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Introduction
Globally, lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related deaths [1,2]. Global cancer statistics for 2020 reported approximately 2.2 million newly diagnosed patients with lung cancer and 1.8 million cancer deaths worldwide [3]. Lung cancer is considered incurable in advanced cases, and the cure rate is only 15%-30% with the standard treatment of cisplatin-based concurrent chemoradiotherapy (CCRT) [4]. In Korea, lung cancer incidence has been increasing steadily since 1999, doubling in the last 20 years [5]. In particular, lung cancer in Korea is prevalent in older patients, who may be more vulnerable to mental health issues due to a higher prevalence of comorbidities compared to younger patients [6].
People with cancer are increasingly experiencing a wide range of psychiatric disorders. The most prevalent conditions include delirium, depression, adjustment disorders, anxiety, sexual dysfunction, and sleep disturbances, affecting 30%-40% of patients with cancer. These issues are particularly common in individuals with advanced-stage cancer [7,8]. Antipsychotic drugs (APDs) can attenuate the subjective symptoms of delirium, agitation, or other mood disorders often accompanying cancer treatment [9,10]. In the context of psycho-oncology, APDs are frequently used to manage various symptoms beyond those typically treated in general psychiatric settings. While their primary use is to manage delirium, confusion, agitation, and manic episodes, they also play a valuable role in mitigating anxiety, insomnia, nausea, and stimulating appetite [11,12]. Furthermore, APDs are frequently used off-label to manage drug-induced psychotic symptoms and alleviate pain in various oncology contexts [13]. In the treatment of lung cancer, challenging multimodality treatments, such as CCRT, can cause or worsen psychiatric symptoms such as delirium. In particular, older patients who are commonly affected by lung cancer may have higher risk of developing treatment-related psychiatric disorders [14]. Moreover, older patients are commonly on medications for their pre-existing conditions alongside cancer treatment. Consequently, when psychiatric disorders develop or symptoms arise that necessitate the use of medication, careful consideration should be given to the administration of APDs. Thus, further research is needed on the use of APDs and an assessment of their current applications. However, to date, no studies have addressed this issue in patients with lung cancer.
Therefore, we aimed to investigate the use of APDs in patients with lung cancer receiving CCRT in a real-world setting. We also explored the survival data from a nationwide healthcare database managed by the National Health Insurance Service (NHIS) in Korea.
Materials and Methods
1. Databases and study population
This study used data from NHIS database between 2010 and 2020. NHIS provided medical claims data for the entire population in Korea. Diagnosis codes in NHIS use the Korean Standard Classification of Diseases. We first screened for patients with diagnosis codes C00-C97 during the period. From the total patients with cancer, we selected eligible patients who were diagnosed with lung cancer and received CCRT. In the dataset, chemotherapy drugs were limited to cisplatin, which is mainly used as a CCRT regimen in advanced-stage lung cancer. CCRT cases were defined by those where chemotherapy was claimed during the period when radiotherapy (RT) was also claimed. Among the patients with lung cancer who received CCRT, we screened the patients who had been prescribed APDs, including aripiprazole, quetiapine, olanzapine, risperidone, haloperidol, and chlorpromazine. The claim data included age, sex, Charlson Comorbidity Index (CCI), and comorbidities, including cardiovascular disease and psychiatric disorders. Excluding cancer, the diagnosis codes included in the analysis were hypertension (I10-I15), myocardial infarction (I21, I22), bipolar disorder (F30, F31), psychotic disorder (F20-F29), depressive disorder (F32-F34), delirium (F05), and other psychiatric disorders (F00-F99). The history of hypertension, myocardial infarction, and psychiatric history (bipolar disorder, psychotic disorder, depressive disorder, delirium, and other psychiatric disorders) included all diagnoses made throughout the study period. The psychiatric history presented in Table 1 includes only psychiatric disorders diagnosed prior to the initiation of CCRT for lung cancer.
Although the diagnosis code for lung cancer included non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), NHIS data did not include information on the stage. However, we could estimate the approximate stage of the patients with lung cancer who received CCRT. In NSCLC, CCRT is administered in stage IIIA and above, or in IIB, when the cancer is inoperable N1. In SCLC, CCRT is administered in limited stage diseases from IIB to IIIC. Therefore, the patients with lung cancer included in the analyses were generally in locally advanced stages.
2. Prescriptions for APDs
Patients with a CCRT claim were considered to have been prescribed an APD if they had at least one APD claim. Patients who were prescribed APD before starting CCRT, with the duration of APD administration overlapping with that of CCRT, as well as those who were prescribed APD during CCRT, were included in the APD groups. Based on the CCRT and APD prescription dates, patients who were prescribed APD before starting CCRT were included in the pre-CCRT group and those who were prescribed APD during CCRT were included in the during-CCRT group.
APD prescriptions were categorized as “simple prescription,” where only one drug was prescribed, and “complex prescription,” where two or more drugs were prescribed simultaneously. The prescription dosage of APD was classified as low or high based on the prescribed dose on a simple prescription basis. Equivalent doses were determined based on chlorpromazine, where 100 mg/day of chlorpromazine is equivalent to quetiapine 60 mg/day, olanzapine 3 mg/day, risperidone 0.8 mg/day, aripiprazole 4 mg/day, and haloperidol 1.6 mg/day. We adopted the concept of high dose from Leucht et al. [15] as follows: chlorpromazine 250 mg/day, quetiapine 150 mg/day, olanzapine 7.5 mg/day, risperidone 2 mg/day, aripiprazole 10 mg/day, and haloperidol 4 mg/day.
3. Statistical analysis
The chi-squared test or independent Student t test were used for comparing the differences in categorical or continuous variables. For all analyses, categorical variables are expressed as frequencies and percentages, whereas continuous variables are expressed as mean±standard deviation. Using the Cox proportional hazards regression analysis, we estimated the risk of mortality with hazard ratios (HRs) and 95% confidence intervals (CIs). We conducted a survival analysis of the prognostic factors that potentially affected overall survival (OS). The starting date of the survival analysis was defined as day 1 of CCRT in patients and the endpoint was defined as the date of the patient’s death or December 31, 2020, for patients who survived. Attrition occurred when patients were no longer available for follow-up due to death, emigration, or loss of National Health Insurance eligibility; thus, data up to the last observation point were included in the analysis. The analysis included APD use, age, hypertension, myocardial infarction, psychiatric history (bipolar disorder, psychotic disorder, depression, delirium, and other psychotic disorders), and CCI. We used univariate analysis to identify the impact of each variable on survival. Subsequently, multivariable analysis was applied to determine the associations between multiple variables and survival, thereby identifying significant factors. All data were analyzed using SAS ver. 9.4 (SAS Institute, Inc.) and R ver. 4.1.3 (R Foundation for Statistical Computing), with a significance level of alpha=0.05.
Results
1. Baseline characteristics of patients and details of prescribed APD
According to the NHIS dataset, of the 977,706 patients with cancer, 23,099 received CCRT after being diagnosed with lung cancer. Among them, 2,662 (11.5%) received APDs during CCRT (Fig. 1).
Among the patients who took APDs during CCRT, 2,375 (89.2%) were male. The age distribution of patients who took APDs during CCRT was as follows: 0.7%, 4.3%, 20.4%, 40.2%, 30.8%, and 3.5% of patients in their 30s, 40s, 50s, 60s, 70s, and 80s, respectively. Among the patients with three or more CCIs, 58.9% took APDs and 56.6% did not. The patients who took APDs had the following underlying medical conditions: 1,619 patients (60.8%) had hypertension (I10-I15) and 174 (6.5%) had a previous myocardial infarction (I21, I22). Additionally, 64.9% of patients using APDs during CCRT had a psychiatric history, compared with 50.9% of patients who did not use APDs during CCRT. The underlying psychiatric conditions included bipolar disorder (F30, F31), psychotic disorder (F20-F29), depressive disorder (F32-F34), delirium (F05), and other psychiatric disorders (F00-F99) in 10.3%, 4.4%, 30.1%, 2.1%, and 30.2% patients, respectively. Compared with the patients who did not use APDs during CCRT, those who took APDs had higher rates of most comorbidities (Table 1).
Information on the types of the prescribed APDs is described in Table 2. For simple prescriptions, the most commonly prescribed APD during CCRT were quetiapine (47.6%), chlorpromazine (39.1%), olanzapine (8.2%), and risperidone (5.2%). The proportion of patients who received complex prescriptions of APDs during CCRT was 5.3% (141 of 2,662 patients). Patients prescribed two APDs accounted for 97.2% of the total, whereas those prescribed three or more APDs accounted for 2.8%. Meanwhile, details of the timing, dosage (low vs. high), and duration of the prescribed APDs during CCRT are shown in Table 2. Of the patients who took APDs during CCRT, 20% and 80% were in the pre-CCRT and during-CCRT groups, respectively. Regarding prescribed dosages, 96.3% of patients received a low dosage, whereas 3.7% received a high dosage. A majority were prescribed for less than 6 months (91.7%), whereas 8.3% of patients were prescribed for more than 6 months during and after CCRT.
2. Survival analysis of patients with lung cancer prescribed APD
In univariate analysis, a significant difference in the OS rate was observed for patients with lung cancer treated with CCRT, depending on whether APD was prescribed. The 2-year OS rates for the APD (+) and APD (–) groups were 20.4% and 36.4%, respectively (p < 0.001) (Fig. 2). Male sex, age ≥ 80 years, higher CCI score, and accompanying hypertension, myocardial infarction, bipolar disorder, psychotic disorders, depression, and delirium were negative prognostic factors. Other psychiatric disorders were excluded from the analysis due to the diversity of conditions and ambiguity in their definitions. We performed multivariate analyses to determine the factors affecting OS. APD use during CCRT was a significant factor for worse OS (HR, 1.62; 95% CI, 1.55 to 1.69; p < 0.001). Moreover, male and age ≥ 80 years significantly affected OS (HR, 1.17 and 2.06, respectively; both p < 0.001). Underlying hypertension (HR, 1.11; 95% CI, 1.07 to 1.14; p < 0.001) and myocardial infarction (HR, 1.12; 95% CI, 1.05 to 1.21; p=0.002) were the significant factors for worse OS. Patients with a history of depression were also associated with poorer OS (HR, 1.10; 95% CI, 1.06 to 1.15; p < 0.001) (Table 3). In addition, we performed further survival analyses using the factors that were significant in the multivariate analyses. For men aged ≥ 80 years who took APDs during CCRT tended to result in worse OS compared with those who did not use APDs (p=0.094) (S1 Fig.). However, no statistically significant difference was observed in OS based on the number of comorbidities (hypertension, myocardial infarction, depression) in male patients with lung cancer aged ≥ 80 years who took APDs (p=0.989) (S2 Fig.).
A subgroup analysis was conducted in patients who took APDs during CCRT. This analysis incorporated APD prescription along with the variables evaluated for all patients who received CCRT. In univariate analysis, the pre-CCRT group exhibited a lower OS than the during-CCRT group, but no statistically significant difference was observed in multivariate analysis. Prescription dosage (low vs. high) and duration (within 6 months vs. over 6 months) showed no significant difference in OS (Table 4).
Discussion
Patients diagnosed with cancer frequently experience concurrent psychiatric disorders along with general psychological distress [16]. Among patients with cancer, 20%-40% experience significant levels of psychological issues, which can negatively impact their treatment course, quality of life, and even survival rates [17,18]. The patients with locally advanced lung cancer who receive CCRT are likely to experience more psychiatric disorders due to their greater tumor burden [2,6,18]. During the study period from 2010 to 2020, lung cancer treatment has advanced significantly, impacting OS rates based on the time of diagnosis. Concurrently, APD prescriptions have increased over time, reflecting the fact that more patients with lung cancer are experiencing psychological difficulties related to cancer treatment (Fig. 3). As shown in Fig. 3, a notable trend of decreasing mortality rates and increasing APD prescription rates was observed among patients with lung cancer. This demographic shift underscores the importance of investigating the psychological vulnerability of patients with lung cancer and the potential impact of APD use on their overall survival.
This study aimed to evaluate APD use in patients with lung cancer who received CCRT and assess its effect on survival. To our knowledge, this is the first study to report the prevalence of APD use and its effect during CCRT in patients with lung cancer in Korea.
Some studies have reported a lower cancer incidence rate within the schizophrenic population, which is likely due to APD use [19-21]. Jeong et al. [22] suggested that certain APDs, such as trifluoperazine, inhibit the progression of NSCLC based on anti-lung-cancer activity of trifluoperazine on A549 human lung cancer cells. In addition, Yang et al. [23] reported quetiapine as a radiosensitizer for liver cancer. Based on these biological grounds, we analyzed the effect of APDs use during CCRT on survival in patients with lung cancer. We hypothesized that the prescription of APDs during CCRT would positively impact survival in patients with locally advanced lung cancer. However, the use of APDs during CCRT was associated with poor prognosis in this study. In our study, a significant association was observed between APD use during CCRT and lower OS. Patients who took APDs had a significantly worse 2-year survival rate than those who did not. The primary APDs used during CCRT in our cohort were chlorpromazine and quetiapine. This finding likely reflects the fact that the study population comprised patients taking APDs during CCRT and is similar to results from a previous study examining APD use during radiotherapy across all cancer patients, including those with lung cancer [24].
Several factors may explain the observed association between APD use and reduced survival rates. First, patients prescribed APDs during CCRT exhibited higher rates of comorbidities including hypertension, myocardial infarction, and delirium, compared with those prescribed APDs over the entire period. These comorbid conditions can adversely affect the survival outcomes in patients with lung cancer. Individuals with such underlying health issues are more likely to be prescribed APDs, and the cumulative effects of these conditions may contribute to the observed decrease in survival rates. Furthermore, APD use may serve as an indicator of more advanced lung cancer or heightened psychological problems associated with the disease and its treatment. Patients with more aggressive cancer or those experiencing significant psychiatric issues may be more prone to receive APDs [25,26], and these factors independently influence survival rates. Second, the high mortality rate associated with psychiatric disorders may also account for the increased mortality among patients using APDs during CCRT. A meta-analysis indicated a pooled relative risk of all-cause mortality of 2.22 among individuals with mental disorders, including schizophrenia, depression, anxiety, and bipolar disorder [27]. In our study, we classified and analyzed psychiatric diagnoses to ascertain the reasons for APD use among patients who took APDs during CCRT. Although not all patients who took APDs had accompanying psychiatric diagnostic codes, those with psychiatric diagnoses demonstrated a statistically significant higher proportion among the patients who took APDs during CCRT. Third, APDs have various side effects, including sedation, metabolic disturbances, and cardiovascular complications [28,29]. These adverse effects can potentially exacerbate a patient’s overall health and treatment tolerance, leading to poorer clinical outcomes.
We also performed subgroup analysis of APD prescriptions that may affect survival in patients using APDs during CCRT. The pre-CCRT group exhibited a lower OS rate than did the during-CCRT group in univariate analysis, but this difference did not reach statistical significance in multivariable analysis. Prescription dosage and duration were also not significant prognostic factors. In patients who took APDs during CCRT, only a lower CCI score was a statistically significant good prognostic factor. These results suggest that the underlying status of patients forced to use APD rather than using APD itself likely contributed to the observed survival rates. Most of the APDs used during CCRT were prescribed during CCRT (80%) and was administered at a low dose (96.3%) and within 6 months (91.7%).
Understanding the rationale for the use of APDs in real-world settings is crucial, as valid reasons for their prescription that suggest the therapeutic benefits may outweigh potential side effects. APDs are frequently prescribed in patients with cancer for various reasons. They are commonly used as adjunctive therapy or monotherapy for managing psychotic symptoms, such as delusions and hallucinations, as well as manic symptoms. Atypical APDs may also serve as adjunctive or monotherapy for managing depressive symptoms that show a weak response to traditional antidepressants, often at higher doses covered by medical insurance. Furthermore, APDs are indicated as adjunctive treatment when psychological distress—such as depression, anxiety, and insomnia—fails to improve with standard antidepressants or anxiolytics. They may also be used to manage delirium and alleviate chemotherapy- or radiotherapy-induced nausea and vomiting, often in off-label and lower doses. Our findings suggest that delirium during CCRT likely contributes to the need for a regimen involving low-dose APDs for short durations. In our study, the proportion of patients with delirium diagnostic codes was extremely low, but in reality, the number of patients experiencing delirium is likely much higher. This is presumably attributed to the fact that delirium among patients with cancer may often be coded under other psychiatric diagnostic codes or not specified in clinical practice. APDs are used for the pharmacological management of delirium and should be administered at the lowest appropriate dose [29]. It is possible that the reason for starting APD during CCRT and using APD for less than 6 months was due to the clinical course of delirium. Additionally, the most commonly used APD in our study was quetiapine, which is often the primary choice for older patients with delirium due to its low incidence of extrapyramidal side effects [30]. Delirium is the most common neurological condition in patients with cancer and is more commonly observed in older patients. Studies have shown that 22%-44% of patients with cancer experience delirium, and the incidence rises to 87% in the final days of life [31]. Although we cannot be completely sure if most patients who took APD during CCRT in our study had delirium, this could be one of the reasons for the high mortality rate. In admitted patients with terminal cancer, higher mortality rates have been reported in patients with delirium than in those without it [32]. Further studies on the effects of APDs on cancer treatment and prognosis are needed.
This study has limitations inherent to its observational design. In an actual clinical setting, APD prescriptions in hospitalized patients during CCRT are often made without coding for delirium (F05 code). In addition, the possibility of APDs prescribed under incorrect F codes cannot be ignored. Our study established an association between APD and OS, but we did not definitively prove that APD use directly resulted in lower survival rates in patients with lung cancer treated with CCRT. This study was based on medical claims, not medical chart reviews. Given the limited clinical presentations in the NHIS dataset, non-claims information, such as smoking or other factors affecting survival, was excluded from the analyses. Additionally, not all the claimed comorbidities were used in the analyses of the factors affecting OS due to the wide variety of underlying conditions. Hence, caution should be taken in interpreting our findings, especially considering that certain non-claim data were not reflected. In particular, the lack of information on staging may limit the clinical application of the findings. However, we predicted locally advanced stages in a relatively limited cohort of patients with lung cancer who had received CCRT. We also focused on comorbidities, such as cardiovascular disease or psychiatric disorders, which may be associated with chest irradiation or APD prescription. Particularly, quetiapine, the most commonly prescribed drug, may increase the risk of major cardiovascular events, and RT to the lung can cause cardiac toxicity [33-35]. Nevertheless, as mentioned above, the inability to accurately identify clinical cases using APD is an inevitable limitation of this study using NHIS data. Nonetheless, this study reflects actual clinical situations related to APD use, and we believe that additional research using electronic medical record that can yield detailed information based on individual data is needed.
Taken together, this is the first study to report on the use of APDs in the growing population of older patients with lung cancer in real-world practice in Korea. We found that 11.5% of the patients with lung cancer took APDs during CCRT. The study’s results highlight the potential negative association between APD use during CCRT and survival in patients with lung cancer. The high mortality rate observed in patients with lung cancer who took APDs during CCRT could be influenced by the underlying conditions that necessitated APD use. Further studies are needed to determine the effects of APD use during CCRT in patients with lung cancer.
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