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Nutrition in acute and chronic diseases

# Weight loss, phase angle, and survival in cancer patients undergoing radiotherapy: a prospective study with 10-year follow-up

## Abstract

### Background/Objectives

Cancer patients undergoing radiotherapy (RT) frequently experience weight loss and changes in body composition, which negatively affect their nutritional status, lead to a poor clinical prognosis, and reduce survival rates. This study aimed to evaluate whether changes in body weight, phase angle, and standardized phase angle are associated with longer survival in cancer patients undergoing RT.

### Methods

This prospective cohort study included 62 cancer patients who underwent RT between 2008 and 2009 and were followed until 2019. Anthropometric and bioelectrical impedance analysis data were assessed before and after RT. The Kaplan–Meier method was used to calculate survival, and mortality risk was assessed using the Cox proportional hazards model.

### Results

Kaplan–Meier analysis indicated no significant difference in survival time after the 10-year follow-up between patients who had weight loss during RT and those with weight maintenance or weight gain during RT. Mortality risk was associated, in the adjusted multivariate analysis, with age (p = 0.023), site of treatment (p = 0.001), and weight loss during RT (p = 0.044). Every 1 kg lost increased the risk of death by 25% compared with patients who maintained or gained weight during RT. Changes in phase angle and standardized phase angle after RT were not associated with increased mortality risk.

### Conclusions

Weight loss during RT, site of treatment, and age are associated with a higher risk of death in cancer patients after the 10-year follow-up.

## Introduction

Mortality in cancer patients has been associated with weight loss and malnutrition [1, 2]. These manifestations are usually observed in patients with advanced cancer and represent major contributors to morbidity and mortality [3].

Phase angle (PA) is a parameter derived from bioelectric impedance analysis (BIA) and is an expression of cell integrity. Higher PA has been associated with better outcomes and survival and is suggested as a prognostic tool for patients in many disease conditions, including cancer [1,2,3]. A standardized PA (SPA) was proposed to correct the PA results for factors such as sex, age, and body mass index and to allow comparison between different populations [4, 5].

Cancer patients undergoing radiotherapy (RT) frequently present with weight loss, which may potentially and negatively affect their nutritional status. PA and SPA are closely associated with weight loss during RT [6]. In patients with head and neck cancer, PA and SPA at diagnosis [7] and weight loss before and during RT [8] were prognostic indicators for 5-year survival. However, it is not well known whether nutritional status and changes in PA and SPA during RT may be related to survival in patients with other types of cancer.

After a 10-year follow-up, using data from a previous study [6], we investigated whether changes in body weight, PA, and SPA during RT are associated with long-term survival in cancer patients.

## Methods

### Study design

A prospective study was conducted at the Oncology Radiation Department of Santa Lucia’s Hospital, Brasília-DF, Brazil, from March 2008 to February 2009. Using a systematic sampling procedure, patients aged ≥ 18 years diagnosed with cancer and with RT indication were included in the study. The exclusion criteria were presence of pacemakers, pregnancy, and inability to perform BIA evaluation. Weight, height, PA, and SPA measurements were obtained before the first RT session (pre-RT nutritional assessment). In the second and final evaluation (post-RT nutritional assessment), weight, PA, and SPA measurements were repeated. Body mass index (BMI) was calculated and classified according to the World Health Organization cut off values. The bioelectrical impedance analysis was performed using a BIA Quantum II instrument (RJL Systems®) [9]. PA was obtained from the arc tangent relationship of reactance or resistance × 180/π and SPA was obtained according to Barbosa-Silva et al.’s study [4]. Detailed study design with demographic, nutritional, and clinical variables and main results pertaining to nutritional status and PA of the participants were published elsewhere [6]. The Human Research Ethics Committee of the Faculty of Health Sciences at the University of Brasilia approved the protocol, and all subjects provided written inform consent.

### Follow-up

A total of 104 patients were enrolled in the pre-RT nutritional evaluation, and 73 of these completed the post-RT nutritional evaluation, for reasons detailed in Fig. 1. In the present study, patients undergoing palliative RT (n = 11) were excluded because of differences in radiation dose and shorter treatment interval, totaling 62 patients (23 men and 39 women) in the 10-year follow-up analysis. Patient survival was defined as the time interval between the first evaluation and date of patient’s death, by any cause, or the date of the last contact or news obtained while the patient was still alive. Mortality data were obtained from the Unified Health System of Brazil and the National Registry of Deceased. The study was completed in June 2019, with an overall 10 years of follow-up.

### Statistical analysis

Descriptive statistics were presented as absolute and relative frequencies for categorical variables and median with interquartile range for continuous variables. The differences between the survivor and non-survivor groups were evaluated using the Mann–Whitney test for continuous variables and chi-square test for associations with other categorical variables.

To evaluate mean survival time, patients were categorized into two groups according to the presence of weight loss during the RT (WL group) or weight maintenance or weight gain during the RT (WM group). Critical weight loss was defined as ≥ 5% from the start until the end of RT.

Mean survival time and standard error were estimated using the Kaplan–Meier survival curves and compared between the groups using the log-rank test. The frequency of deaths of these two groups at the 10-year study period was compared between the groups using the Pearson chi-square test.

Mortality risk was assessed using the Cox proportional hazards model [10] adjusted for sex, age, tumor stage, site of irradiation, weight loss during RT, SPA at the end of RT, and changes in PA during treatment. Univariate analysis was performed, adjusting the Cox proportional hazards model separately for each of the variables, and a multiple Cox proportional hazards model (adjusted analysis) was fitted considering all study variables.

The analyses were performed using SPSS (version 21.0, IBM, Armonk, NY, USA, 2012), and a P value < 0.05 was considered statistically significant.

## Results

In this follow-up study, demographic, nutritional, and clinical characteristics of patients according to survival and non-survival status are shown in Table 1. Particularly, 61% of patients were at clinical stages I and II, and the most common treatment site was the pelvis (39%), followed by the breast (37%). Except for the treatment site variable, no significant difference was found between the survivors and non-survivors.

According to the BMI, 50% of patients had normal weight, 48.4% were overweight or obese, and only 1.6% were underweight. Weight loss was present in 56% of patients at the end of RT, and among these, 22% had critical weight loss.

The overall survival rate at the 10-year follow-up in all patients was 67.7%. The mean survival time was 89 ± 6.67 months in the WL group and 96 ± 7.95 months in the WM group (p = 0.263), and this difference was not statistically significant (Fig. 2).

In the Cox univariate analysis (Table 2), significant results were observed for site of treatment and weight loss during treatment (p = 0.005). Patients who had head and neck/upper abdomen/thorax, pelvis, and other irradiated sites were associated with a higher risk of death than were patients who underwent breast RT. Weight loss during RT increased the risk of death (HR, 1.24; 95% CI, 1.06–1.43). Other variables did not show significant results.

Adjusted analysis showed that the risk of death was higher in older patients (HR, 3.47; 95% CI, 1.19–10.15). The patient’s treatment site (p = 0.001) and weight loss during RT (HR, 1.25; 95% CI, 1.01–1.55) maintained their higher risk. Other variables, such as PA and SPA, and other variables did not show a significant association (Table 2). According to these results, for every 1 kg lost during RT, the risk of death increased by 25% compared with patients who maintained or gained weight.

## Discussion

This study aimed to identify whether changes in body weight, PA, or SPA during RT in cancer patients are associated with long-term survival. In the 10-year follow-up, we found that weight loss during RT increased the risk of death compared to those patients who maintained or gained weight. Therefore, in the present study, weight change during RT was shown to be an important predictor of long-term survival in patients with different types of cancer.

RT is one of the most widely used clinical treatment options for cancer patients worldwide because of its low cost and effectiveness [11]. Despite being crucial for locoregional control of solid tumors, RT has adverse effects and is associated with acute toxicities, including dysphagia and anorexia, which can affect the optimal dietary intake and increase the risk of weight loss and malnutrition [12]. Previous studies on critical weight loss during RT have indicated worse disease-specific or overall survival of head and neck [8, 13] and non-small cell lung cancer patients [14, 15]. In the present study, 98% were patients with BMI above 18.5 kg/m2 (normal range according to WHO [16]), carrying heterogeneous types of cancer at various disease stages and, even in this group of patients, weight loss during RT contributed to worse prognosis in the 10-year survival. In fact, according to the BMI, most patients were well nourished, sustaining the concept that BMI is insufficient to detect changes in body composition associated with malignancy [17] and that the risk of malnutrition is not excluded in patients classified as normal or overweight on BMI measurement. In addition, based on the Cox equation [10], our data showed that every 1 kg lost during RT leads to an increased risk of death by 25% compared with patients who did not lose weight. This result is significant even in breast cancer patients, who usually do not present weight loss, and represent 37% of our study sample.

The present study showed that weight loss was associated with a higher risk of death, independent of tumor stage. Similar results were observed in non-small cell lung cancer patients receiving chemoradiotherapy [14] and head and neck cancer patients receiving radiotherapy or chemo plus radiotherapy [13]. Our result strengthens weight loss as a predictive factor for long-term survival, but other prospective studies are needed to corroborate this finding.

In the last decade, studies have demonstrated the role of PA as a prognostic marker in different clinical situations and an indicator of nutritional status. Moreover, SPA has been proposed as an independent prognostic factor related to higher nutritional risk, functional status, and survival in several health conditions, including cancer [4, 5, 18]. However, most studies evaluating the prognostic role of PA and SPA in patients had a short follow-up period, usually in patients with advanced disease, poor nutritional status and with a retrospective design [18]. In our study, we observed no association between PA change during RT and survival time. Nor, the SPA at the end of RT proved to be a predictor of survival at the 10-year follow-up. A possible explanation for this nonsignificant result is that at the end of the treatment, only 27% of the study population had SPA below the 5th percentile [6].

Finally, although we did not record the patient’s subsequent clinical outcomes, such as the cause of death during the follow-up period, variation in body weight during RT is an important predictive factor that must be considered during treatment. Using the Cox proportional hazards model [10], we can estimate the probability of a patient surviving for > t months, based on the variables considered in the study, using the equation S(t | x) = [S0(t)]exp{x’β}. For example, the probability of a female individual with stage III breast cancer, who is at least 60 years of age, lost 0.5 kg during treatment, presented SPA equal to −1 at the beginning of the treatment, and had a reduction of 0.25 in the SPA during the treatment, surviving for 3 years (t = 36 months), is given by

$$\begin{array}{*{20}{c}} \qquad\qquad\qquad\qquad\qquad\qquad\qquad\qquad\,{{\mathrm{S}}\left( {{\mathrm{t}} = 36{\mathrm{|x}}} \right)} \, = \, {\left[ {{\mathrm{S}}_0\left( {36} \right)} \right]^{\exp \left\{ {0 \,+\, 1.235 \,-\, 0.363 \,+\, 0\, +\, 0.5\, \times\, 0.199\, +\, 1 \,\times\, 0.464\, - \,0.25 \,\times \,0.190} \right\}}} \\ \qquad\qquad = \, {[{\mathbf{0}}{\mathbf{.923}}]^{{\mathbf{exp}}\{ {\mathbf{1}}{\mathbf{.388}}\} }} \\ \!\!\!\!\!\! = \,{{\mathbf{73}}{\mathrm{\% }}} \end{array}$$

where S0(36) = 0.923 is the baseline survival function at t = 36 months. Similarly, estimates of the probabilities of this same individual surviving for 5 years (t = 60 months; S0[60] = 0.870) and 10 years (t = 120 months; S0[120] = 0.776) are given by 57% and 36%, respectively. This model, although theoretical, corroborates the clinical findings related to survival and weight loss in cancer patients and is useful for individualized treatment planning.

The major strengths of this study include its prospective design and long-term follow-up, which allowed a better survival analysis of a heterogeneous group of cancer patients. In addition, the use of pre- and post- RT PA and SPA along with changes in body weight contributed to an improved survival analysis. The main limitation is the small sample size, which may restrict the generalization of the results. Future prospective studies are needed to substantiate the results presented here.

In conclusion this study showed that weight loss during RT, along with site of treatment and age, is associated with a higher risk of death in long-term follow-up cancer patients. Finally, adequate nutritional interventions to prevent weight loss and management of symptoms during treatment of cancer patients undergoing RT are fundamental for their survival, regardless of their nutritional status.

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## Acknowledgements

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.

## Author information

Authors

### Contributions

EMSP: study concept, responsible for data acquisition, analysis and manuscript drafting. MCG: manuscript drafting and critical review. EYN: statistical analysis. MKI: study concept and manuscript critical review. NP: study concept, data interpretation, manuscript review and final approval.

### Corresponding author

Correspondence to Elemarcia M. S. Paixão.

## Ethics declarations

### Conflict of interest

The authors declare that they have no conflict of interest.

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Reprints and Permissions

Paixão, E.M.S., Gonzalez, M.C., Nakano, E.Y. et al. Weight loss, phase angle, and survival in cancer patients undergoing radiotherapy: a prospective study with 10-year follow-up. Eur J Clin Nutr 75, 823–828 (2021). https://doi.org/10.1038/s41430-020-00799-w

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