Worldwide, an estimated 644,000 new cases of H&NC are diagnosed each year, with two-thirds of these cases occurring in developing countries (1). In the United States, H&NC accounts for 3.2% (39,750) of all new cancers and 2.2% (12,460) of all cancer deaths (2). Malnutrition is common in patients with H&NC. Nutritional deficits have a significant impact on mortality, morbidity and quality of life in patients with H&NC (3).

Methods or tools designed to measure and monitor nutritional status can play a dynamic role in the recovery and quality of life for this patient population. Bioelectrical impedance analysis (BIA) has been established as a valuable tool in the evaluation of body composition and nutritional status in many patients' conditions including cancer of lung, gastrointestinal tract, cancer of pleura and ureter (4-6). BIA evaluates body components such as resistance (R) and reactance (Xc) by recording a voltage drop in applied current (7). Resistance is the opposition to the flow of an electric current, primarily related to the amount of water present in the tissues. Reactance is the resistive effect produced by the tissue interfaces and cell membranes (8). Reactance causes the current to lag behind the voltage creating a phase shift, which is quantified geometrically as the angular transformation of the ratio of reactance to resistance, or phase angle (PA).

Bioelectrical impedance vector analysis (BIVA) technique is a promising tool, using the pure data obtained by BIA evaluation for the screening and monitoring of nutrition and hydration status. BIVA has the potential to be used as a routine method in the clinical setting for assessment and management of body fluids (9). Bioelectrical impedance vector analysis allows non-invasive evaluation of soft tissue hydration and mass through pattern analysis of vector plots as height, normalized resistance, and reactance measurements (10). BIVA has been used to allow detection, monitoring and control of hydration and nutrition status using vector displacement for the feedback on treatment among patients with Alzheimer's disease (11), in stable and non-stable heart failure patients (12), in critically-ill and cardiorenal patients (13), in haemodialysis patients (14), in peritoneal dialysis patients (15) and in cancer patients (16).

In healthy populations BIVA method has been used in modeling the human body shape (17) and monitoring the variation of the hydrate status in healthy term newborns (18).

In particular, phase angle measured at 50 kHz, because of its reproducibility quality, has been used to determine and predict both the state of health in a healthy population and an altered state observed in the diseased population, with diseased conditions including cancer (10-18).

The aim of our study was to perform bioelectrical impedance analysis to investigate whether the position on the R-Xc plane of impedance vectors from adult male patients with H&NC differed from healthy male age- and BMI-matched control subjects.


MATERIALS AND METHODS
Study design

This study investigated whether the position on the R-Xc plane of impedance vectors from adult male patients with H&NC differed from healthy male age- and BMI-matched control subjects. No interventions were made based on the impedance data of patients.

This study was conducted according to the guidelines set forth in the Declaration of Helsinki, and all procedures involving human subjects/patients were approved by the Research Ethics Committee of the Medical University of Lublin, Poland. All patients gave their written informed consent as a precondition of participation in the study.

Stydy population

Between October 2009 and May 2010 56 subjects underwent examination of tissue electrical properties. Twenty-eight pre-surgical male patients with H&NC were examined between the ages of 42 and 79 years old. The histological diagnosis of these patients was squamous cell carcinoma (SCC). This study included 12 patients with laryngeal SCC, 9 patients with oropharyngeal SCC, 6 patients with oral cavity SCC, 2 patients with hypopharyngeal SCC and 1 patient with nasal cavity SCC. All patients were treated at the Otolaryngology Department, Head and Neck Oncology, of the Medical University of Lublin. Twenty-eight healthy male subjects from the same region matched by age and BMI were selected as the control group for this study. The group of patients with H&NC underwent a baseline nutritional assessment, which included laboratory measurements of serum albumin, transferrin and total protein, subjective global assessment (SGA) and BIA. The control group underwent a baseline nutritional assessment, which included SGA and BIA.

Bioimpedance

BIA was performed by a medical doctor using ImpediMed bioimpedance analysis SFB7 BioImp v1.55 (Pinkenba Qld 4008, Australia). BIA was performed after a 10 minute rest period while the patients were lying supine on a bed, with their legs apart and their arms not touching their torso. All evaluations were conducted on the patients' right side by using the 4 surface standard electrode (tetra polar) technique on the hand and foot. R and Xc were measured directly in ohms at 5, 50, 100, 200 kHz. R and Xc values were measured three times in each patient, and the mean values were used. PA was obtained from the arc-tangent ratio Xc:R. To transform the result from radians to degrees, the result that was obtained was multiplied by 180°/p.

Bioelectrical impedance vector analysis

According to the RXc graph method (27) measurements of R and Xc were standardized by the H subjects (i.e., R/H and Xc/H) and expressed in ohms per meter. By using the bivariate normal distribution of R/H and Xc/H, we calculated the bivariate 95% confidence limits for mean impedance vectors of cancer patients and healthy subjects (i.e., the limit containing the magnitude and the phase angle of the mean vectors with 95% probability). Two mean vectors, from two independent groups of subjects, were compared with the two-sample Hotelling's T2 test. Separate 95% confidence limits indicate a statistically significant difference between mean vector positions on the R-Xc plane, i.e., in their R/H, Xc/H, or both components or in their magnitude, phase angle or both (P <0.05, which is equivalent to a significant Hotelling T2test) (27).

Statistical methods

Our results are expressed as mean±S.D. The Shapiro-Wilk (S-W) test was used to assess the distribution conformity of examined parameters with a normal distribution; the Fisher (F) test was used to assess variance homogeneity. For group comparisons of metric data we used the Mann-Whitney-U-test. A p value <0.05 was considered statistically significant. The statistical analysis for this study was performed using the computer software STATISTICA v.8.0 (StatSoft, Poland). BIVA was done with BIVA software (version 2002).


RESULTS
There were no significant difference in mean values of age, weight, height and BMI between the two groups (H&NC and healthy subjects) (Table 1). As shown in Fig. 1, there was a significant displacement of the average impedance vector in cancer patients as compared with healthy controls, as indicated by separate 95% confidence limits of mean vectors (T2=13.8, P< 0.0024) due to reduced Xc values (p=0.03) with increased R values (p=0.04).

Table 1. Baseline characteristics of the H&NC patient and control group; n=28.

Fig. 1. Mean vectors of 95% confidence limits in H&NC patients (dotted black line) and healthy subjects (solid black line).

As previously stated, many research studies refer to the great reproducibility of direct bioimpedance measurements (R, X, PA) at 50 kHz. Due to the logic of this reasoning, we have chosen to illustrate our results only for 50 kHz (Fig. 1).


DISCUSSION
Malnutrition is known to be associated with adverse outcomes in cancer patients. In general, patients who have been and/or are being treated for head and neck cancer have a compromised nutritional status (19). BIA has been validated for the assessment of body composition and nutritional status in patients with cancer (20). In this study we observed a different vector distribution in H&NC group as compared with healthy subjects mateched by sex, age and BMI. The vector displacement of patients with H&NC was characterized by a reduced Xc component and, consequently, a smaller phase angle, with increased R component (Fig. 1). The study by Toso et al. reported that altered tissue properties might reflect previous complex systemic alternations induced by cancer (10). The observed impedance pattern indicated altered electrical properties of tissue, presumably of the body cell mass, because the Xc component of the impedance vector is determined mainly by dielectric properties of cell membranes of soft tissue (21-25). In our group of patients a pure disorder of soft tissue hydration can not be ruled out because the R component of the impedance vector was increased in comparison with the control group. Indeed, as documented in the literature, impedance vectors were longer and steeper in dehydration (e.g., after fluid removal by hemodialysis) (26-28). In our small study population of H&NC patients, we observed that there was a smaller distribution of water between the extra and intra cellular compartments, and that there was a greater resistance of electric current due to the smaller distribution of water in these patients. The hypothesis of altered tissue structure due to alterations induced by cancer is also consistent with findings by Kadar and colleagues (29).

The clinical usefulness of early detection of cancer metabolic activity independent of tumor mass would be determined by an increased precision of prognosis and the identification of subjects at risk for malnutrition and subsequent cancer cachexia, which can be useful in the tailoring of therapy. Our SGA results indicated that 61% of this group was well-nourished, 32% was moderately malnourished and only 7% was severely malnourished. When one considers all available information from BIA, real malnutrition may be obscured by the subjectivity of SGA, and BIA may be a more sensitive measure of the nutritional status of cancer patients.

To the best of our knowledge, this is the first study to evaluate soft tissue hydration and mass through pattern analysis of vector plots as height, normalized resistance, and reactance measurements by bioelectric impedance vector analysis among pre-surgical H&NC patients. Our study was largely restricted to newly diagnosed patients (only 4 patients had previous treatment history). The results observed in our study provide valuable information on the nutritional status of the patient prior to surgery. Other methods of assessing nutritional status in this patient population, such as SGA, may not be sensitive enough to determine a deficiency. In our opinion, further research with a larger sample size could support our results, provide an avenue for early nutritional intervention and corrective nutritional replacement, ultimately combined with oncology intervention leading to increased survival in this patient population (30). Previous studies, such as a study by De Luis DA. et al. (31) were conducted on a population of Spanish ambulatory post-surgical male patients. However, there was not an evaluation of soft tissue hydration and mass through pattern analysis of vector plots as height, normalized resistance, and reactance measurements by BIVA. Their study did not indicate how long after the surgical procedure the BIA measurements were taken. The difference in the time period of performing BIA measurement is significant as post-operative patients may experience a rapid improvement in nutritional status.

Evaluating soft tissue hydration and mass through pattern analysis of vector plots as height, normalized resistance, and reactance measurements by bioelectric impedance vector analysis among pre-surgical H&NC patients can provide a quick, simple and reproducible means to determine nutritional status. This quick assessment of the nutritional status of the patient can allow for early corrective intervention.


CONCLUSION
Pre-surgical patients diagnosed with H&NC have altered tissue electrical properties. Prospective outcome prediction and volume status assessment are difficult tasks. Rapidly available, non-invasive, bioelectric impedance vector analysis may offer objective measures to improve clinical decision-making and predict outcomes. Monitoring vector displacement trajectory toward the reference target vector position may represent useful feedback in support therapy planning of individual patients before surgery in patients with H&NC patients in order to reduce post-operational complications due to malnutrition. Further observations of a larger patient group would be valuable to monitor nutritional and therapeutic interventions in this patient population.

Acknowledgements: The authors wish to thank Professor Antonio Piccoli, University of Padua, Italy, for kindly providing the BIVA Software 2002.

Conflict of interests: None declared.


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