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

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.), Detroit, Michigan
Division of Hematology-Oncology, Department of Otolaryngology—Head and Neck Surgery (T.D.D., H.S.P., S.C.M., R.H.M.), Detroit, Michigan
Department of Radiation Oncology (F.H.S.), Detroit, Michigan
Wayne State University School of Medicine, Department of Pediatrics and Children’s Hospital of Michigan (J.K.), Detroit, Michigan

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


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 EVIDENCE OF ZINC DEFICIENCY...
 IMPLICATIONS OF PROTEIN...
 REFERENCES
 
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 CD4+ CD45RA+ 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 hospitalizations. These observations have broad implications in the management of patients with head and neck cancer.

Key words: zinc deficiency, head and neck cancer, immune dysfunction


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
EVIDENCE OF ZINC DEFICIENCY...
 IMPLICATIONS OF PROTEIN...
 REFERENCES
 
Nutritional status is known to profoundly impact treatment morbidity and overall prognosis in head and neck cancer patients [1–12]. Various prognostic nutritional indices have been developed to predict treatment complications and overall survival [13]. It has been observed that radiation and chemotherapy 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 nutritional deficiencies improved operative morbidity in patients with gastrointestinal malignancies [14,15]. A detailed evaluation of nutritional status of patients with head and neck cancer patients is, however, lacking particularly during their initial 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 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 functions [20–24]. Mild zinc deficiency is associated with decreased 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 regulation 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 immune 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
TOP
 ABSTRACT
 INTRODUCTION
 EVIDENCE OF ZINC DEFICIENCY...
IMPLICATIONS OF PROTEIN...
 REFERENCES
 
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 documented, squamous cell carcinoma of the oral cavity, oropharynx, 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 (Karnofsky 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 Association), 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, computerized tomographic examination of the neck, chest radiograph, 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 Staging Cancer, Philadelphia, JB Lippincott, 1988). Patients were interviewed to determine their smoking and alcohol consumption 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 nutritionist 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]: PNI=158-16.6(ALB)-0.78(TSF)-0.20(TFN)-5.8(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, candida, trichophyton), 1 if one or more antigens elicit <=5 mm induration, 2 if one or more antigens elicit >=5 mm induration). Patients were categorized as either normal or (NUTR+, PNI <=20%), or malnourished (NUTR-, PNI >20%).
  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 administration 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 µg/dl were classified as zinc-deficient (ZINC-). After 1992, lymphocyte 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 (ZINC-) subjects when their lymphocyte zinc was <=50 µg/1010 cells and granulocyte zinc was <=42 µg/1010 cells. Others were classified as zinc-sufficient (ZINC+). 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 appropriate 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 hospitalization, 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 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-sufficient 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 behaviors were compared for the ZINC- and ZINC+ groups and the NUTR- and NUTR+ 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 (N0+N1) and advanced (N2+N3) 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 analysis 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 significantly lower than the controls, all other nutrient intakes were similar in the three groups (control group 1, ZINC- cancer subjects group 2, and ZINC+ cancer subjects group 3).


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

 
"Normozincemic" subjects were defined as those individuals whose zinc concentrations were: lymphocytes, 56.6±6.4 µg/1010 cells; granulocytes, 47.5±5.2 µg/1010 cells; and platelets, 2.7±0.5 µg/1010 cells (mean±SD). 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 production of IL-2, serum thymulin activity, and activity of lymphocyte 5'-NT occurred early (within 8 weeks) during depletion 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 ZINC- cancer subjects (group 2) in comparison to the ZINC+ cancer subjects (group 3).



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  		Fig. 1. Zinc intake (mean±SD) of head and neck cancer patients (zinc deficient and zinc sufficient) and zinc sufficient normal control volunteers 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].

 
Table 2 shows the body composition as obtained by bioelectric impedance technique in the three groups. Both groups of cancer subjects (ZINC- and ZINC+) 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 ZINC- and ZINC+ 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).


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

 


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  		Fig. 2. Hemoglobin, serum iron, total iron binding capacity (TIBC) and plasma cooper levels (mean±SD) for the three groups of subjects are shown. Except for the changes in TIBC which was decreased in both cancer groups in comparison to normal control volunteers, other parameters were similar in the three groups. The figure is based on data published earlier [29].

 
Serum albumin and serum transferrin levels were decreased in both ZINC- and ZINC+ 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 ZINC- and ZINC+ groups of subjects.



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  		Fig. 3. Serum albumin, pre-albumin, transferrin and PNI (mean±SD) 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].

 
Fig. 4 shows the results of zinc determination in plasma, lymphocytes, and granulocytes in ZINC- and ZINC+ 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.



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  		Fig. 4. Zinc levels (mean±SD) in plasma, lymphocytes, and granulocytes 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 comparison to the zinc-sufficient subjects were observed. The figure is based on data published earlier [29].

 
Fig. 5 and 6 show that the productions of IL-2 and TNF-{alpha} were significantly decreased in zinc-deficient subjects in both groups (cancer and healthy volunteers), whereas the productions 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 production of IL-1ß 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 subjects in both groups.



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  		Fig. 5. Production of IL-2 and TNF-{alpha} by PMNC and NK cell lytic activity (mean±SD) in zinc-sufficient and zinc-deficient subjects (controls and cancer patients) are shown here. These parameters were significantly decreased due to zinc deficiency. The figure is based on data published earlier [29].

 


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  		Fig. 6. Production (mean±SD) of IL-4, IL-5 and IL-6 by PMNC were not affected due to zinc deficiency, however, IL-1ß was increased in zinc-deficient subjects. The figure is based on data published earlier [29].

 
Fig. 7 shows the ratios of CD4+/CD8+ and CD4+CD45RA+/CD4+CD45R0+ 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 CD4+/CD8+ and CD4+CD45RA+/CD4+CD45R0+ cells were decreased in the zinc-deficient subjects.



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  		Fig. 7. CD4+/CD8+ ratio and CD45RA+/CD45R0+ in CD4+ cells (mean±SD) were decreased in zinc-deficient subjects in comparison to zinc-sufficient normal volunteers. The figure is based on data published earlier [29].

 
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 (NUTR-) whereas 43% (20/47) were nutritionally sufficient (NUTR+) 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 59±11 years for the ZINC- group and 58±10 years for the ZINC+ group. Nutritionally sufficient patients were slightly older, 61±10 years, than their NUTR- counterparts, 57±10 years (p=0.096).

Zinc status and nutrition status were not associated (p=0.6). However, zinc status was significantly associated with both tumor size (p=0.002) and disease stage (p=.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).


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  		Table 3. Effect of Zinc and Nutrition Status on Specific Baseline Variables

 
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 hospital 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 interaction (Table 4). Only zinc status had a significant effect on unplanned hospital days (zinc deficient vs. zinc sufficient, 22±32 vs. 1.5±2.9 (mean±SD), p=.04). Zinc and nutrition interaction was significant for post-operative febrile days (p=0.03) and for disease-free interval (p=0.01). 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.


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  		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

 
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 interaction between the zinc status and nutritional status.


   IMPLICATIONS OF PROTEIN NUTRITIONAL STATUS AND ZINC STATUS ON IMMUNITY AND CLINICAL MORBIDITIES IN HEAD AND NECK CANCER PATIENTS
TOP
 ABSTRACT
 INTRODUCTION
 EVIDENCE OF ZINC DEFICIENCY...
 IMPLICATIONS OF PROTEIN...
REFERENCES
 
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 homogenous 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 comparison to cereal proteins [25] and this may have been an important factor in the development of zinc deficiency in our group of subjects.

We observed an association between zinc deficiency and advanced disease stage. One could argue that this association was the result of local and systemic tumor effects influencing dietary intake and increased catabolism. However, in that case a similar relationship between the disease stage and protein nutritional status would be predicted, but this was not demonstrated 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 significant 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 immunity (antibody-mediated) associated with TH2. In mice IL-2, along with IFN-{gamma} and TNF-ß, is a defining product of the TH1 subset, whereas product of IL-4, IL-5, IL-6, and IL-10 cytokines which influence B-cell development and augment humoral 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-{gamma} 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 significantly to zinc status whereas no such correlation was seen with PNI, alcohol intake, or smoking in our subjects. Whether or not 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 carcinogen-induced tumors [38]. Animal studies have shown that zinc administration may slow the progression of induced tumors [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 must be carried out to document the effect of zinc supplementation 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 deficiency 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 patients was only slightly lower than the controls, the total iron binding capacity was decreased and this decrease was statistically significant. This observation indicates that the iron utilization in the cancer patients was decreased, even though the 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, overall stage of the cancer and unplanned hospitalizations. The longest disease-free interval was observed for the group which had both zinc sufficient and nutrition sufficient status. If these results are confirmed in larger studies, zinc supplementation may be recommended for head and neck cancer patients at presentation in order to reduce treatment and disease-related morbidities, improve immune functions and delay disease recurrence, and perhaps even prevent second primary tumors.


   ACKNOWLEDGMENTS
 
Supported in part by National Institutes of Health, National Cancer Institute Grant No. CA 43838, and Labcatal Laboratories, Paris, France.

We gratefully acknowledge the technical help of Amy Brownell, Nancy Fine, and James Nowak. We also thank Sally Bates for secretarial help.

Received January 1, 1998. Accepted May 1, 1998.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 EVIDENCE OF ZINC DEFICIENCY...
 IMPLICATIONS OF PROTEIN...
 REFERENCES
 

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