.49 0.05 0.02

1a 4/15 .00 (= 0/15) 0.00–0.22 <0.01 <0.012a 0/15 .27 (= 4/15) 0.08–0.55 0.02 0.011b 1/5 .20 (= 1/5) 0.00–0.72 1.00 >0.502b 1/5 .20 (= 1/5) 0.00–0.72 1.00 >0.50

aAbbreviation is as follows: CI, confidence interval.

RESULTSThe mean age of the total group of patients under study was

62.1 ± 2.6 yr (63.2 ± 3.9 for Group 1 and 61.0 ± 3.8 for Group2). Among them, 4 were female and 36 male. Characteristicsof the patients on enrollment were similar for the two groups,reflecting the homogeneity of the patients. There were no sig-nificant differences with regard to gender, mean age, nutritionalstatus, location, and stage of the disease (Table 2). Eighteenmales and two females were included in each study group. Theprimary tumor sites were larynx and hypopharynx in 32 patients(16 in Group 1 and 16 in Group 2) and oral cavity and tongue in8 patients (4 in Group 1 and 4 in Group 2). There were no StageI patients. There were 4 Stage II patients (2 for each group), 27

Stage III patients (14 for Group 1 and 13 for Group 2), and 9Stage IV patients (4 for Group 1 and 5 for Group 2). Also, nosignificant differences between the two groups existed at entry,on a basis of the measurements conducted during the survey(Table 3).

Ten patients underwent resection of the tumor located in theoral cavity. Thirty patients underwent total or partial laryngec-tomy or pharyngolaryngectomy with the same distributions ofsurgery in Groups 1 and 2. Unilateral or bilateral neck dissectionwas performed in 19 patients (9 in Group 1 and 10 in Group 2).No episodes of bleeding or death were observed in the 8-day,postoperative period of time. Gastrointestinal tract tolerance ofboth formula diets was excellent in both groups, and no dropouts

TABLE 2Descriptive characteristics of the patients that were recruited for the study

Group

Total Well Nourished Malnourished

Characteristic 1 (n = 20) 2 (n = 20) 1a (n = 15) 2a (n = 15) 1b (n = 5) 2b (n = 5)

GenderMale 18 18 14 14 4 4Female 2 2 1 1 1 1

Age (yr)Minimum 42 48 42 48 60 55Maximum 72 75 72 74 68 75Mean ± 95% uncertainty 63.2 ± 3.9 61.0 ± 3.8 63.0 ± 5.3 60.3 ± 4.3 63.8 ± 3.8 63.0 ± 12.5

Neoplasm placementLarynx/hypopharynx 16 16 12 12 4 4Oral cavity/tongue 4 4 1 1 1 1

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TAB

LE

3St

atis

tics

for

the

mea

sure

men

tsbe

ing

cond

ucte

d(m

ean

±95

%un

cert

aint

yw

ithtd

istr

ibut

ion

assu

med

)a

Mea

sure

dT

ime

ofV

aria

ble

Uni

tsM

easu

rem

ent

Tota

lGro

upG

roup

1G

roup

2G

roup

1aG

roup

2aG

roup

1bG

roup

2b

IL-6

[pg/

ml]

Preo

pera

tivel

y3.

3±

1.2

3.1

±1.

73.

5±

2.0

3.1

±2.

12.

5±

2.1

2.9

±3.

76.

4±

5.7

Post

oper

ativ

ely

5.6

±1.

44.

1±

1.7

7.0

±2.

33.

4±

1.6

6.9

±3.

06.

1±

6.5

7.6

±4.

9Po

st–p

redi

ffer

ence

2.3

±1.

8∗∗1.

0±

2.2

3.6

±2.

8∗∗0.

3±

2.9

4.4

±3.

5∗∗3.

1±

3.0∗∗

1.2

±5.

2

P=

0.12

P=

0.06

P=

0.21

TN

F[p

g/m

l]Pr

eope

rativ

ely

1.6

±0.

41.

6±

0.5

1.5

±0.

71.

6±

0.6

1.5

±0.

81.

8±

1.4

1.7

±2.

2Po

stop

erat

ivel

y2.

8±

0.8

2.7

±0.

92.

9±

1.4

2.5

±1.

03.

2±

1.8

3.2

±2.

82.

2±

3.0

Post

–pre

diff

eren

ce1.

2±

0.7∗∗

1.1

±0.

8∗∗1.

4±

1.1∗∗

1.0

±1.

11.

7±

1.5∗∗

1.4

±1.

60.

5±

1.3

P=

0.40

P=

0.30

P=

0.29

CR

P[m

g/dl

]Pr

eope

rativ

ely

2.1

±1.

12.

5±

2.0

1.6

±1.

12.

3±

2.0

1.5

±1.

33.

3±

7.9

2.2

±2.

7Po

stop

erat

ivel

y3.

3±

1.1

3.8

±1.

92.

9±

1.4

3.2

±1.

93.

1±

1.9

5.5

±7.

12.

2±

2.2

Post

–pre

diff

eren

ce1.

2±

0.9∗∗

1.2

±1.

31.

2±

1.5

0.9

±1.

41.

7±

2.0

2.2

±3.

8−0

.1±

1.5

P=

0.49

P=

0.30

P=

0.14

Fibr

inog

en[m

g/dl

](×

102 )

Preo

pera

tivel

y4.

8±

0.7

4.8

±0.

94.

8±

1.0

4.5

±1.

04.

0±

1.0

5.6

±2.

87.

3±

2.0

Post

oper

ativ

ely

6.4

±0.

56.

2±

0.8

6.7

±0.

76.

0±

1.0

6.5

±0.

96.

9±

1.9

7.1

±1.

6Po

st–p

redi

ffer

ence

1.6

±0.

7∗∗1.

4±

1.0∗∗

1.8

±1.

1∗∗1.

5±

1.2∗∗

2.5

±1.

3∗∗1.

3±

2.2

−0.2

±1.

3

P=

0.29

P=

0.11

P=

0.06

Alb

umin

e[m

g/dl

](×

103 )

Preo

pera

tivel

y3.

9±

0.2

3.7

±0.

34.

0±

0.3

3.9

±0.

24.

3±

0.3

3.1

±0.

63.

4±

0.8

Post

oper

ativ

ely

3.6

±0.

23.

4±

0.3

3.8

±0.

23.

6±

0.3

4.0

±0.

22.

9±

0.7

3.4

±0.

5Po

st–p

redi

ffer

ence

−0.3

±0.

1∗−0

.3±

0.2∗

−0.2

±0.

2∗−0

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0.3∗

−0.3

±0.

2∗−0

.2±

0.1∗

0.0

±0.

7

P=

0.28

P=

0.43

P=

0.16

Prea

lbum

ine

[g/l]

Preo

pera

tivel

y0.

25±

0.03

0.26

±0.

050.

23±

0.03

0.25

±0.

050.

25±

0.03

0.28

±0.

200.

20±

0.06

Post

oper

ativ

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0.19

±0.

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17±

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1110 D. FELEKIS ET AL.

occurred because of intolerance. All descriptive characteristicsfor the groups of patients are shown in Table 2.

Changes in Immunological MarkersNo statistically significant differences were observed in the

values of IL-6, TNF, CRP, fibrogen, albumine, and prealboumineconcentrations between the two groups and the four subgroupspreoperatively (Table 3).

Table 3 also shows that patients receiving Nutrison and pa-tients receiving Impact had no statistically significant differenceof all the evaluated markers at a postoperative time, which holdsalso for the respective groups of well-nourished and malnour-ished patients.

For IL-6 (correlation coefficient r = .15) and fibrinogen(r = .29), no relation was observed between the preoperative andthe postoperative measurements. The linear regression analysisgives a practically horizontal line to connect the preoperativemeasurements to the postoperative.

For the rest of the markers, namely, TNF (r = .55), CRP(r = .64), albumin (r = .69), and prealbumin (r = .51), aweak relation between the preoperative and the postoperativemeasurement was observed. The conclusion on this is that anypostoperative change in the measurements of the immunologi-cal markers could be considered only as a random outcome andnot systematic on the corresponding preoperative measurements(e.g., postoperative additional or proportional change over thepreoperative measurements).

In more detail, TNF and CRP showed a slight increase post-operatively (see Table 3), whereas albumin and prealbuminshowed, respectively, a slight decrease. This holds when ex-amining the total group of the under study patients, but it is notstatistically evident for Groups 1 and 2 and their subgroups. Forall the above measurements, no significant difference was ob-served between Groups 1 and 2 and their subgroups on the basisof the difference between the postoperative and the preoperativemeasurement (see the P values below the corresponding pairsof estimated differences in Table 3).

ComplicationsWith respect to minor complications, a slight increase of the

temperature (<38◦), without an indefinable source of infection,was observed in 3 patients of Group 1 and in 2 patients of Group2. No significant difference was observed between the variousgroups in relation to the proportion of patients having minorpostoperative complications.

Regarding major complications, in Group 1, 2 patients de-veloped pneumonia, 1 patient a urinary tract infection, and 2patients developed fistula. In Group 2, only 1 patient developedwound infection. Assuming that the outcome in Group 1 is theoptimum expected from a group that would not receive anytreatment at all, there is a significant decrease in the observedoutcome within Group 2 comparing the proportion of patientshaving major postoperative complications (P < 0.05 for a 2-

sided test). This conclusion holds also for the Subgroups 1a and2a of well-nourished patients (P < 0.02 for a 2-sided test). Alldata presenting the number of complications as well as the com-parison between the ratios of complications within the 2 closedcohorts using the exact binomial method are shown in Table 1.

DISCUSSIONSurgical head and neck cancer patients experience activation

of cytokines and some degree of suppression of the cellulardefense function following surgical stress. The alterations in thehost defense mechanisms make these patients highly susceptibleto infections, and this remains an important contributing factorto poorer clinical postoperative outcomes. Recent studies havesuggested that the immune system may be modulated by theuse of specific nutritional substrates (19). Nutrients such asarginine, RNA, and ω-3 fatty acids that stimulate the cellulardefense system may influence outcomes toward a more efficientdefense response; and therefore, they may reduce infectiouscomplications in these patients.

Among markers reflecting the severity of the systemic in-flammatory response, the serum levels of the principle proin-flamatory cytokines Il-6, IL-1β, and TNF-α are the most widelystudied since they are inflammatory mediators and may finallyresult in systemic inflammatory reaction.

IL-6 is a pleiotropic cytokine that regulates proliferation anddifferentiation of leukocytes in T, B, and natural killer cellsand acts as an endogenous pyrogen and inductor of acute phaseproteins. The persistent increase in systemic IL-6 concentra-tions has been related to postoperative infectious complications(20,21).

Pulse increase of TNF-α has been correlated with poor post-operative clinical conditions. In addition, TNF-α acts synergisti-cally with IL-1β. IL-1 β mainly produced by gamma interferonactivated monocytes or during phagocytosis is an essential signalfor T-cell dependent immune responses. It induces natural killercell and lymphokine activated killer cell cytotoxicity (21,22).

Fibrinogen is a soluble protein synthesized in the liver andcirculates in the blood. At the time of an injury, fibrinogen isconverted to fibrin, which is an insoluble material that formsblood clots. Levels increase with tissue inflammation or tissuedestruction (23).

CRP is classified as an acute phase reactant, synthesized byhepatocytes, and is normally present in trace amount in theplasma. The rate of synthesis increases within a few hours fol-lowing an initial insult such as tissue injury or infection, withpeak levels obtained 48–72 h following the onset of inflamma-tion. An elevated CRP level is unequivocal evidence of an activetissue-damaging process and thus provides a simple screeningtest for inflammatory status (24).

De Luis et al. (25) evaluated the effect of postoperative en-teral nutrition supplemented with arginine in surgical head andneck cancer patients by studying inflammatory parameters. Theyfound that adding arginine did not change inflammatory status.

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EFFECTS OF PERIOPERATIVE IMMUNO-ENHANCED NUTRITION 1111

Both groups of patients, receiving enriched or standard enteralformula, had similar protein levels as well as IL-6, TNF-α, andCRP levels. CRP decreased in both groups, whereas TNF-α andIL-6 did not change at all.

Casas-Rodera et al. (26) compared postoperative immuno-enhanced enteral diet with a control diet in head and neck cancerpatients, and they found no significant intergroup differences inalbumin and prealbumin, TNF-α, and CRP. On the other hand,they demonstrated more frequent wound and general infectionsin the control group.

From our results, it was judged that the nutritional state aswell as the inflammatory response was not affected by addingimmuno-enhancing nutrients on enteral feeding. For IL-6 andfibrinogen, no relation was observed between the preoperativeand the postoperative measurements, and TNF and CRP showeda slight increase postoperatively, whereas albumin and prealbu-min showed, respectively, a slight decrease (27). Concerningcomplications, we found a statistically significant difference inmajor complications between patients receiving Impact and pa-tients receiving Nutrison. Our observations are in accordancewith the literature. A prospective multicenter study on a largenumber (N = 154) of gastrointestinal cancer patients revealedthat preoperative administration of an enteral immunonutritionsignificantly decreased the early occurrence of postoperative in-fections (28). Similarly, Braga et al. (1,29) have reported a reduc-tion of postoperative infectious complications using immuno-enhanced diet. De Luis et al. (25) studied clinical outcomes inpost postsurgical head and neck cancer patients after supplemen-tation with a high dose of enteral arginine formula and foundthat would-be complications were less frequent in the enrichednutrition group compared to the controls.

Van Bokhorst-de van der Schueren et al. (30) reported thathead and neck cancer patients with weight loss exceeding 10%during the last 6 mo before surgery are at a great risk of theoccurrence of major complications. In this study, we investi-gated whether the preoperative nutritional state influences in-flammatory reaction and immunity in head and neck cancerpatients who underwent major surgery. Patients were groupedinto a good-nutrition group and a group suggested to have latentprotein-calorie malnutrition based on the preoperative weightloss <10% during the last 6 mo before admission in the clinic.A novel finding derived from this study is that well-nourishedpatients who received immunonutrition experienced consider-ably fewer complications compared with the well-nourishedpatients treated with a standard enteral formula. Our data arein accordance with Gianotti et al. (16) who demonstrated thatin well-nourished gastrointestinal cancer patients, the admin-istration of specific compounds such as arginine, RNA, andω-3 fatty acids may improve outcome when compared witha conventional treatment. Although our series is small, it is afirst indication that that perioperative supplementation with sub-strates with immuno-activating effects such as arginine, RNA,and ω-3 fatty acids improves the postoperative outcomes in headand neck cancer patients by a pharmacological rather than by a

nutritional mechanism. We continue our trial to verify this hy-pothesis in a large population of well-nourished head and neckpatients undergoing major surgery.

ACKNOWLEDGMENTThe authors declare that there is no conflict of interest and

no funding also.

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