The risk of malnutrition and its clinical implications in older patients with cancer

Malnutrition is a common geriatric syndrome with multiple negative outcomes including mortality. However, there is a scarcity of literature that focuses on the relationship between malnutrition risk and its clinical implications on geriatric syndromes and mortality among cancer patients. The aim of this study is to determine the clinical importance of malnutrition risk in geriatric oncology practice. 180 patients with cancer who were ≥ 65 years were included in the study. All patients were questioned in terms of geriatric syndromes, including polypharmacy, frailty, probable sarcopenia, fall risk, dynapenia, depression, cognitive impairment, insomnia, and excessive daytime sleepiness. Mini Nutritional Assessment scores > 23.5 and 17–23.5 were categorized as well-nourished and malnutrition risk, respectively. Of the 180 patients (mean age 73.0 ± 5.6 years, female: 50%), the prevalence of malnutrition risk was 28.9%. There was no statistically significant difference between the groups in terms of age, gender, education, marital status, body mass index, and comorbidities except for chronic obstructive pulmonary disease (p > 0.05). After adjustment for age, sex, and body mass index; polypharmacy (odds ratio [OR]: 3.17; 95% confidence interval [CI], 1.48–6.81), reduced calf circumference (OR: 3.72; 95% CI, 1.22–11.38), fall risk (OR: 2.72; 95% CI, 1.03–7.23), depression (OR: 6.24; 95% CI, 2.75–14.18), insomnia (OR: 4.89; 95% CI, 2.16–11.05), and frailty (OR: 2.44; 95% CI, 1.75–3.40) were associated with malnutrition risk compared to well-nourished patients (p < 0.05). Median survival in patients with malnutrition risk was 21.3 months (range 14.1–28.4 95% CI) and median survival in patients who were defined as well nourished was not reached (p < 0.001). The risk of malnutrition was associated with a higher risk for all-cause mortality in older patients with cancer, and was associated with many geriatric syndromes, including polypharmacy, fall risk, frailty, insomnia, and depression.


Introductıon
Nutritional problems are common in older adults, and aging-related physiological changes increase the nutritional risk for older adults [1].Due to age-related decreases in appetites, senses of taste and smell, and socioeconomic factors such as low social support or living alone, older adults are susceptible to malnutrition [1,2].While the malnutrition rate is 6% in outpatients and 22% in hospitalized older adults, it is more common in older adults with cancer (42%) [3].Not only age-related factors, but also tumor-related symptoms, and adverse effects of treatment can contribute to development of nutritional problems in older patients with cancer [4,5].In multiple studies, polypharmacy, dementia, constipation, difficulty in swallowing, loss of appetite, decline in cognitive and physical functions, loss of interest in life, and sleep disturbances were found as risk factors for malnutrition in cancer patients [6][7][8].The relationship between mortality and malnutrition in older patients with cancer has been observed that approximately 20% of cancer patients die due to malnutrition and its complications rather than malignancy [7,9,10].The presence of additional comorbidities, geriatric syndromes such as malnutrition, and depression in some older patients with cancer cause them to be more fragile and adversely affect chemotherapy tolerance [11,12].Therefore, a comprehensive geriatric assessment, especially nutritional screening, is recommended for older patients with cancer before treatment decisions.
Malnutrition is a condition in which inadequate calories and protein are delivered to the portal blood system, which may be treated either by correcting the cause or providing enteral or parental nutritional support.Malnutrition risk (i.e., the stage before malnutrition) can be determined by the validated screening tools such as Mini Nutritional Assessment (MNA) [13,14].MNA consists of anthropometry, illness, multiple medications used, psychological stress, neuropsychological problems, living status, dietary characteristics, and self-perception about the patients' own health and nutrition [15].Malnutrition risk may occur owing to several factors, including conditions within the MNA, age, cancer type, treatment, comorbidities, and socio-economic status [6].Importantly, all these factors are also risk factors for malnutrition per se.Therefore, the recent ESPEN clinical nutrition guideline in geriatrics was developed for older persons with malnutrition or at risk of malnutrition [14].
Some studies have shown that the risk of malnutrition is as important as malnutrition not only for older patients but also in geriatric oncology patients [5,6].For example, a study of 365 hospitalized older patients found that the risk of malnutrition was associated with depression, falls, and insomnia [12].In a study by Zükeran et al., it was observed that frailty is higher in older patients at risk of malnutrition [16].In another study with older patients with cancer, a close relationship was found between malnutrition risk and 12-month mortality [17].Therefore, older patients with cancer should be carefully evaluated for malnutrition risk and a systematic approach is necessary.Early intervention of patients at risk of malnutrition may positively affect the treatment tolerance of patients, increase their quality of life, and decrease the mortality.Therefore, it is very important to determine the frequency of malnutrition risk, causing factors, and its effect on mortality.
However, to the best of our knowledge, there are no studies on the relationship between geriatric syndromes/ comprehensive geriatric assessment parameters and risk of malnutrition in older patients with cancer.Thus, the aim of this study is to determine clinical importance of malnutrition risk and its clinical implications on geriatric syndromes and mortality in geriatric oncology practice.

Methods
This study included 180 patients who were admitted to one oncology outpatient clinic in Turkey between October 2020 and February 2022.Patients aged 65 years and older with a cancer diagnosis were included in the study.Patients with severe vision and hearing impairment that prevent communication and understanding commands during the examination, or had acute cerebrovascular event, sepsis, acute renal failure, and acute respiratory failure, as well as those with missing data in file records, patients with dementia or delirium were excluded.Additionally, after nutritional evaluation by Mini Nutritional Assessment (MNA), if the patients were categorized as having malnutrition (MNA < 17), they were also excluded to find the risk of malnutrition's effect on clinical findings.This study was approved by the Ethics in Research Committee of the local ethical review board.
Demographic characteristics of the patients, such as age, gender, marital, living and education status, smoking history, and history of falling, were collected by self report.Cancer type and stage at the time of the comprehensive geriatric assessment and treatment history were determined by an oncologist.The 8th edition TNM staging system was used for tumor staging.Cancer diagnostic groups were established which included breast, gastrointestinal, thoracic, gynecologic, prostate, bladder, and sarcoma.For each patient, number of medications and comorbid diseases [diabetes mellitus (DM), hypertension (HT), hyperlipidemia (HL), coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), and congestive heart failure (CHF)] were collected according to the patients and caregivers' self report.
Functional status was measured using the Eastern Cooperative Oncology Group (ECOG) performance status (PS).Body mass index (BMI) was calculated for each patient using the standardized formula: weight (kg)/height (m 2 ).
The median survival was defined as the time from the geriatric assessment to death or until the last day of follow-up.

Comprehensive geriatric assessment
The Comprehensive Geriatric Assessments (CGAs) of all 180 older patients with cancer were evaluated by trained geriatricians.Polypharmacy is stated as the concomitant use of five or more drugs [18].The modified Fried physical frailty scale was used to assess frailty defined by the physical model and the presence of three or more criteria for weight loss, low physical activity, slowness, and fatigue [19].Yesavage Geriatric Depression Scale-15 (GDS-15) is used to assess for depression and ≥ 5 is associated with a possible diagnosis of depression [20].To determine the risk of falling, Tinetti Balance and Gait test and the time up and go (TUG) tests were used.Tinetti Balance and Gait test score below 19 and TUG above 13.5 s was accepted as fall risk.In the TUG test; the patient is asked to get up from the chair he or she is sitting in, without using the arms if possible, to walk for 3 m, and to turn back and sit on the chair again and the time is recorded [21,22]

Evaluation of nutritional status
MNA was performed on all patients to detect malnutrition risk.If the total score was ≥ 23.5, 17-23, or < 17, it was accepted as normal nutrition, malnutrition risk, or malnutrition, respectively [15].Patients with malnutrition were excluded from the study.The MNA test is composed of simple measurements and 18 brief questions that can be completed in < 10 min, anthropometric measurement questions related to BMI, weight loss, mid-arm, and calf circumference; global assessment (six questions related to lifestyle, medication, and mobility); and dietary questionnaire and subjective assessment (eight questions related to the number of meals, food and fluid intake, the autonomy of feeding, and self-perception of health and nutrition) [29].

Statistical analysis
Statistical analysis was performed using Statistical Package for Social Sciences version 25 (SPSS, v25).Qualitative variables were described by frequencies and percentages, continuous variables by mean and standard deviation, or median and range.The normal distribution range was determined by the Kolmogorov-Smirnov test.T test and Chisquare test were used for describing patient characteristics and comparing subgroups of people with malnutrition risk and normal nutrition.A binary logistic regression analysis was performed to identify factors suggestive of malnutrition risk.Odds ratios were calculated to evaluate the magnitude of the impact of the significant variables with 95% confidence interval (CI).Survival analysis was performed using the Kaplan-Meier method and log-rank test.The statistical significance level was accepted as a p value < 0.05.

Cross-sectional analysis
The study included 180 older patients with cancer with a mean age of 73.0 ± 5.6 years, and 50% of the patients were female.There was no statistically significant difference between the groups in terms of age, gender, education, and BMI (p > 0.05).
Most of the patients were married (75.8%) and only 11.1% of the patients were active smoker; however, 46.7% had smoking history.61 patients (33.9%) were diabetic, 108 patients (60%) had hypertension, 22 patients (12.2%) had hyperlipidemia, 33 patients (18.3%) had CAD, and only 6 patients (3.3%) had COPD.Patients were divided into two groups, based on their MNA.A total of 52 (28.9%) patients were defined with malnutrition risk.COPD was significantly higher in the patient group at risk of malnutrition (9.6% vs 0.8%, p = 0.003), whereas there were no differences in terms of the other comorbidities between the two groups (p > 0.05).A total of 42.2% of patients had stage 4 malignancy, 71.7% had a history of chemotherapy, 41.1% had a history of radiotherapy, 67.8% had a history of oncological surgery, and there was no statistical difference between these groups (Table 1).
Based on the CGA, in patients at malnutrition risk; the fall risk (by both Tinetti Balance and Gait test, and TUG test), polypharmacy, depression, insomnia, sarcopenia, and frailty were higher than in patients categorized as well nourished (p < 0.05).The calf circumferences were shorter in patients with malnutrition risk (p < 0.05).In patients with malnutrition risk, MMSE, Tinetti Balance and Gait test scores were lower, and TUG test, SARC-F, Yesavage geriatric depression scale-15, and ISI scores were higher (p < 0.05).There was no statistically significant difference in dynapenia and EDS between the groups (p > 0.05) (Table 2).

Follow-up analysis
Median survival in patients with malnutrition risk was 21.3 months (95% CI: 14.1-28.4)and median survival in patients who were well nourished was not reached (p < 0.001).For the 12 months, the survival rate was 86% and 66% in patients who were well nourished and with malnutrition risk, respectively, and for the 24 months, survival rate was 76% and 32% in patients with well-nourished and malnutrition risk, respectively.Kaplan-Meier curve for the median survival according to malnutrition risk and well nourished are shown in Fig. 1.

Discussion
In this study, we evaluated 180 older patients with cancer, excluding patients with malnutrition, and 28.9% of these patients had malnutrition risk.There was no difference in age, gender, education, marital status, BMI, stage of cancer disease, ECOG PS, and oncological treatment history between the well nourished and at risk of malnutrition patients.Malnutrition risk was associated with polypharmacy, depression, insomnia, impaired balance and gait, higher fall risk, and frailty.Moreover, malnutrition risk was also associated with a higher risk for all-cause mortality in older patients; 24-month median survival rate was 76% in well-nourished patients, while it was 32% in patients with malnutrition risk.
Malnutrition risk is observed as frequently as malnutrition in cancer patients, in studies conducted in geriatric oncology practice, over one-quarter were at high risk for malnutrition [5,6,30].Interestingly, there was no difference between malnutrition risk and well-nourished patients in terms of age and BMI in our study.In a recent study of older obese patients, undernutrition was determined in approximately one-third of the patients [29], and in another study of patients with varying cancer diagnoses, of those classified as overweight or obese by BMI, malnutrition risk was observed in 24% and 20%, respectively [6].In another study conducted with older patients with cancer, no significant difference was found between BMI in patients with and without malnutrition [31].Taken together, these findings suggest that BMI is an inadequate and misleading indicator in determining the malnutrition risk.
Frailty is a clinical syndrome characterized by progressive decline in physiological functions and increased vulnerability for morbidity and death [19].Approximately 43% of geriatric oncology patients are diagnosed with frailty [32], and a high proportion experience frailty and malnutrition concurrently [19,[31][32][33].In our study, frailty was associated with patients at risk of malnutrition, which is similar with a previous study [16].Sarcopenia, which is another geriatric syndrome and closely associated with frailty, is characterized by a generalized and progressive loss of muscle mass and strength and a decrease in physical performance [34].Sarcopenia is associated with risk of chemotherapy toxicity, post-operative complications, disability, frailty, fall risk, and Another important result of our study is: the fall risk is more common in patients with malnutrition risk.The risk of falling is higher in cancer patients than in non-cancer .Some studies have shown a relationship between fall risk and malnutrition.For example, Jacques et al. found that malnutrition is associated with fall risk in older patients [8].In a study with older Chinese inpatients, malnutrition risk was found to be associated with the number of falls [12].In our study, according to Tinetti Balance and Gait test, and the TUG test, which is commonly used in geriatric outpatient clinics, the fall risk was higher in geriatric oncology patients with malnutrition risk.Depression is the most common mental health problem in older patients with cancer.Loss of appetite is a major component of depression, not only loss of body weight but also loss of interest in self-care, apathy, and physical weakness, and can lead to reduced food intake and ultimately malnutrition risk [44,45].Because of these reasons, Liu R et al. and Kadakia KC et al. reported that malnutrition risk was strongly associated with depression, consistent with our study [6,12].In our study, depression was associated with patients at risk of malnutrition.Therefore, evaluation of depression, which is common in older patients with cancer, and providing the necessary support will contribute to more effective management of cancer treatment and nutritional problems.
All cancer groups have significantly higher levels of sleep problems than the general population.Patients with insomnia may have difficulty in falling asleep, staying asleep, or a combination of the two [46].In the present study, insomnia was associated with patients at risk of malnutrition compared to those who were not at risk of malnutrition.Orexin, a neuropeptide released from the hypothalamus to increase appetite, was higher in patients with insomnia than those without insomnia [47].Insomnia itself may also affect dietary behaviors and intake [48].Previous study conducted with older patients without cancer supports this result [47].However, future studies are needed to further establish this relationship.
Polypharmacy is more common in older patients with cancer than those without cancer, owing to medication required to prevent or reduce the side effects of cancer treatment in addition to multiple morbidity [49,50].The use of higher number of drugs is associated with numerous side effects, such as diarrhea or constipation, nausea, stomach pain, and decreased appetite, potentially resulting in a reduced food intake [18].In addition, it has been observed that polypharmacy had a significant relationship with physical function, malnutrition, and depression [51,52].Some studies reported that older people with polypharmacy have significantly lower MNA scores than older people without polypharmacy [52, 53].However, in these studies, patients with malnutrition and malnutrition risk were analyzed as a single group.In our study, we evaluated only patients with malnutrition risk, and a significant relationship was found between the malnutrition risk and polypharmacy, where malnutrition risk was associated in patients with polypharmacy.Therefore, reviewing unnecessary drug use at each visit may prevent patients from drug side effects, drug-drug Fig. 1 Median survival of patients with well-nourished and malnutrition risk interactions, and related complications, such as malnutrition risk, depression, and mortality.
Many studies have shown that malnutrition is associated with high morbidity and mortality, chemotherapy toxicity, and many geriatric syndromes in older patients with cancer.For example, a study conducted with older patients with advanced colorectal cancer receiving chemotherapy showed that malnutrition was associated with poor tolerance of chemotherapy and increased mortality in patients treated with palliative intent [33].Unlike previous studies, we found that malnutrition risk was associated with a higher risk for all-cause mortality in geriatric oncology practice.Similar to our study, in a study conducted in geriatric cancer patients, 29% of the patients were found to be malnourished, 41.2% of them were at risk of malnutrition, and no correlation was found between BMI and survival, while higher mortality was observed in patients with malnutrition risk [30].The reason for the high mortality rate in patients with malnutrition risk may be related to nutritional problems and higher incidence of geriatric syndrome.
Studies have demonstrated that chronic diseases, medications, age-related conditions (e.g., decline in taste and/ or olfactory perception), less social support, marital status, educational levels, income level, and psychological stress are associated with malnutrition risk in older patients [13].Understanding the complex interplay of factors that affect malnutrition risk in older cancer patients is crucial for developing effective interventions to prevent and treat nutritional complications [2,13].To effectively prevent the complications associated with the risk of malnutrition, it is necessary to implement all strategies used to prevent malnutrition.
Findings from the present study must be interpreted in light of its limitations.This was based on a single-center study.The patients included in the study were a heterogeneous group consisting of many cancer types and stages.Moreover, patients were at different stages of cancer treatment, such as patients receiving chemotherapy or treatment completed, this will likely influence the nutritional status of patients.Moreover, there were no data on the causes of death of the patients, and thus, we could only assess allcause mortality.Finally, the results cannot be generalized to all geriatric oncology patients, as only outpatient clinic patients were included in the study.However, the present study has multiple strengths; we evaluated CGA concurrently.Moreover, for the diagnosis of malnutrition risk, we used MNA-long form, and our sample size was sufficient.

Conclusions
The risk of malnutrition is common and associated with polypharmacy, depression, insomnia, impaired balance and gait, higher fall risk, frailty, sarcopenia, and higher mortality in older patients with cancer.Therefore, clinicians should be alerted to patients with malnutrition risk.Interventions to improve nutrition in patients with risk of malnutrition may reduce geriatric syndromes and mortality.These findings have shown that the risk of malnutrition assessment, just like malnutrition, should be evaluated in geriatric oncology practice.

Declarations
Conflict of interest The authors declare that they have no conflict of interest.

Ethical approval
The study was approved by the local ethics committee (identifier: 02/32).

Statement of human and animal rights
All the procedures performed in this study involving human participants were in accord ance with the ethical standards of the institutional and national research committee and with the 1964 Declaration of Helsinki and its later amendments.

Table 1
Patients characteristics according to nutritional status Bold value shows statistical significance results (p < 0.05) BMI Body mass index, CAD Coronary artery disease, CHF Chronic heart failure, COPD Chronic obstructive pulmonary disease, DM Diabetes mellitus, ECOG Eastern Cooperative Oncology Group, PS Performance Status, HL Hyperlipidemia, HT Hypertension, SD

Table 2
CM Centimeter, EDS Excessive Daytime Sleepiness, ESS Epworth Sleepiness Scale, GDS Geriatric Depression Scale, ISI Insomnia Severity Index, MMSE Mini-Mental Status Examination, SARC-F Strength, Assistance in walking, Rise from a chair, Climb stairs, Falls, Sec second patients; age, chemotherapy-induced neuropathy, and poor physical performance are some of the reasons that increase the risk of falling in cancer patients[42].Importantly, in geriatric oncology patients with bone metastasis, falling can cause severe fractures, decreases in function, and higher mortality[43] All participants provided written informed consent before the study was initiated.13.Besora-Moreno M, Llauradó E, Tarro L et al (2020) Social and economic factors and malnutrition or the risk of malnutrition in the elderly: a systematic review and meta-analysis of observational studies.Nutrients 12:737 14.Volkert D, Beck AM, Cederholm T et al (2022) ESPEN practical guideline: clinical nutrition and hydration in geriatrics.Liperoti R, Russo A et al (2012) Sarcopenia as a risk factor for falls in elderly individuals: results from the ilSI-RENTE study.Clin Nutr 31:652-658 39.Mayr R, Gierth M, Zeman F et al (2018) Sarcopenia as a comorbidity-independent predictor of survival following radical cystectomy for bladder cancer.J Cachexia Sarcopenia Muscle 9:505-513 40.D'almeida CA, WaF P, De Pinho NB et al (2020) Prevalence of malnutrition in older hospitalized cancer patients a multicenter and multiregional study.J Nutr Health Aging 24:166-171 41.Soysal P, Veronese N, Arik F et al (2019) Mini nutritional assessment scale-short form can be useful for frailty screening in older adults.Clin Interv Aging 14:693-699 42.Rattanakrong N, Siriphorn A, Boonyong S (2022) Incidence and risk factors associated with falls among women with breast cancer during taxane-based chemotherapy.Support Care Cancer 30:7499-7508 43.Morris R, Lewis A (2020) Falls and cancer.Clin Oncol (R Coll Radiol) 32:569-578 44.Ülger Z, Halil M, Kalan I et al (2010) Comprehensive assessment of malnutrition risk and related factors in a large group of community-dwelling older adults.Clin Nutr 29:507-511 45.Roohafza H, Sarrafzadegan N, Sadeghi M et al (2013) The association between stress levels and food consumption among Iranian population.Arch Iran Med 16:145-148 46.Hernandez Torres C, Hsu T (2017) Comprehensive geriatric assessment in the older adult with cancer: a review.Eur Urol Focus 3:330-339 47.Tang S, Huang W, Lu S et al (2017) Increased plasma orexin-A levels in patients with insomnia disorder are not associated with prepro-orexin or orexin receptor gene polymorphisms.Peptides 88:55-61 48.Soysal P, Smith L, Dokuzlar O et al (2019) Relationship between nutritional status and insomnia severity in older adults.J Am Med Dir Assoc 20:1593-1598 49.Bardel A, Wallander MA, Svärdsudd K (2000) Reported current use of prescription drugs and some of its determinants among 35 to 65-year-old women in mid-Sweden: a population-based study.J Clin Epidemiol 53:637-643 50.Kose E, Wakabayashi H, Yasuno N (2021) Polypharmacy and malnutrition management of elderly perioperative patients with cancer: a systematic review.Nutrients 13:1961 51.Farre TB, Formiga F, Ferrer A et al (2014) Risk of being undernourished in a cohort of community-dwelling 85-year-olds: The O ctabaix study.Geriatr Gerontol Int 14:702-709 52.Maseda A, Gómez-Caamaño S, Lorenzo-López L et al (2016) Health determinants of nutritional status in community-dwelling older population: the VERISAÚDE study.Public Health Nutr 19:2220-2228 53.Ramgoolie P, Nichols S (2016) Polypharmacy and the risk of malnutrition among independently-living elderly persons in Trinidad.West Indian Med J. https:// doi.org/ 10. 7727/ wimj.2014.285