Review Article

Nutritional and Zinc Status of Head and Neck Cancer

Patients: An Interpretive Review

Ananda S. Prasad, MD, PhD, MACN, Frances W.J. Beck, PhD, Timothy D. Doerr, MD, Falah H. Shamsa, PhD,
Hayward S. Penny, MS, RD, Steven C. Marks, MD, Joseph Kaplan, MD, Omer Kucuk, MD, and Robert H. Mathog, MD
Department of Internal Medicine (A.S.P., F.W.J.B., O.K.), Division of Hematology-Oncology, Department of Otolaryngology—
Head and Neck Surgery (T.D.D., H.S.P., S.C.M., R.H.M.), Department of Radiation Oncology (F.H.S.), Wayne State University
School of Medicine, Department of Pediatrics and Children’s Hospital of Michigan (J.K.), Detroit, Michigan
Key words: zinc deficiency, head and neck cancer, immune dysfunction

In this review, we provide evidence based on our studies, for zinc deficiency and cell mediated immune
disorders, and the effects of protein and zinc status on clinical morbidities in patients with head and neck cancer.
We investigated subjects with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, larynx,
and hypopharynx. Patients with metastatic disease and with severe co-morbidity were excluded. Nutritional
assessment included dietary history, body composition, and prognostic nutritional index (PNI) determination.
Zinc status was determined by zinc assay in plasma, lymphocytes, and granulocytes. Pretreatment zinc status and
nutritional status were correlated with clinical outcomes in 47 patients. Assessment of immune functions
included production of TH1 and TH2 cytokines, T cell subpopulations and cutaneous delayed hypersensitivity
reaction to common antigens.
At baseline approximately 50% of our subjects were zinc-deficient based on cellular zinc criteria and had
decreased production of TH1 cytokines but not TH2 cytokines, decreased NK cell lytic activity and decreased
proportion of CD41 CD45RA1 cells in the peripheral blood. The tumor size and overall stage of the disease
correlated with baseline zinc status but not with PNI, alcohol intake, or smoking. Zinc deficiency was associated
with increased unplanned hospitalizations. The disease-free interval was highest for the group which had both
zinc sufficient and nutrition sufficient status.
Zinc deficiency and cell mediated immune dysfunctions were frequently present in patients with head and
neck cancer when seen initially. Zinc deficiency resulted in an imbalance of TH1 and TH2 functions. Zinc
deficiency was associated with increased tumor size, overall stage of the cancer and increased unplanned hospital-
izations. These observations have broad implications in the management of patients with head and neck cancer.

INTRODUCTION patients is, however, lacking particularly during their initial

Nutritional status is known to profoundly impact treatment
morbidity and overall prognosis in head and neck cancer pa-
tients [1–12]. Various prognostic nutritional indices have been
developed to predict treatment complications and overall sur-
vival [13]. It has been observed that radiation and chemother-
apy are better tolerated by cancer patients and may be even
more effective in nutritionally adequate individuals [3–5,8]. It
is previously reported that pretreatment correction of nutri-
tional deficiencies improved operative morbidity in patients
with gastrointestinal malignancies [14,15]. A detailed evalua-
tion of nutritional status of patients with head and neck cancer
presentation.
Abdulla et al [16] observed that plasma zinc was decreased
and the copper:zinc ratio in the plasma was significantly higher
in 13 patients with squamous cell carcinoma of the head and
neck in comparison to healthy controls. Those cancer patients
who showed a marked decrease in plasma zinc levels died
within 12 months. The authors suggested that plasma zinc and
copper:zinc ratio may be of value as a potential screening and
predicting test in patients with head and neck cancer. Garofalo
et al [17] however, did not observe a significant change in
plasma zinc of head and neck cancer patients.
It is now well known that serum or plasma zinc is not a

Address reprint requests to: Ananda Prasad, MD, PhD, MACN, University Health Center 5C, 4201 St. Antoine, Detroit, MI 48201.

Journal of the American College of Nutrition, Vol. 17, No. 5, 409 –418 (1998)
Published by the American College of Nutrition

409
Zinc Deficiency in Head and Neck Cancer Patients
sensitive indicator of zinc status in humans [18,19], particularly
if zinc deficiency is mild or marginal. Our studies have shown
that the assay of zinc in lymphocytes and granulocytes provides
a more accurate assessment of zinc status [18,19].
Zinc is known to play an important role in immune func-
tions [20 –24]. Mild zinc deficiency is associated with de-
creased thymulin activity and decreased production of IL-2
[18]. Inasmuch as IL-2 plays a central role in the expansion and
maintenance of thymocytes and peripheral T cell populations,
the generation of anti-viral and anti-tumor specific cytotoxic T
cells, delayed type hypersensitivity responses, and up regula-
tion of NK and T cytolytic activities, it is conceivable that even
a mild deficiency of zinc could lead to enhanced susceptibility
to infections and malignancies by impairing production of this
cytokine [20 –25]. We have recently published our observations
regarding zinc status, the effects of zinc deficiency on immune
functions, and the relationship of these parameters to clinical
morbidities in head and neck cancer patients [26 –29]. The
purpose of this paper is to review and summarize the current
knowledge concerning zinc status, nutritional status and im-
mune functions in patients with head and neck cancer. We hope
that this review will stimulate further research in this area,
inasmuch as it has been neglected thus far.
EVIDENCE OF ZINC DEFICIENCY
AND IMMUNE DISORDERS IN HEAD
AND NECK CANCER PATIENTS
We enrolled all eligible patients with a newly diagnosed
head and neck cancer presenting to the Detroit Medical Center,
Wayne State University, Detroit, Michigan or the Veterans
Administration Medical Center, Allen Park, Michigan, between
June 1987 and June 1995 for studies. Subjects were legally
competent adults with newly diagnosed, histologically docu-
mented, squamous cell carcinoma of the oral cavity, orophar-
ynx, larynx, and hypopharynx. Excluded from eligibility were:
i) patients with histories of prior cancers with the exception of
in-situ carcinoma of any site, or definitively treated basal cell or
squamous cell carcinoma of the skin or cervix, ii) patients with
suspected or proven metastatic disease beyond the cervical
lymph nodes, iii) patients with severe co-morbidity who were
unable to tolerate standard therapies and diabetic and cirrhotic
patients and iv) patients with poor performance status (Karnof-
sky score ,80), poor renal function (creatinine .1.5 mg), poor
liver function (bilirubin .1.5 mg), poor bone marrow function
(WBC ,4000, Hb ,10 g/dl, and platelets ,100,000/cu mm),
poor cardiac function (class III and IV New York Heart Asso-
ciation), and patients who received previous chemotherapy and
radiotherapy. Studies were performed after approval by Wayne
State University Human Investigation Committee. An informed
consent was obtained from each subject prior to enrollment on
the study.
All patients underwent history and physical examination,
410
computerized tomographic examination of the neck, chest ra-
diograph, panendoscopy for diagnosis and staging of their
primary lesion and histologic confirmation prior to inclusion.
At enrollment, demographic data including age and gender
were recorded. The range of ages of cancer subjects was 29 to
77 years. Fifty-two percent of the subjects were blacks, 45%
were whites, and 3% were other races. Seventy-seven percent
of the subjects were males. Tumor primary site and TNM
staging were determined for each participant using the AJCC
manual (American Joint Committee on Cancer named for Stag-
ing Cancer, Philadelphia, JB Lippincott, 1988). Patients were
interviewed to determine their smoking and alcohol consump-
tion habits. For this study, alcohol consumption was divided
into two groups: heavy drinkers, who drank more than one
drink daily; and moderate or rare drinkers, (moderate drinker
who drank one to five drinks weekly; and rare drinkers, who
either abstained or had a drink only on rare occasions). Subjects
were classified as non-smokers who never smoked. All those
who were currently smoking or had smoked in the past were
classified as smokers.
All subjects were evaluated for nutritional adequacy at
baseline and periodically during the study. A trained nutrition-
ist obtained detailed dietary history by the 3-day food records
technique. Three-day food diaries were analyzed for nutrient
content with the computer program Nutritionist IV, Version
2.0, by N-Square Computing (San Bruno, CA). Alcohol intake,
duration and amount were recorded. Also, a smoking history
(quantity and duration) was recorded. The following were
included for nutritional status assessment:
1. Anthropometric data including height, body weight, mid-
arm circumference, and skinfold thickness measurements
was recorded.
2. Lean body mass, body fat and body water were determined
by means of electrical impedance technique (RJL Systems,
St. Clair Shores, MI). Our subjects were properly hydrated,
were in good physical condition and were resting prior to the
studies.
3. Total serum protein, albumin, transferrin, cholesterol, and
total triglyceride were determined by standard methods.
4. Prognostic nutritional indicator (PNI) was determined as
described by Buzby et al [13]: PNI5158216.6(ALB)20.78
(TSF)20.20(TFN)25.8(DH). Where PNI is the risk of a
complication for an individual patient, ALB is the serum
albumin level (g/100 ml), TSF is triceps skin fold thickness
(mm), TFN is serum transferrin level (mg/100 ml) and DH
is cutaneous delayed hypersensitivity reactivity to recall
antigens (0 nonreactive to all three antigens (mumps, can-
dida, trichophyton), 1 if one or more antigens elicit #5 mm
induration, 2 if one or more antigens elicit $5 mm indura-
tion). Patients were categorized as either normal or
(NUTR1, PNI #20%), or malnourished (NUTR2, PNI
.20%).
VOL. 17, NO. 5

5. Baseline clinical studies including complete blood counts,
creatinine, liver chemistries and SMA-12 were performed.
6. Iron, copper, as well as zinc status were included in our
assessment. Iron status was assessed by measuring serum
iron, and total iron binding capacity; and copper status was
determined by measuring serum copper. The rationale for
assessing the status of all three of these trace elements is
based on the fact that iron, copper and zinc share similar
chemical properties and compete for similar binding sites in
cells. It is well known that serum copper and ceruloplasmin
levels are increased in hypozincemic states [25]. Intestinal
absorption of zinc is decreased due to oral iron administra-
tion and zinc administration is known to decrease copper
burden in patients with Wilson’s disease and sickle cell
anemia [25].
Baseline zinc status was determined for all subjects. Prior to
1992, zinc status was assessed by using plasma zinc levels as
determined by a flame atomic absorption spectrophotometer
technique (Perkin Elmer, Norwalk, CT). Levels #80 mg/dl
were classified as zinc-deficient (ZINC2). After 1992, lym-
phocyte and granulocyte zinc assays were used to determine
zinc status. Cellular zinc concentrations were analyzed from
freshly isolated peripheral blood lymphocytes using a Varian
SpectrAA-40 flameless atomic absorption spectrophotometer
with a Zeeman background corrector (Varian Instruments, Palo
Alto, CA). Based on our previous studies [18,19], we defined
zinc-deficient (ZINC2) subjects when their lymphocyte zinc
was #50 mg/1010 cells and granulocyte zinc was #42 mg/1010
cells. Others were classified as zinc-sufficient (ZINC1).
Mononuclear cell cytokine production, T cell subpopulation
and NK cell lytic activity were assessed by methods previously
published [26 –30].
All patients diagnosed with head and neck cancer were
treated very aggressively and followed very closely at our
institution. Since a majority (approximately 60%) of these
patients were expected to relapse within 2 years despite using
multimodality treatments, we followed these patients very
closely during and after treatment. It was anticipated that since
all the clinical endpoints of the study, i.e., time to relapse,
clinical documentation of relapse, number, cause and duration
of infections and hospitalizations were a routine part of our
practice, this information was available on all patients. Specific
morbidity measures were followed as dependent variables ap-
propriate for patients receiving surgery, radiation therapy, or
chemotherapy. Patients were followed during the study period
until recurrence or death. Patients who had no evidence of
cancer (clinical and pathological) and who died within the
study period were considered disease-free deaths. For this
study, a treatment morbidity was defined as any documented
medical or surgical complication which necessitated hospital-
ization, surgical intervention, or delays in completing the
planned treatment. Unplanned hospital days were defined as
days spent in the hospital or hospital emergency room beyond
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
Zinc Deficiency in Head and Neck Cancer Patients
the planned cancer treatment. Treatment delays were defined as
unplanned breaks or pauses in the course of treatment.
The ages of our controls for zinc and other laboratory assays
were 25 to 50 years and they were of mixed races and sexes.
Our previous studies have shown no differences in the zinc
concentrations and cytokines productions between zinc-suffi-
cient elder (ages 50 to 80 years) and zinc-sufficient subjects of
younger age group (18 to 50 years) [31]. As such, we felt
justified in using younger age controls for laboratory assays.
Demographics, tumor variables, smoking and alcohol be-
haviors were compared for the ZINC2 and ZINC1 groups and
the NUTR2 and NUTR1 groups. For statistical analysis,
tumor sites in the oral cavity and oropharynx were combined
and compared to combined laryngeal and hypopharyngeal sites.
Nodal status was analyzed for limited (N01N1) and advanced
(N21N3) nodal disease. For overall disease stage, early stage
I and stage II tumors were combined in one group for analysis.
A chi-square and Fisher’s exact tests were used to evaluate
the effect of zinc deficiency on the various variables such as
sex, site, tumor size, nodes status, and stage etc. Similar anal-
ysis was repeated to assess the effect of nutritional status
(deficiency) on the various variables. An association between
zinc status and nutritional status was also analyzed. Mantel-
Haenzel method was applied to assess the effect of zinc status
on various continuous variables after adjusting further for the
effect of nutrition.
Table 1 shows the dietary intake of various nutrients in
cancer subjects and controls. In general, except for the percent
ideal protein intake by the cancer subjects which was signifi-
cantly lower than the controls, all other nutrient intakes were
similar in the three groups (control group 1, ZINC2 cancer
subjects group 2, and ZINC1 cancer subjects group 3).
“Normozincemic” subjects were defined as those individu-
als whose zinc concentrations were: lymphocytes, 56.666.4
mg/1010 cells; granulocytes, 47.565.2 mg/1010 cells; and plate-
lets, 2.760.5 mg/1010 cells (mean6SD). In our previous study
in which we induced a mild deficiency of zinc experimentally
in healthy human volunteers by dietary restriction of zinc, we
observed that functional changes in lymphocytes such as pro-
duction of IL-2, serum thymulin activity, and activity of lym-
phocyte 59-NT occurred early (within 8 weeks) during deple-
tion phase. During the early phase of zinc depletion, however,
the concentrations of zinc in lymphocytes and granulocytes
were only approximately 1 SD below the normal mean and
plasma zinc concentrations remained unchanged. We have,
therefore, considered levels below 1 SD from the mean for both
lymphocytes and granulocytes zinc as indicators of mild zinc
deficiency, inasmuch as the functional changes were observed
at these levels of cellular zinc.
Fig. 1 shows the daily zinc intake in the three groups. In
general, the total zinc intake was similar in the three groups.
Interestingly, however, the zinc intake from animal protein was
less in the ZINC2 cancer subjects (group 2) in comparison to
the ZINC1 cancer subjects (group 3).
411
Zinc Deficiency in Head and Neck Cancer Patients

Table 1. Dietary Intake of Controls and Head and Neck Cancer Subjects

Duncan’s
ANOVA
Parameter Group* n5 Mean 1/2 SD Multiple Range
P Value
Comparison
Percent ideal protein intake 1 22 121.89 35.45
2 31 80.67 37.15 0.0003 2,1
3 34 86.61 37.12 3,1
Percent ideal kcal intake 1 22 108.93 34.36
2 31 92.86 35.73 0.2600
3 34 95.27 39.57
Percent kcal in supplements 1 — no supplements
2 32 26.11 34.17 0.9400
3 33 25.47 38.54
Dietary copper (mg) 1 23 1.66 0.93
2 32 1.53 0.82 N.S.
3 34 1.46 0.83
Dietary iron (mg) 1 22 14.32 5.60
2 32 15.88 8.91 0.6900
3 34 16.20 9.22
Total fat (grams) 1 23 91.93 57.23
2 31 71.90 31.03 0.2300
3 34 81.94 36.84
Vitamin A (retinol equivalents) 1 22 1031.69 644.15
2 32 1295.37 1092.82 0.3700
3 33 1411.04 1048.37
Beta carotene (retinol equivalents) 1 23 9901.67 878.00
2 32 497.22 750.94 0.3200
3 32 919.18 1684.86
Vitamin C (mg) 1 23 127.86 81.38
2 32 186.33 239.42 0.3900
3 34 180.10 135.86
Vitamin E (mg) 1 23 18.94 9.42
2 32 24.74 19.05 0.3400
3 33 25.55 19.80
Calcium (mg) 1 23 786.52 386.37
2 31 1036.95 570.20 0.2300
3 34 962.11 588.29
Group 15Normal zinc sufficient volunteers.
Group 25Zinc deficient head and neck cancer subjects.
Group 35Zinc sufficient head and neck cancer subjects.

Table 2 shows the body composition as obtained by bio-
electric impedance technique in the three groups. Both groups
of cancer subjects (ZINC2 and ZINC1) showed decreased
percent ideal weight, triceps and subscapular skin fold, arm
muscle circumference, percent body fat, and body mass index
in comparison to the controls. Percent body water and lean
body mass were increased in the cancer patients. Although in
comparison to the controls, cancer subjects showed the above
differences, in general their values were not abnormally low
and no difference between ZINC2 and ZINC1 groups was
observed. There was no significant difference in hemoglobin
concentration between the three groups (Fig. 2). Although the
serum iron in the three groups was similar, the total iron
binding capacity in both the cancer groups was decreased in
comparison to the controls (Fig. 2).
Serum albumin and serum transferrin levels were decreased
in both ZINC2 and ZINC1 cancer groups in comparison to the
controls (Fig. 3). Buzby’s prognostic nutritional indicator (PNI)
index showed mean values greater than 30% in both the cancer
groups. According to Buzby, patients with PNI scores $20%
are regarded as nutritionally deficient. Using this criteria, 50%
of our subjects were nutritionally deficient. Increased PNI
scores were approximately equally distributed between the
ZINC2 and ZINC1 groups of subjects.
Fig. 4 shows the results of zinc determination in plasma,
lymphocytes, and granulocytes in ZINC2 and ZINC1 subjects
with head and neck cancer and healthy volunteers. In cancer
patients and in healthy volunteers, plasma zinc concentrations
showed no decrease in zinc-deficient subjects. By the cellular
zinc criteria, a mild deficiency of zinc was diagnosed in 25% of
the normal healthy volunteers and 48% of the head and neck
cancer subjects. An examination of the nutritional intake of
zinc in zinc-deficient normal healthy volunteers showed that
their zinc intake was only 9 mg/day (RDA 15 mg) which was
not optimal, and this was related to self-restricted caloric intake
in control subjects who were zinc-deficient.

412 VOL. 17, NO. 5


Fig. 1. Zinc intake (mean6SD) of head and neck cancer patients (zinc
deficient and zinc sufficient) and zinc sufficient normal control volun-
teers are shown here. The zinc intake includes zinc from food and
supplements. Daily zinc intake from food was similar in all three
groups. Daily zinc intake from meats was significantly less in zinc-
deficient cancer group in comparison to zinc-sufficient cancer group.
The figure is based on data published earlier [29].
Fig. 5 and 6 show that the productions of IL-2 and TNF-a
were significantly decreased in zinc-deficient subjects in both
groups (cancer and healthy volunteers), whereas the produc-
tions of IL-4, IL-5 and IL-6 were not affected by zinc status.
The mean IL-4 production in cancer patients was higher than in
non-cancer subjects, but statistically the difference was not
significant. In zinc-deficient subjects of both groups, the pro-
duction of IL-1b was significantly increased in comparison to
the zinc sufficient subjects. NK cell lytic activity was decreased
in zinc-deficient subjects in comparison to zinc-sufficient sub-
jects in both groups.
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
Zinc Deficiency in Head and Neck Cancer Patients
Fig. 7 shows the ratios of CD41/CD81 and
CD41CD45RA1/CD41CD45R01 in non-cancer, healthy,
zinc-deficient and zinc-sufficient volunteers and zinc-deficient
head and neck cancer patients. The total lymphocyte count was
not affected by mild deficiency of zinc (data not shown);
however, the ratios of CD41/CD81 and CD41CD45RA1/
CD41CD45R01 cells were decreased in the zinc-deficient
subjects.
Complete nutritional and zinc status data were available for
47 patients in whom morbidity measures were available. 57%
(27/47) patients were classified as nutritionally deficient
(NUTR2) whereas 43% (20/47) were nutritionally sufficient
(NUTR1) based on their PNI indices. In 20 subjects who were
evaluated for morbidity measures during 1987–1992, only
plasma zinc levels were available. In other 27 subjects, cellular
zinc data were obtained between 1992–1995. We combined the
data from 1987–1995. The mean age was 59611 years for the
ZINC2 group and 58610 years for the ZINC1 group. Nutri-
tionally sufficient patients were slightly older, 61610 years,
than their NUTR2 counterparts, 57610 years (p50.096).
Zinc status and nutrition status were not associated (p50.6).
However, zinc status was significantly associated with both
tumor size (p50.002) and disease stage (p5.04). Nutrition
status was marginally associated with the site of the tumor.
Nutritionally sufficient subjects had less incidence of cancer in
the oral cavity and oro-pharynx (Table 3).
An analysis of social habits among participants in this study
showed a substantial tobacco and alcohol use among all groups
without a clear difference based on either zinc or nutrition
status. Thus, our studies showed that the tumor size and overall
stage of the tumor correlated significantly only to zinc status, and
showed no correlation with PNI, alcohol intake, or smoking.
In order to evaluate the combined effects of zinc status and
nutritional status on various variables such as unplanned hos-
pital days, number of treatment related medical morbidities,
post-operative febrile days, disease-free interval, number of
treatment delays and total days of delay in treatment, a two-way
analysis of variance (ANOVA) model was used which included
main effects of zinc status, nutritional status and their interac-
tion (Table 4). Only zinc status had a significant effect on
unplanned hospital days (zinc deficient vs. zinc sufficient,
22632 vs. 1.562.9 (mean6SD), p5.04). Zinc and nutrition
interaction was significant for post-operative febrile days
(p50.03) and for disease-free interval (p50.01). Fifty percent
of the morbidities (pulmonary and non-pulmonary) were due to
infectious episodes. Weight loss did not correlate with either
zinc status or nutrition status.
Thus, our data show that zinc status of head and neck cancer
patients affects significantly cell-mediated immune functions
and clinical morbidities. With respect to disease-free interval
and post-operative febrile days, there appears to be an interac-
tion between the zinc status and nutritional status.
413
Zinc Deficiency in Head and Neck Cancer Patients

Table 2. Body Composition of Controls and Head and Neck Cancer Subjects

Duncan’s
ANOVA
Parameter Group* n5 Mean 1/2 SD Multiple Range
P Value
Comparison
Percent ideal body weight 1 25 125.61 21.08
2 32 102.30 25.31 0.0300 2,1
3 34 102.21 15.13 3,1
Triceps skinfold (mm) 1 18 20.61 9.33
2 32 13.93 9.65 0.0020 2,1
3 33 11.24 7.06 3,1
Subscapular skinfold (mm) 1 21 18.26 6.16
2 30 13.84 6.46 0.0300 2,1
3 30 13.32 5.70 3,1
Muscle Circ. (mm) 1 21 32.27 4.70
2 32 29.25 4.15 0.0300 2,1
3 34 29.92 4.29 3,1
Percent body fat 1 25 31.72 7.21
2 32 24.76 9.81 0.0050 2,1
3 32 25.71 7.78 3,1
Percent lean body mass 1 25 68.23 7.21
2 32 75.22 9.82 0.0050 2.1
3 32 74.28 7.78 3.1
Percent body water 1 25 49.94 5.27
2 32 55.16 9.37 0.0200 2.1
3 34 53.87 4.32 3.1
Body mass index (BMI) 1 25 26.92 5.02
2 32 23.44 5.56 0.0200 2,1
3 34 23.77 4.32 3,1
Group 15Normal zinc-sufficient volunteers.
Group 25Zinc-deficient head and neck cancer subjects.
Group 35Zinc-sufficient head and neck cancer subjects.

IMPLICATIONS OF PROTEIN
NUTRITIONAL STATUS AND ZINC
STATUS ON IMMUNITY AND
CLINICAL MORBIDITIES IN HEAD
AND NECK CANCER PATIENTS
We recognize that combining the zinc status data from two
periods (prior to 1992 and post 1992) may have a skewing
effect, inasmuch as cellular zinc data were available only after
1992, nonetheless, both criteria provided a group of homoge-
nous zinc-deficient population for analysis and it is also clear
that zinc deficiency is fairly common in patients with head and
neck cancer. We believe that the zinc deficiency in our patients
preceded the onset of tumor and was most likely related to poor
dietary habits, alcohol intake, and or smoking. The zinc intake
from animal protein was significantly less in the zinc-deficient
cancer subjects in comparison to the zinc-sufficient group. Zinc
availability is considerably greater from animal protein in com-
parison to cereal proteins [25] and this may have been an
important factor in the development of zinc deficiency in our Fig. 2. Hemoglobin, serum iron, total iron binding capacity (TIBC) and
plasma cooper levels (mean6SD) for the three groups of subjects are
group of subjects.
shown. Except for the changes in TIBC which was decreased in both
We observed an association between zinc deficiency and
cancer groups in comparison to normal control volunteers, other pa-
advanced disease stage. One could argue that this association
rameters were similar in the three groups. The figure is based on data
was the result of local and systemic tumor effects influencing published earlier [29].
dietary intake and increased catabolism. However, in that case

414 VOL. 17, NO. 5

 Zinc Deficiency in Head and Neck Cancer Patients

a similar relationship between the disease stage and protein

nutritional status would be predicted, but this was not demon-
strated in our study. When first seen, our subjects had localized
tumors, their body weight was stable, food intake was not
decreased, they were afebrile and presented no evidence for
increased catabolism. Zinc deficiency was identified in 63% of
protein deficient subjects but also in 70% of patients with
normal protein status, thus indicating that zinc deficiency could
exist independent of protein status in head and neck cancer
patients.
Our study indicates that the baseline zinc status appears to
predict treatment complications. We observed statistically sig-
nificant fewer unplanned hospitalizations in the zinc sufficient
group in comparison to the zinc deficient group of subjects.
Inasmuch as the majority of treatment-related morbidities were
due to infectious episodes, the important role of zinc in cell-
mediated immunity may explain some of our findings.
The separation of T helper cells into the TH1 and TH2
categories according to their function in cell-mediated and
humoral immunity is a concept that is proving useful in the
understanding of the immune system. In this system, each
category of cells secretes a characteristic set of cytokines that
functions as a network to push the system either towards
cellular immunity (delayed type hypersensitivity and cellular
cytotoxicity) associated with TH1 or towards humoral immu-
nity (antibody-mediated) associated with TH2. In mice IL-2,

Fig. 4. Zinc levels (mean6SD) in plasma, lymphocytes, and granulo-

cytes in zinc-sufficient and zinc-deficient head and neck cancer patients
and non-cancer control subjects are shown here. Significant decrease in
lymphocyte and granulocyte zinc in zinc-deficient subjects in compar-
ison to the zinc-sufficient subjects were observed. The figure is based
on data published earlier [29].

along with IFN-g and TNF-b, is a defining product of the TH1

Fig. 3. Serum albumin, pre-albumin, transferrin and PNI (mean6SD)
are shown here. Serum albumin and transferrin levels were decreased
in both cancer group in comparison to the controls. PNI was similar in
both groups of cancer patients. The figure is based on data published
earlier [29].
subset, whereas product of IL-4, IL-5, IL-6, and IL-10 cyto-
kines which influence B-cell development and augment hu-
moral responses are products of the TH2 subsets [32–34].
Our results showed that the functions of TH1 cells were
compromised as evidenced by decreased production of IL-2
and IFN-g in zinc deficient head and neck cancer patients,
whereas the TH2 cytokines were unaffected. NK cell lytic
activity was also decreased in zinc deficient patients. Thus our
study indicates that an imbalance between the functions of TH1
and TH2 cells may have been responsible for cell mediated
immune function disorders in zinc deficient cancer patients. In
the subjects in whom cytokines were measured, the criteria for
zinc deficiency were based only on cellular zinc levels.
The stage of the disease also profoundly affects morbidities
and survival in head and neck cancer patients. In this study, the
tumor size and stage of the disease were associated signifi-
cantly to zinc status whereas no such correlation was seen with
PNI, alcohol intake, or smoking in our subjects. Whether or not

JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 415

Zinc Deficiency in Head and Neck Cancer Patients
Fig. 5. Production of IL-2 and TNF-a by PMNC and NK cell lytic
activity (mean6SD) in zinc-sufficient and zinc-deficient subjects (con-
trols and cancer patients) are shown here. These parameters were
significantly decreased due to zinc deficiency. The figure is based on
data published earlier [29].
zinc and nutrition have an effect on the disease-free interval
independent of the stage of the cancer, needs to be examined in
a larger study sample.
Zinc may influence squamous cell carcinoma of the head
and neck in several ways. Its role in DNA synthesis, and in
T-cell cytolytic activity are well established and its deficiency
may lead to progression or recurrence of malignancy [35–37].
Dietary zinc deficiency increases the methylbenzylnitrosamine
induced formation of 06-methylguanine in the esophageal DNA
of the rat and these adducts are known to induce guanine to
adenine point mutations which are responsible for certain car-
cinogen-induced tumors [38]. Animal studies have shown that
zinc administration may slow the progression of induced tu-
mors [25] and studies in humans also show that administration
of zinc and other micronutrients may have therapeutic effects in
patients with oral precancerous lesions [9]. Further research
416
Fig. 6. Production (mean6SD) of IL-4, IL-5 and IL-6 by PMNC were
not affected due to zinc deficiency, however, IL-1b was increased in
zinc-deficient subjects. The figure is based on data published earlier
[29].
must be carried out to document the effect of zinc supplemen-
tation in zinc deficient patients with squamous cell carcinoma
of the head and neck.
The nutritional intake of various nutrients in cancer patients
was not remarkably different from the control subjects in our
study. It’s interesting to note, however, that the PNI was
abnormally increased in 57% of the cancer patients. This may
be related to an overall high incidence of anergy seen in our
subjects inasmuch as anergy is used for calculation of PNI.
Fifty-seven percent of the zinc deficient and 50% of the zinc
sufficient group demonstrated anergy to common antigens. The
anergy in the zinc deficient group may be explained on the
basis of cell mediated immune dysfunctions due to zinc defi-
ciency as observed in our study, but the mechanism for anergy
in zinc-sufficient group remains unclear and deserves further
investigation.
We observed that 25% of our healthy control subjects also
had zinc deficiency based on cellular zinc criteria. The daily
zinc intake of this group was only 9 mg whereas RDA for zinc
is 15 mg. These subjects were also heavy exercisers and tended
to restrict their caloric intake. We conclude that the daily zinc
intake in these subjects was suboptimal.
Although the hemoglobin concentration in the cancer pa-
tients was only slightly lower than the controls, the total iron
binding capacity was decreased and this decrease was statisti-
cally significant. This observation indicates that the iron utili-
zation in the cancer patients was decreased, even though the
VOL. 17, NO. 5
 Zinc Deficiency in Head and Neck Cancer Patients

Table 4. P Values Based on Two-way Analysis of Variance

(ANOVA) with Main Effects of Zinc Status, Nutrition Status
and Their Interaction on Specific Variables

Zinc 3
Zinc Nutrition
Specific Variables Nutrition
p5 p5
p5
Unplanned hospital
days 0.04* 0.36 0.60
Treatment (medical
morbidities) 0.09 0.30 0.83
Post-op (febrile days) 0.24 0.19 0.03*
Disease-free interval 0.20 0.05* 0.04*
Number of treatment
delays 0.10 0.20 0.50
Days of treatment
delays 0.20 0.13 0.40
Significance at alpha50.05.
Post-op febrile days were significantly less in patients who were zinc sufficient
and nutrition sufficient.
Disease-free interval was prolonged in patients who were zinc-sufficient and
nutrition sufficient.
Modified from data published earlier [28].

cancer was localized. Plasma copper showed no change in the

cancer subjects.
In summary, zinc deficiency and cell mediated immune
dysfunctions are present in a large percentage of head and neck
cancer patients at initial presentation. Our studies showed that
zinc deficiency was associated with increased tumor size, over-
all stage of the cancer and unplanned hospitalizations. The
Fig. 7. CD41/CD81 ratio and CD45RA1/CD45R01 in CD41 cells
longest disease-free interval was observed for the group which
(mean6SD) were decreased in zinc-deficient subjects in comparison to
zinc-sufficient normal volunteers. The figure is based on data published had both zinc sufficient and nutrition sufficient status. If these
earlier [29]. results are confirmed in larger studies, zinc supplementation
may be recommended for head and neck cancer patients at
Table 3. Effect of Zinc and Nutrition Status on Specific presentation in order to reduce treatment and disease-related
Baseline Variables morbidities, improve immune functions and delay disease re-
currence, and perhaps even prevent second primary tumors.
ZINC2 vs.
ZINC2 vs. NUTR2 vs.
Specific ZINC1 Adj
ZINC1 NUTR1
Variables for Nutrition
p5 p5
p5
ACKNOWLEDGMENTS
% Males 0.500 0.700 0.300
% at site Supported in part by National Institutes of Health, National
(112)* 0.500 0.050 0.300
Cancer Institute Grant No. CA 43838, and Labcatal Laborato-
Tumor size
(112)** 0.002 1.000 0.003 ries, Paris, France.
% in Stages I We gratefully acknowledge the technical help of Amy
and II*** 0.040 0.240 0.240 Brownell, Nancy Fine, and James Nowak. We also thank Sally
% Smokers 0.700 0.140 0.700 Bates for secretarial help.
% Alcoholics 0.400 0.600 0.200
Number of subjects: ZINC2, n534, NUTR2, n527, ZINC1, n518, NUTR1,
n520.
* Nutritionally sufficient subjects had fewer incidences of cancer in the oral
cavity and pharynx.
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Received January 1998; revision accepted May 1998.
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