Pre-radiotherapy frailty and associated determinants in elderly patients with thoracic tumors

Introduction

Frailty is a non-specific state characterized by a decline in physiological reserves and dysregulation of systemic functions in the elderly, resulting in increased vulnerability and reduced self-stabilization and stress-resistant capabilities (1). Among the patients with malignant tumors in our country, those with common thoracic malignancies like lung cancer, esophageal cancer, mediastinal tumor and thymoma comprise approximately one-third of the total incidence, with mortality rates ranking first, fourth, and seventh, respectively (2). The changing demographics have contributed to increased cancer incidence among the elderly, with available data indicating that approximately 45–55% of newly diagnosed cancer patients require radiotherapy (RT) (3). Radiation influences critical frail mechanisms like cellular senescence, inflammation, macromolecule/organelle dysfunction, and stem and progenitor cell dysfunction as reported in the research (4). Patients with elevated frailty scores are at an increased risk of being unable to complete RT. Frailty affects the physical functioning, psychosocial, emotional, and mental well-being of elderly patients with tumor, increasing the likelihood of adverse outcomes such as falls, disability, delirium, and mortality during hospitalization. Given the potentially reversible nature of frailty, early identification and intervention may bolster the resilience of frail patients against stressors like RT. Consequently, assessing the frailty status of patients before RT is imperative, facilitating subsequent anti-cancer treatment.

In this study, we focused on elderly patients with thoracic tumors undergoing RT, assessing the prevalence of frailty through on-site questionnaire surveys and conducting statistical analysis of relevant influencing factors. The objective of these findings was to furnish a reference framework for future clinical management and intervention strategies targeting frailty in elderly patients undergoing RT for thoracic tumors. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-324/rc).

Methods

Study subjects

From October 2023 to August 2024, a total of 139 patients who underwent radiotherapies for the first time were randomly selected as the participants of the study from the Department of Thoracic Oncology. Inclusion criteria were (I) patients diagnosed with thoracic tumors such as esophageal cancer, lung cancer, mediastinal tumors and thymoma in the pathological report, hospitalized for RT, including patients with positive postoperative margins and those undergoing adjuvant RT after radical surgery; (II) age ≥60 years; (III) patients who had signed the informed consent forms. Exclusion criteria comprised of (I) patients with severe mental or verbal communication disorders; (II) patients who had received other treatments (chemotherapy, immunotherapy, targeted therapy) before RT; and (III) patients diagnosed with mental disorders. The sample size of this study was determined based on the method of “calculating sample size based on the number of items”, with a sample size ranging from 5 to 10 times the maximum number of items, equivalent to 75 to 150 individuals (5). To reduce data errors, the sample size was increased by 20%, resulting in the final inclusion of 139 participants.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was conducted with approval from the Medical Ethics Committee of Zhejiang Cancer Hospital (No. IRB-2023-886). Written informed consent was obtained from all participants.

Study tools

General Information Questionnaire

The questionnaire was designed based on domestic and international literature, comprising of two sections: general socio-demographic material and disease-related information. The former encompassed gender, age, education level, type of health insurance, body mass index (BMI), duration and mode of exercise, self-assessed health status, among others. The latter encompassed sleep conditions (self-reported early morning awakening, frequent awakenings, insomnia, difficulty falling asleep, etc.), comorbidities, multiple medications, and blood test indicators.

Tilburg Frailty Index (TFI)

TFI is a self-reported frailty assessment scale developed by Dutch scholars Gobbens et al. in 2010, grounded on the integral conceptual model of frailty (6). The scale encompasses three domains: physical frailty, psychological frailty, and social frailty. Physical frailty is assessed through eight components such as health status, weight loss, difficulty in walking, balance, vision problems, hearing problems, grip strength, and fatigue. Social frailty is assessed through three components, including living alone, social relationships, and social support. Psychological frailty is assessed through four items, which cover memory, depressive state, anxiety issues, and coping abilities. Eleven components are scored using a binary scoring scale (“yes” or “no”), while four components are scored using a three-category scale (“yes”, “sometimes”, “no”). The total score ranges from 0 to 15, with a score of 5 or above indicating frailty. A higher score signifies more severe frailty, and on average, it takes 14 minutes to complete the questionnaire. In this study, the Chinese version of TFI, as reported by Xi et al., was adopted, with a Cronbach’s α coefficient of 0.710 for the scale (7).

Oral Frailty Screening Scale

The Oral Frailty Screening Scale comprises of 8 items: (I) difficulty in eating hard food compared to 6 months ago; (II) occasionally choking when sipping tea or soup; (III) using dentures; (IV) concern about oral dryness; (V) decrease in frequency of going out compared to 6 months ago; (VI) ability to chew hard food like pickled radish or shredded and dried squid; (VII) brushing teeth at least twice a day; and (VIII) visiting a dentist at least once a year. Based on the standard protocol, items 1, 2, and 3 are weighted as two points, while the rest are weighted as one point each. For the first 3 items, a “yes” response scores 2 points, and a “no” response scores 0 points; for items 4 and 5, a “yes” response scores 1 point, and a “no” response scores 0 points; for items 6, 7, and 8, a “no” response scores 1 point, and a “yes” response scores 0 points. The maximum total score is 11 points, with a low risk for 0–2 points, medium risk for 3 points, and high risk for more than 4 points. Nomura et al. used structural equation modeling to assess the structural validity and item response theory to assess the item characteristics of the questionnaire, endorsing its use for screening oral frailty (8). However, the questionnaire features three latent variables: “brushing teeth at least twice a day”, “regularly attending dental clinic”, and “using dentures”, along with three items with low discriminatory power, indicating potential enhancements to the scoring system.

Psychological Distress Scale

This assessment tool, developed and endorsed by the National Comprehensive Cancer Network (NCCN) of the United States, consists of two components: the Distress Thermometer (DT) and the Problem List (PL). It assesses the level of psychological distress experienced by patients over the preceding week, serving as a quick screening tool to identify distress among patients diagnosed with cancer. The scale comprises of eleven levels ranging from 0 to 10, where 0 denotes the absence of distress in tumor patients and 10 represents extreme distress. A score of DT ≥4 indicates significant psychological distress. Zhang et al. assessed the sensitivity and specificity of the Chinese version of this scale, demonstrating a sensitivity of 0.80 and a specificity of 0.70, indicating good reliability and validity (9).

Methods of data collection

In this study, we administered the on-site questionnaire survey via the Wenjuanxing platform. The research team underwent standardized training to ensure consistency in language guidance. Prior to distributing the questionnaires, a detailed explanation of the purpose, content, and the time required to complete the questionnaire from the study was provided to each participant. Informed consent was obtained from every participant, who then signed an informed consent form. When the questionnaire was completed, it was collected and immediately cross-checked on-site to rectify any omissions, thereby ensuring the authenticity and reliability of the data. For participants unable to complete the questionnaire independently, team members completed it based off a question-and-answer format and filled in the questionnaire accordingly. A total of 139 questionnaires were distributed and 139 valid responses were obtained, resulting in a valid response rate of 100%.

Statistical analysis

Data entry was carried out using Excel 2016, while statistical analysis was performed using SPSS 26.0 software. Quantitative data were expressed as mean ± standard deviation and analyzed using the t-test. Count data was compared using the χ² test or exact probability method, and one-way analysis of variance and two-category Logistic regression were used for statistical analysis.

Results

Pre-RT frailty status quo in elderly thoracic tumor patients

A total of 139 eligible participants, comprising of 115 males and 24 females, were enrolled in this study. Among these elderly thoracic tumor patients, 28.1% were identified as frail prior to RT, exhibiting a frailty score of 3.75±2.429. The breakdown of frailty components was as follows: social frailty (1.56±0.772), psychological frailty (0.68±0.965), physical frailty (1.51±1.525), and oral frailty (3.38±1.987). The incidence of the four frailty domains is detailed in Table 1. In this study, among the subjects, 10 cases developed grade I–II radiation dermatitis, 64 cases developed grade I–II radiation esophagitis, four cases experienced falls, and one case developed aspiration pneumonia during the later phase of RT. All of the above-mentioned patients were provided with supportive treatment, and their RT was not interrupted.

Univariate analysis of factors affecting pre-RT frailty in elderly patients with thoracic tumors

All study participants were divided based on gender, age, clinical diagnosis, clinical primary caregiver, education level, marital history, occupation, health insurance type, height, weight, BMI, Barthel Index (BI), comorbid chronic diseases, multiple medications, nutritional risk scores, fall risk scores, pain scores, psychological distress scores, sleep issues, duration and mode of exercise, as well as albumin, prealbumin, and hemoglobin levels. Univariate analysis was performed to compare the frailty scores among the different groups. The results indicated that age, albumin levels, psychological distress, sleep issues, number of medications, duration and mode of exercise, and comorbidities significantly influenced the frailty scores among elderly patients with thoracic tumors, with all differences being statistically significant.

Multivariate analysis of factors affecting pre-RT frailty in elderly patients with thoracic tumors

To assess the impact of each variable on pre-RT frailty in elderly patients with thoracic tumor, logistic regression analysis was conducted. The dependent variable was defined as “presence of frailty before radiotherapy” (assigned values: frailty =1, non-frailty =0). The independent variables comprised of those with statistically significant results identified in the univariate analysis presented in Table 2, with corresponding values assigned accordingly. The results indicated that age, albumin levels, chronic comorbidities, duration of exercise, psychological distress scores, sleep issues, and number of medications were the primary factors influencing pre-RT frailty in elderly patients with thoracic tumors. Please refer to Tables 3,4 for detailed results. The Wald χ² values for these factors are 9.809, 1.262, 9.433, 5.220, 0.712, 0.545, and 4.862, respectively, with corresponding P values of 0.002, 0.26, 0.002, 0.02, 0.40, 0.46, and 0.03.

Discussion

Status quo of pre-RT frailty in elderly patients with thoracic tumors

Viña et al. proposed the free radical theory of frailty, indicating that “frailty is associated with oxidative damage to tissues and macromolecules” (10). Conventional fractionated RT generates a substantial quantity of free radicals. Findings from their study revealed increased levels of lipid peroxidation and protein oxidation in frail patients, indicating a potential association between frailty and oxidative stress. Previous research has indicated a median incidence of frailty in elderly cancer patients of 42% (3). In this study, a group of 139 elderly patients diagnosed with thoracic tumors were included. Results indicated that 28.1% of these patients presented with frailty prior to RT, a lower prevalence compared to that reported by Franco et al. (11) (72.7%).

This primary reason may be attributed to differences in the study population. The participants in the aforementioned study consisted exclusively of stage I/II non-small cell lung cancer (NSCLC) patients scheduled for stereotactic body radiation therapy (SBRT). SBRT is specifically indicated for elderly patients or those with significant comorbidities ineligible for surgery, potentially influencing outcomes. At the same time, the results of this study were higher than those reported by Morito et al. (12) for preoperative esophageal cancer patients (16.00%). The potential reasons may be related to the different frailty scales used, the different assessment times chosen, and the lack of homogeneity in the subjects being evaluated. Within our study group, varying degrees of frailty were observed across physical, social, psychological, and oral health domains, with notable prominence in social and psychological aspects. Specifically, 56 patients experienced social frailty. Ma et al. found an association between social frailty and recent major life events, and it is noteworthy that patients in our study had recently undergone major thoracic tumor surgeries and were in the process of recuperating at home before initiating RT (13). During this period, increased levels of family concern resulted in limited opportunities for patients to assert personal decisions or control over their lives. Also, 55 patients experienced psychological frailty.

Deng et al. assessed the relationship between psychological distress and frailty, revealing a positive correlation between the two (14). Cancer treatment encompasses various modalities such as surgery, chemotherapy, immunotherapy, and RT, either individually or in combination based on cancer type and stage of cancer. The whole anticancer treatment process is protracted, during which patients may manifest typical emotional responses like vulnerability, sadness, and fear, as well as more severe psychological disorders like depression, anxiety, fear, social withdrawal, and existential or spiritual crises (15).

Therefore, clinical healthcare providers should prioritize the monitoring of emotional fluctuations in patients undergoing RT. Efforts should be made to facilitate group activities during hospitalization to enhance the social engagement and roles of patients. By addressing psychological distress and reducing social isolation among patients with cancer undergoing RT, healthcare providers may potentially affect the progression of frailty, either directly or indirectly.

Analysis of factors influencing the occurrence of pre-RT frailty in elderly patients with thoracic tumors

The risk of pre-RT frailty varies among elderly patients with thoracic tumors across different age groups

Frailty represents a non-specific condition commonly associated with aging. Regression analysis results underscored age as a significant influencing factor on frailty levels among elderly patients with thoracic tumors, indicating that older patients are more prone to pre-RT frailty. In a domestic study conducted by Zhang et al., it was discovered that patients over 70 years old had a significantly higher likelihood of increased frailty compared to those under 70 years old (16). Age, proves to be a limited predictor of cancer tolerance and prognosis, in the context of elderly patients with tumors (17). The infiltration of cancer cells into various systemic functions in patients with thoracic tumors exacerbates the body’s vulnerability. Therefore, the requirement for RT in later disease stages may contribute to a decline in both physical health and psychological well-being to some extent. The subjects of this study were elderly cancer patients over 60 years old, who were at a higher risk of developing sarcopenia. Due to the aging factor, the immunity and regulatory capacity of the body gradually weaken, which can easily lead to cancer-related fatigue. This in turn causes a reduction in physical activity and anorexia in patients, thereby increasing the incidence of sarcopenia. Therefore, frailty and sarcopenia both serve as warning signs for clinical outcomes (18).

However, it is imperative to note that frailty should not serve as a new discriminatory criterion impeding the access to cancer treatment for elderly oncology patients, particularly for those with well-preserved physical and psychological functions (19). Therefore, despite the unclear underlying mechanisms of frailty, oncology healthcare professionals should prioritize early assessment and screening of frailty before RT. Prompt implementation of intervention measures is essential to forestall the development of frailty. For instance, particular attention should be paid to patients over 70 years old. During hospitalization, safety precautions should be well implemented to prevent adverse events such as falls.

Risk of pre-RT frailty in elderly thoracic tumor patients with different albumin levels

Albumin is a primary biochemical indicator commonly used in clinical settings to reflect the nutritional status of a patient. Picca et al. found a negative correlation between albumin levels and the risk of frailty, indicating that lower albumin levels are associated with a higher risk of frailty (19). The findings of this study also corroborated that low albumin levels are a risk factor leading to frailty in elderly patients with thoracic tumor before RT. The potential reasons for this outcome may be attributed to the fact that the patients in this study were postoperative individuals with thoracic tumors, experiencing significant physical trauma, and still in the recovery phase. What is more, some of our research subjects were esophageal cancer patients, who belong to the category of gastrointestinal malignancies. The phase 3 randomized clinical trial by Hall et al. (20), which included 559 patients with advanced gastrointestinal malignancies, has shown that these patients are at a higher risk of developing frailty syndrome. The analysis suggests that this may be due to the impact of gastrointestinal malignancies on gastrointestinal function, leading to a decline in the patients’ digestive and absorptive capacities, which in turn affects the intake of nutrients, thereby causing the patients to become frail. Also, malnutrition-related adverse outcomes, like sarcopenia, osteoporosis, cognitive impairment, and falls, can exacerbate the onset and progression of frailty. The interrelationship between these two factors underscores the necessity for healthcare professionals to continuously monitor both albumin levels and the nutritional status of these patients. It is imperative to conduct nutritional risk assessments and devise tailored dietary plans based on individual needs. These measures may enhance the nutritional status of patients and potentially reverse pre-RT frailty in elderly patients with thoracic oncology.

Elderly patients with multiple comorbidities and multiple medications exhibit a high degree of frailty

Patients with thoracic tumors frequently suffer from comorbidities such as hypertension, coronary heart disease, cerebral infarction, diabetes, and other underlying diseases. Regression analysis results in this study demonstrated that comorbidities and multiple medications were positively correlated with the degree of frailty in elderly patients with thoracic tumors, serving as significant influencing factors. Specifically, an increase in the number of comorbidities and medications corresponded with higher frailty scores, consistent with the findings of Xie et al. and Takeuchi et al. (21,22).

The incidence of frailty in elderly inpatients is associated with the number of underlying diseases and oral medications. These could be that patients with thoracic tumors often present with multiple chronic diseases, accompanied by symptoms such as pain, anxiety, depression, and sleep disorders, necessitating a range of medications for anti-tumor treatment. The interaction among multiple medications can further aggravate the decline in systemic functions and significantly reduce physiological reserves across various systems. Patients remain in a prolonged state of chronic consumption, leading to the development of frailty. Therefore, healthcare providers should prioritize the assessment of comorbidities and the use of multiple medications in patients undergoing RT for thoracic tumors. It is crucial to actively manage comorbidities, dynamically adjust medications promptly, and enhance drug management to slow down the progression of frailty.

Elderly patients with thoracic tumors who frequently engage in resistance exercise exhibit a lower incidence of frailty

Exercise interventions are crucial ways to prevent frailty. Consequently, numerous studies, both domestic and international, have sought to alleviate frailty by enhancing the physical function of elderly patients. The findings of this study indicate that the duration and mode of exercise are associated with frailty. Specifically, the mode of exercise, particularly resistance exercise, is associated with reduced frailty, consistent with the findings of Zhang et al. (23). Inflammatory cytokines in the body are correlated with the progression and severity of frailty, affecting muscle mass and increasing mortality risk among the elderly population. Resistance exercise can reduce the level of nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome in patients.

After RT for thoracic malignant tumors, the body undergoes inflammatory responses, with the incidence of radiation pneumonitis ranging from 15% to 45%. Also, patients may experience inflammation characterized by hyperemia, edema of the esophageal mucosa, increased mucus production, localized pain, and exacerbated dysphagia. Therefore, enhancing the levels of inflammatory factors in patients can significantly ameliorate frailty indicators and play a crucial role in slowing down its progress. At the same time, attention should be paid to swallowing function training, and correct dietary education to prevent aspiration should be provided to avoid the occurrence of aspiration pneumonia.

Conclusions

Frailty is characterized by a reduction in the functional reserves of the heart, lungs, kidneys, and bone marrow, an increased risk of gastrointestinal mucosal injury, declining levels in memory, cognition, and hormones, and changes in muscle and body composition. This condition can compromise tolerance to cancer treatments, and elderly patients may face an increased risk of treatment-related toxicities. In this study, the incidence of frailty among elderly patients with thoracic tumors was 28.1%, with varying degrees of frailty in physical, social, psychological, and oral domains, particularly significant in the social and psychological domains. The primary influencing factors of pre-RT frailty in these patients were age, comorbidities, multiple medications, mode of exercise, and albumin levels.

Therefore, it is recommended that healthcare professionals, particularly nurses, assess the risk of frailty in elderly patients with thoracic tumors before RT. This involves conducting frailty screenings and early identification of frailty, as well as analyzing potential influencing factors. Prompt implementation of preventive interventions is crucial. These may include resistance exercises, ensuring adequate nutritional supply, and adjusting medications. The objective of these measures is to delay the onset of frailty in elderly patients with thoracic tumors, thereby enhancing clinical treatment efficacy and enhancing the quality of life for these patients.

Participants in this study were patients from a tertiary A-class specialized oncology hospital in Zhejiang diagnosed with thoracic cancer, which presents certain limitations in terms of sample size and disease groups. Future research should use different frailty scales to conduct longitudinal surveys across multiple regions and centers, to assess the prevention and treatment of frailty from various perspectives. Also, plasma samples should be collected to identify biomarkers of frailty, providing more robust evidence for the prevention and delay of the onset of frailty and its progression.

Acknowledgments

We would like to acknowledge the hard and dedicated work of all the staff that implemented the intervention and evaluation components of the study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-324/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-324/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-324/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-324/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was conducted with approval from the Medical Ethics Committee of Zhejiang Cancer Hospital (No. IRB-2023-886). Written informed consent was obtained from all participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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