Psychological distress in advanced non-small cell lung cancer: Impact on targeted therapy and quality of life

Abstract

BACKGROUND

Psychological distress is highly prevalent in patients with advanced non-small cell lung cancer (NSCLC). Although previous studies have explored the impact of psychological distress on chemotherapy tolerance and quality of life, the correlation between the level of psychological distress and the efficacy of targeted therapy and quality of life in patients with NSCLC remains unclear. It is also unclear whether psychological distress is associated with the incidence of adverse reactions to targeted therapy.

AIM

To explore the effects of psychological distress on targeted therapy outcomes and quality of life in patients with advanced NSCLC.

METHODS

A total of 143 patients with NSCLC who received guideline-recommended standard targeted therapy based on genetic testing results were enrolled. Psychological distress and quality of life were assessed using the Distress Thermometer (DT) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire before and after targeted therapy. Changes in psychological distress and quality of life, as well as the correlation between them, were analyzed.

RESULTS

The progression-free survival in non-DT patients with advanced NSCLC who received comprehensive targeted therapy was significantly better than that in the DT patients (hazard ratio: 0.425; 95% confidence interval: 0.298-0.608; P < 0.01). Similarly, when targeted therapy was combined with chemotherapy, the non-distress (non-DT) group also demonstrated significantly prolonged progression-free survival compared with the psychological distress (DT) group (hazard ratio: 0.395; 95% confidence interval: 0.238-0.656; P < 0.01). After targeted therapy combined with chemotherapy, clinical efficacy in the non-distress group was significantly superior to that in the distress group (P < 0.001). Quality of life scores before and after targeted therapy showed significant differences between the two groups, with the non-distress group achieving significantly higher scores than the distress group (P < 0.001). The adverse events were similar between the two groups, mainly including elevated transaminases, vomiting, rash, and diarrhea.

CONCLUSION

The psychological distress could affect the quality of life of NSCLC patients during targeted therapy, providing a theoretical basis for improving the quality of life of patients with advanced NSCLC. And psychological distress is one of the factors affecting the effect of targeted therapy in patients with advanced NSCLC.

Key Words: Psychological distress; Targeted therapy; Quality of life; Non-small cell lung cancer; Prognosis

Core Tip: This study is the first to demonstrate that psychological distress significantly impairs the efficacy of targeted therapy and quality of life in patients with advanced non-small cell lung cancer. Patients without distress showed superior objective response rates, disease control rates, and progression-free survival. Psychological distress is a critical factor affecting treatment outcomes, highlighting the need for routine distress screening and psychological support during non-small cell lung cancer targeted therapy.

INTRODUCTION

According to the 2023 global cancer statistics, lung cancer is second only to breast cancer and is the leading cause of cancer death[1]. Lung cancer can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer, NSCLC accounts for 80%, and small cell lung cancer accounts for 20%[2]. Among them, NSCLC can be divided into adenocarcinoma, squamous cell carcinoma and large cell carcinoma, lung adenocarcinoma accounts for about 40% and NSCLC accounts for 60%[3]. With the development of genetic detection technology, more and more gene mutations in lung adenocarcinoma tissues have been detected, and targeted drug treatment for gene mutation targets has gradually emerged, and the survival rate of NSCLC with genetic mutations has been improved.

Constitutive activation of receptor tyrosine kinases (RTKs) represents a common tumorigenic mechanism, and inhibition of RTK activity can be exploited for targeted antitumor therapy. The most frequent RTK-related genetic alterations in NSCLC are epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) mutations. The frequency of EGFR mutations in NSCLC ranges from 10% to 30%, and EGFR tyrosine kinase inhibitors (TKIs) exert therapeutic effects by inhibiting EGFR phosphorylation. ALK mutations occur in 3%-13% of NSCLC[4]. ALK inhibitors are recommended for the treatment of patients harboring ALK mutations, and the ALK inhibitors commonly used in clinical practice include crizotinib, alectinib, and lorlatinib[5,6].

Psychological problems in cancer patients throughout the period of illness have attracted more and more attention. A cross-sectional study in China showed that the incidence of psychological pain in the disease population was 14.08%, and the incidence of psychological pain in tumor patients was 20%, and the risk of psychological pain in tumor patients was higher, and medical care needed to pay more attention to the psychological problems of psychological pain of tumor patients[7]. The psychological pain associated with tumors is manifested as inner sensitivity, sadness, fear, anxiety, depression, social isolation, etc., which may also cause loss of body functions. At the same time, in the treatment of tumors, it will cause corresponding body damage, such as memory loss, cognitive function damage, low mood, body organ damage, etc., which increase the incidence of psychological pain[8,9]. In particular, in studies of patients with advanced tumors, quality of life was poorer, and depressive symptoms were more present[10-14]. Linden et al[15] reported that among various cancer types, lung cancer is associated with a higher prevalence of anxiety and depression, as well as elevated levels of psychological distress.

Prior studies have demonstrated that psychological distress may influence cancer treatment outcomes. In patients with gastrointestinal cancers, psychological distress has been found to be negatively correlated with quality of life scores, an association that is particularly pronounced in female patients[16]. Similarly, among breast cancer patients, the presence of psychological distress is associated with impaired quality of life and may adversely affect long-term treatment outcomes[17]. Regarding treatment efficacy, previous research has reported that psychological distress may exert a negative impact on the efficacy of palliative chemotherapy in patients with advanced gastric cancer[18]. In lung cancer patients, psychological distress has been observed to potentially correlate with the response to immunotherapy[19,20].

Psychological distress can influence the interplay between host inflammatory responses and the tumor microenvironment. Under stress conditions, immune cell functions are consequently altered[21]. Distress promotes the release of neurotransmitters derived from nerve fibers within the tumor microenvironment; these neurotransmitters bind to specific neurotransmitter receptors, further activating tumor cells as well as infiltrating immune cells and endothelial cells, which in turn continue to shape the evolution of the tumor microenvironment, creating a vicious cycle[22]. Similarly, immune system dysfunction triggered by psychological distress may lead to immune evasion by tumor cells, thereby adversely affecting patient prognosis and resulting in high mortality and low survival rates among cancer patients[23,24].

However, in the process of targeted therapy for advanced NSCLC, there is no relevant report on the effect of psychological distress on the treatment of advanced NSCLC. Due to the influence of regional cultural differences, in the process of tumor treatment for Chinese patients with advanced NSCLC, clinicians pay little attention to the psychological changes of such patients, which has not attracted enough attention Therefore, 143 patients with advanced NSCLC receiving targeted therapy were included in this study to investigate the correlation between psychological distress and quality of life and the efficacy of targeted therapy.

MATERIALS AND METHODS

This study enrolled 143 patients with pathologically confirmed advanced NSCLC harboring oncogenic driver mutations, all of whom received targeted therapy at Anhui Chest Hospital. Based on Distress Thermometer (DT) scores, patients were divided into a distress group (DT ≥ 4) and a non-distress group (DT < 4)[25,26]. Clinical data, including age, sex, socioeconomic status, and treatment modality, were collected for all patients. This study was approved by the Ethics Committee of Anhui Chest Hospital (approval No. K2023-019), and written informed consent was voluntarily obtained from all patients.

Inclusion criteria

(1) Patients with pathologically and radiographically confirmed advanced NSCLC harboring EGFR exon 19 mutation, EGFR exon 21 mutation, or ALK rearrangement, who have not received any prior targeted therapy; (2) Patients are expected to have a survival duration exceeding 6 months after receiving the corresponding targeted therapy (for prospective studies) or patients who have achieved a survival duration exceeding 6 months after receiving the corresponding targeted therapy (for retrospective studies; (3) Karnofsky Performance Status score ≥ 70, with no history of cognitive dysfunction, depression, or other psychiatric disorders prior to diagnosis, and with normal verbal communication and comprehension abilities to complete questionnaire-based assessments; and (4) Age ≥ 18 years, capable of providing voluntary written informed consent.

Exclusion criteria

(1) Mixed small cell/NSCLC histology; (2) Driver oncogene mutations other than EGFR or ALK (e.g., KRAS, ROS1, BRAF, MET, RET, NTRK); (3) Prior systemic therapy (chemotherapy, immunotherapy, or investigational agents) for advanced NSCLC; (4) Participation in another interventional clinical trial; (5) Serious uncontrolled medical conditions affecting survival or compliance, including active uncontrolled infection, severe cardiac disease (e.g., symptomatic heart failure, unstable angina, uncontrolled arrhythmia), or other non-malignant life-limiting comorbidities (e.g., end-stage renal failure, severe chronic obstructive pulmonary disease, decompensated cirrhosis); (6) Known hypersensitivity to targeted therapy agents; (7) Other active malignancy within the past 3 years, except non-melanoma skin cancer, cervical carcinoma in situ, or low-risk early prostate cancer; (8) Pregnancy, breastfeeding, or unwillingness to use effective contraception (in fertile patients); and (9) Inability to provide informed consent or complete questionnaires due to severe psychiatric disorder, cognitive impairment, or substance abuse.

Procedure

Eligible hospitalized patients with advanced NSCLC harboring positive driver gene mutations were identified through the Department of Pathology and clinical databases. To protect patient privacy and ensure the right to adequate informed consent, a one-to-one informed consent discussion was conducted by a specialized psycho-oncology expert in a dedicated informed consent room, and written informed consent was obtained from each patient.

Baseline clinical data were collected and questionnaires were administered by trained research physicians. To ensure the authenticity and reliability of the questionnaire data, all research physicians responsible for data collection received professional training prior to initiating the study. Questionnaires were collected at two time points: Before the initiation of targeted therapy and at the time of first disease progression. The assessment instruments included the DT for psychological distress and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) for health-related quality of life (HRQoL). Clinical efficacy was evaluated after two cycles of targeted therapy according to the Response Evaluation Criteria in Solid Tumors. The efficacy assessments were independently reviewed by two senior oncologists to ensure consistency. All patients were followed up until death, dropout, or withdrawal from the study. Final clinical data analyses were performed by professional statisticians.

Clinical measures

DT: The DT is a screening tool recommended by the National Comprehensive Cancer Network to assess psychological distress in patients with cancer. It is a visual analog scale ranging from 0 to 10, where higher scores indicate higher levels of distress. According to previous research, a cut-off value of 4 on the DT yielded the best balance of sensitivity and specificity[27]. Consequently, a cut-off of 4 was established for this study. Participants with DT score ≥ 4 were allocated to the psychological distress group, and those with DT score < 4 were allocated to the non-psychological distress group. A score of 4 or higher is commonly used as the cut-off point for clinically significant distress. In addition to the single-item thermometer, the tool typically includes a companion problem list. The problem list comprises 39 items, which are categorized into five domains: Practical problems, communication problems, emotional problems, physical problems, and religious/spiritual concerns. The DT has been validated globally and translated into 26 languages. It is convenient and time-saving for routine clinical use. Therefore, the DT is an easy-to-administer and effective tool for evaluating psychological distress[28,29].

EORTC QLQ-C30: HRQoL was assessed using the EORTC QLQ-C30. The instrument comprises five functional scales (physical, role, cognitive, emotional, and social functioning), a global health status/quality of life scale, three symptom scales (fatigue, nausea and vomiting, and pain), and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most items are scored on a four-point verbal rating scale (1 = “not at all” to 4 = “very much”), with the exception of the global health status scale, which uses a seven-point response format ranging from 1 (“very poor”) to 7 (“excellent”). Higher scores on the symptom scales and single items indicate more severe symptoms, whereas higher scores on the functional scales and global health status scale represent better functioning and higher HRQoL. All raw scores are linearly transformed to a scale of 0 to 100 according to the European Organization for Research and Treatment of Cancer scoring manual. The QLQ-C30 summary score (overall HRQoL) was calculated as the combined average of the 13 scale and item scores (excluding the global health status scale and the financial difficulties item), with higher scores indicating better HRQoL. The summary score was computed only when all 13 required component scores were available.

Genetic testing and targeted therapy

The DNA sequence of EGFR was analyzed. The sample was collected from lung cancer tissue, pleural fluid tumor cells, circulating tumor cells, and peripheral blood free DNA by bronchoscope, lung puncture and other methods. Pathological diagnoses were made by pathology experts in the Department of Pathology, Anhui Provincial Chest Hospital. Each diagnostic report was independently reviewed and confirmed by two pathologists. Genetic testing was performed using high-throughput sequencing (next-generation sequencing). The testing panel covered 139 lung cancerrelated genes, which were selected based on Chinese big data and the authoritative The Cancer Genome Atlas database. The panel comprehensively covered hot spot mutations associated with lung cancer (including mutations, insertions, deletions, fusions, and copy number variations), as well as lung cancer therapeutic targets recommended by the National Comprehensive Cancer Network guidelines.

Targeted therapy drugs: The classification and administration methods of the targeted therapy drugs used in this study are described below. All patients received oral targeted therapy according to their respective driver gene mutations. For patients with EGFR-sensitive mutations, first-generation EGFR-TKIs (gefitinib 250 mg once daily, erlotinib 150 mg once daily, or icotinib 125 mg three times daily), second-generation EGFR-TKIs (afatinib 40 mg once daily or dacomitinib 45 mg once daily), or third-generation EGFR-TKI (osimertinib 80 mg once daily) were administered. For patients with ALK rearrangements, first-generation ALK-TKI (crizotinib 250 mg twice daily) or second-generation ALK-TKI (alectinib 600 mg twice daily) was administered. Treatment was continued until disease progression, unacceptable adverse events, or patient withdrawal.

Evaluation of treatment efficacy

Treatment efficacy was assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Responses were defined as follows: Complete response (CR) (disappearance of all target lesions), partial response (PR) (≥ 30% decrease in sum of longest diameters from baseline), stable disease (SD) [neither PR nor progressive disease (PD)], and PD (≥ 20% increase in sum of longest diameters from baseline or new lesions). Tumor evaluations were performed at baseline and every two cycles of targeted therapy. Confirmatory assessments for CR, PR, or PD were required at least 4 weeks after the initial assessment. Progression-free survival (PFS) was defined as the time from targeted therapy initiation to disease progression or death from any cause, whichever occurred first.

Statistical analysis

All statistical analyses were performed using SPSS version 26 (IBM Corp., Armonk, NY, United States). Continuous variables were tested for normality using the Kolmogorov-Smirnov test. Between-group differences were compared using two-tailed independent-samples t-tests for continuous variables and χ² tests (or Fisher’s exact test when expected frequencies were < 5) for categorical variables. Categorical data were presented as n (%). Quality of life scores were compared between the distress and non-distress groups using two-tailed independent- samples t-tests. P < 0.05 was considered statistically significant. Results are expressed as means ± SDs.

RESULTS

Baseline demographic and clinical characteristics of patients

As shown in Figure 1 and Table 1, the 143 enrolled patients were divided into two groups based on a cut-off score of 4 on the DT: The psychological distress group (DT group, n = 72; DT score ≥ 4) and the non-psychological distress group (non-DT group, n = 71; DT score < 4). No statistically significant differences were observed between the two groups in any of the demographic or clinical variables assessed, including age (t = 1.77, P = 0.079), sex (χ² = 0.010, P = 0.921), monthly household income (χ² = 0.248, P = 0.883), education level (χ² = 0.408, P = 0.945), medical payment method (χ² = 0.134, P = 0.714), method of pathological material acquisition (χ² = 3.326, P = 0.190), tumor stage (χ² = 4.004, P = 0.135), mutation status (χ² = 1.709, P = 0.425), methods of targeted therapy (χ² = 1.304, P = 0.861), targeted therapy drugs (χ² = 3.910, P = 0.418), and Karnofsky Performance Status score (χ² = 1.572, P = 0.210).

Figure 1 Flow chart of this study. EORTC QLQ-C30: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30.

Table 1 Comparison of demographic characteristics and clinical data of patients with non-small cell lung cancer in the Distress Thermometer group and non-Distress Thermometer group.

Characteristic	Non-DT (n = 71)	DT (n = 72)	χ2/t/Z	P value
Age, mean ± SD	58.93 ± 10.09	62.31 ± 12.56	1.77	0.079
Sex			0.010	0.921
Male	29	30
Female	42	42
Education			0.408	0.945
Illiteracy	23	20
Primary school	22	23
Middle school	23	26
University	3	3
Method of pathological materials			3.326	0.190
Lung puncture	40	30
Bronchoscope	22	32
Other	9	10
Tumor stage			4.004	0.135
Stage III	12	5
Stage IVA	27	26
Stage IVB	32	41
Mutations			1.709	0.425
EGFR 19	28	32
EGFR 21	26	29
ALK	17	11
Methods of targeted therapy			1.304	0.861
Targeted therapy (MONO)	22	17
Targeted therapy + CO	34	37
Targeted therapy + CO + RO	8	8
Targeted therapy + RO	4	6
Targeted therapy + AO	3	4
Targeted therapy drugs			3.910	0.418
1 TKI	34	36
2 TKI	9	8
3 TKI	11	18
1 ALK inhibitor	5	4
2 ALK inhibitor	12	6
Karnofsky Performance Status			1.572	0.210
80	32	40
90	39	32

DT: Distress Thermometer; EGFR: Epidermal growth factor receptor; ALK: Anaplastic lymphoma kinase; MONO: Monotherapy; CO: Chemotherapy; RO: Radiotherapy; AO: Anti-angiogenic therapy; TKI: Tyrosine kinase inhibitor.

Comparison of treatment effects in the targeted therapy groups

In the psychological distress (DT) group, no patient achieved a CR, while 29 achieved a PR, 34 had SD, and 9 had PD. In the non-DT group, similarly, no patient achieved CR, whereas 56 achieved PR, 14 had SD, and 1 had PD (Table 2). This difference between the two groups was statistically significant (χ² = 23.304, P < 0.001).

Table 2 Comparison of the efficacy of targeted-therapy in patients with advanced non-small cell lung cancer in the Distress Thermometer group and non-Distress Thermometer group.

Efficacy outcome	Group		χ2	P value
	DT (n = 72)	Non-DT (n = 71)
CR	0	0	23.304	< 0.001
PR	29	56
SD	34	14
PD	9	1

CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease.

Comparison of treatment effects in the targeted therapy and chemotherapy groups

In the psychological distress (DT) group, no patient achieved a CR; 14 had a PR, 18 had SD, and 5 had PD. In the non-DT group, similarly, no patient achieved CR, while 29 achieved PR, 4 had SD, and 1 had PD (Table 3). The difference between the two groups was statistically significant (χ² = 16.711, P < 0.001).

Table 3 Comparison of the efficacy of targeted therapy combined with chemotherapy in advanced non-small cell lung cancer patients in the psychological distress group and no psychological distress group.

Efficacy outcome	Group		χ2	P value
	DT (n = 37)	Non-DT (n = 34)
CR	0	0	16.711	< 0.001
PR	14	29
SD	18	4
PD	5	1

CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease.

The objective response rate and disease control rate in patients receiving targeted therapy

As shown in Figure 2, the objective response rate (ORR) and disease control rate (DCR) in the psychological distress (DT) group were 40.3% and 87.5%, respectively, compared to 78.9% and 98.6% in the non-psychological distress (non-DT) group. The ORR and DCR in the DT group were significantly lower than those in the non-DT group. Collectively, these findings indicate that patients without psychological distress achieved better overall responses to targeted therapy than those with psychological distress.

Figure 2 Comparison of objective response rate and disease control rate of targeted combination therapy between the psychological distress group and the non-psychological distress group. A: Targeted combination therapy in non-small cell lung cancer with psychological distress patients; B: Targeted combination therapy in non-small cell lung cancer with non-psychological distress patients. NSCLC: Non-small cell lung cancer; ORR: Objective response rate; DCR: Disease control rate; PR: Partial response; SD: Stable disease; PD: Progressive disease.

Figure 3 demonstrates that in patients receiving targeted therapy combined with chemotherapy, the ORR and DCR were significantly lower in the psychological distress group (37.8% and 86.5%, respectively) than in the non-psychological distress (non-DT) group (85.3% and 97.1%, respectively). Overall, patients without psychological distress exhibited superior efficacy to targeted therapy combined with chemotherapy compared to those with psychological distress.

Figure 3 Comparison of objective response rate and disease control rate of targeted combination chemotherapy between the psychological distress group and the non-psychological distress group. A: Targeted-therapy combination chemotherapy in non-small cell lung cancer with psychological distress patients; B: Targeted-therapy combination chemotherapy in non-small cell lung cancer with non-psychological distress patients. NSCLC: Non-small cell lung cancer; ORR: Objective response rate; DCR: Disease control rate; PR: Partial response; SD: Stable disease; PD: Progressive disease.

Change between psychological distress and quality of life

Table 4 summarizes the relationship between psychological distress and quality of life. Before targeted therapy, the total quality of life scores of 143 patients were 79.53 ± 10.91 in the psychological distress (DT) group and 87.85 ± 6.92 in the non-psychological distress (non-DT) group, with a statistically significant difference between the two groups (t = -5.454, P < 0.001). After targeted therapy, the total quality of life scores were 75.59 ± 11.57 in the DT group and 89.25 ± 6.89 in the non-DT group, again showing a statistically significant difference (t = -8.599, P < 0.001).

Table 4 Influence of Distress Thermometer on quality of life of non-small cell lung cancer patients during targeted therapy, mean ± SD.

Quality of life	Group		t	P value
	DT (n = 72)	Non-DT (n = 71)
EORTC QLQ-C30 score (per 10 points) 1	79.53 ± 10.91	87.85 ± 6.92	-5.454	< 0.001
EORTC QLQ-C30 score (per 10 points) 2	75.59 ± 11.57	89.25 ± 6.89	-8.599	< 0.001

DT: Distress Thermometer; EORTC QLQ-C30: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30.

PFS in patients receiving treatment

Figure 4A demonstrates that among patients with advanced NSCLC receiving comprehensive targeted therapy, PFS was significantly better in those without psychological distress than in those with psychological distress (hazard ratio: 0.425; 95% confidence interval: 0.298-0.608; P < 0.01). Figure 4B shows that among patients with advanced NSCLC receiving targeted therapy combined with chemotherapy, PFS was also significantly better in the group without psychological distress compared to the group with psychological distress (hazard ratio: 0.395; 95% confidence interval: 0.238-0.656; P < 0.01).

Figure 4 Progression-free survival of the patient receiving treatment. A: Targeted comprehensive therapy; B: Targeted combination chemotherapy.

Adverse events in patients receiving targeted therapy

Table 5 shows that the adverse event profiles were similar between the two groups of patients with advanced NSCLC. The most common adverse events were aminotransferase rise, rash, vomiting, diarrhea, and thrombocytopenia. The incidence of rash was 12.50% in the psychological distress (DT) group and 9.86% in the non-psychological distress (non-DT) group. The incidence of diarrhea was 12.50% in the DT group and 14.08% in the non-DT group.

Table 5 Adverse events of the patient receiving treatment, n (%).

Adverse event	Group
	DT (n = 72)	Non-DT (n = 71)
Rash	9 (12.5)	7 (9.86)
Diarrhea	9 (12.5)	10 (14.08)
Thrombocytopenia	5 (6.94)	8 (11.27)
Aminotransferase rise	11 (15.28)	16 (22.54)
Stomatitis	3 (4.17)	3 (4.23)
Vomiting	11 (15.28)	8 (11.27)
Pneumonitis	1 (1.39)	1 (1.41)
Sinus bradycardia	2 (2.78)	2 (2.82)
Paronychia	1 (1.39)	1 (1.41)
Others	0 (0.00)	2 (2.82)

DT: Distress Thermometer.

DISCUSSION

This study explored the relationship between psychological distress and the efficacy and quality of life of targeted therapy in patients with advanced NSCLC. We found that psychological distress is one of the factors affecting the efficacy and quality of life of targeted therapy in this population. The ORR and DCR in advanced NSCLC patients with psychological distress were significantly lower than those in patients without distress. Notably, in patients receiving targeted therapy combined with chemotherapy, the clinical efficacy in the non-psychological distress group was markedly higher than that in the distress group. Previous studies have demonstrated that targeted therapy plus chemotherapy confers a significant efficacy advantage over targeted therapy alone[30], but these studies did not incorporate psychological factors. A case report has documented the emergence of psychiatric disturbances, including consciousness abnormalities, in a patient following targeted therapy[31]. However, no studies to date have investigated the relationship between psychological distress and the efficacy of targeted therapy.

PFS was significantly shorter in patients with advanced NSCLC and psychological distress than in those without psychological distress. This difference was also evident among patients receiving targeted therapy combined with chemotherapy, suggesting that psychological distress may influence long-term clinical outcomes. In the present study, the quality of life scores in the distress group were higher than those in the non-distress group both before and after targeted therapy; however, the quality of life scores in the distress group decreased after treatment, which may be attributable to treatment-related adverse events. Previous studies have reported that adverse events associated with targeted therapy can impair quality of life in patients receiving EGFR-TKI therapy. Monitoring of inflammatory cells may enable early prediction of changes in quality of life[32]. Clinical research has also demonstrated that appropriate interventions for patients with psychological distress may exert a positive impact on quality of life. For instance, an adolescent peer support intervention study found that an 8-week intervention significantly improved the psychological status and enhanced the quality of life in this population. In newly diagnosed breast cancer patients, a telephone-based support intervention significantly alleviated psychological distress, anxiety, and other negative emotions, and led to markedly improved quality of life compared with the control group[33,34]. Appropriate psychological interventions may represent an important strategy for improving the quality of life of these patients and warrant further investigation in future studies. Lung cancer has the highest incidence among all malignancies worldwide. With continuous advancements in lung cancer research and clinical trials, and with improvements in living standards, attention has gradually turned toward the impact of psychological factors[35]. Targeted therapy has brought substantial benefits to patients harboring oncogenic driver mutations, prolonging the survival of patients with advanced lung cancer. However, suboptimal treatment responses observed in some patients during clinical practice have drawn attention to the possibility that psychological factors may affect therapeutic outcomes.

In the treatment of lung cancer, targeted therapy can be combined with chemotherapy and radiotherapy[36]. Targeted therapy is more specific than chemotherapy and is associated with relatively milder adverse effects, whereas chemotherapy primarily acts on rapidly dividing cells, resulting in a broader spectrum of adverse effects and more systemic impact[37]. In this study, the incidence of adverse events was similar between the two groups, with the main types being elevated transaminases, vomiting, rash, and diarrhea, consistent with previous literature reports[38,39]. Psychological distress did not significantly influence the adverse events of targeted therapy. Currently, existing studies have shown that patients receiving targeted therapy for NSCLC have a lower probability of experiencing psychological distress than those receiving chemotherapy. In this study, a higher proportion of patients who received targeted therapy combined with chemotherapy experienced psychological distress compared with those receiving single-agent targeted therapy. The higher proportion of psychological distress in the combination therapy group may be attributed to differences in disease severity, symptom burden, patient perception, and potential selection bias. Socioeconomic factors may also affect the adverse effects of targeted therapy. Previous studies among patients receiving targeted agents have demonstrated that educational level correlates with the severity of skin-related adverse events[40]. In this study, patients were stratified using the DT, a specific and practical tool that can effectively evaluate the psychological status of patients.

Genetic testing is widely applied in lung cancer, and the corresponding first-, second-, and third-generation TKIs have also been extensively used in clinical practice[41]. Given the mechanisms of small-molecule targeted agents and the fact that their use prolongs both PFS and overall survival, the quality of life and psychological assessment of patients have attracted increasing attention. In lung adenocarcinoma tissues, it has been observed that tumor necrosis factor-α levels are significantly elevated in tumors harboring EGFR mutations compared with those without EGFR mutations, and this elevation shows no significant correlation with interleukin-6[42]. TNF-α plays an important role in the monitoring of psychological distress in patients with advanced cancer, demonstrating a positive correlation with psychological stress and serving as a predictor of psychological distress in this population[43,44]. Therefore, whether monitoring TNF-α may enable early detection of psychological distress in patients with advanced NSCLC harboring EGFR mutations is a direction that warrants attention in future research.

This study employed the DT score and the EORTC QLQ-C30 score to evaluate patients with advanced NSCLC harboring genetic mutations and to further explore the correlation between psychological distress and the efficacy of targeted therapy, a relationship that has not been investigated in previous studies. The above findings suggest that early intervention for patients’ psychological and emotional issues during clinical treatment may help avert potential negative impacts on therapeutic efficacy. This study has several limitations. It is a single-center, small-sample cross-sectional study; therefore, multicenter longitudinal studies are warranted to further validate the precise relationship between psychological distress and both the efficacy of targeted therapy and quality of life, as well as the possible molecular mechanisms involved.

CONCLUSION

In patients with advanced NSCLC harboring oncogenic driver mutations, concomitant psychological distress impairs quality of life, which remains unimproved after targeted therapy. Furthermore, psychological distress adversely affects the clinical efficacy of targeted therapy in these patients. Early identification of such individuals and subsequent psychological intervention may improve their prognosis, providing a theoretical rationale for enhancing the efficacy of targeted therapy in clinical practice. In the future, we will further investigate appropriate methods for monitoring psychological distress and optimal intervention strategies for this patient population.