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Anxiety After Diagnosis Predicts Lung Cancer–Specific and Overall Survival in Patients With Stage III Non–Small Cell Lung Cancer: A Population-Based Cohort Study
University of British Columbia, Vancouver, British Columbia, CanadaDepartment of Obstetrics and Gynecology—Campus Groβhadern, University of Munich, Germany
Address correspondence to: Wolfgang Linden, PhD, Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, British Columbia V6T 1Z4, Canada.
University of British Columbia, Vancouver, British Columbia, CanadaRadiation Therapy Program, BC Cancer Agency, Centre for the North, Prince George, British Columbia, Canada
The question as to whether anxiety and depression are related to mortality in patients with lung cancer is inconclusive.
Objectives
Therefore, the present study is examining associations of anxiety and depression in a large representative sample of patients with Stage III non-small cell lung cancer.
Methods
Patients (n = 684) were routinely assessed for anxiety and depression with the PsychoSocial Screen for Cancer questionnaire after diagnosis of lung cancer and before treatment initiation between 2004 and 2010. Survival data were retrieved in May 2012. Cox proportional hazards regression analyses had been used as statistical procedures allowing adjustment for demographic, biomedical, and treatment variables.
Results
In analyses controlling for demographic, biomedical, and treatment prognosticators, anxiety but not depression was associated with increased lung cancer–specific (hazard ratio 1.04; 95% confidence interval 1.01–1.07; P = 0.035) and all-cause (hazard ratio 1.04; 95% confidence interval 1.01–1.07; P = 0.005) mortality. Secondary analyses revealed a confounder effect of performance status on the association between depression and mortality, such that the removal of performance status identified a significant relationship of depression on lung cancer–specific and all-cause mortality.
Conclusion
In a large population-based sample of patients with non–small cell lung cancer analyses demonstrated associations of anxiety with mortality, adding to the evidence that psychosocial factors might play a role in disease progression in this patient group. Because emotional distress is associated with continued smoking and lack of success of smoking cessation attempts, psychological interventions potentially could influence length of survival in lung cancer patients.
Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database.
Epidemiology of lung cancer: diagnosis and management of lung cancer, 3rd ed.: American College of Chest Physicians evidence-based clinical practice guidelines.
Not surprisingly, patients with lung cancer are considerably emotionally distressed. In a large epidemiologic study, lung cancer patients reported the greatest levels of anxiety and depression after diagnosis
Feelings of guilt and stigma as a result of having provoked the disease with one's smoking behavior may contribute to distress on top of the poor prognosis.
Although a diagnosis of cancer is predictably perceived as a major health threat, subjective patient responses to the same diagnosis vary.
Psychoneuroimmunologic models assume a mechanism by which anxiety and depression can affect survival in cancer patients. Under this framework, psychological processes such as anxiety and depression follow a pathway ultimately resulting in impaired nervous system and immune function, which in turn can promote preterm death.
The question whether emotional distress affects survival in cancer patients is of scientific interest since decades and had been studies in mixed samples of cancer patients and distinct cancer types. In patients with lung cancer, earlier studies showed conflicting findings, possibly because of methodologic limitations such as small sample size, poor sample aggregation (e.g., some studies combined small cell and non–small cell lung cancer without adequate control), and lack of biomedical and treatment descriptors and their control. In a small sample of 40 Stage IV lung cancer patients, an association existed between initial quality of life and survival,
using a similar design failed to show such a link. A study including 122 patients with Stage III and IV lung cancer patients also did not identify relationships between psychosocial factors and survival.
could not confirm a relationship between depression and mortality but demonstrated the relevance of depressive coping for survival. In contrast, an epidemiologic study reported that psychiatric comorbidities decreased survival.
Yet given the epidemiologic nature of the study biomedical and treatment variables had not been controlled for. To date, no study controlling for biologic risk factors examined associations between anxiety and mortality in patients with non–small cell lung cancer, although anxiety is a highly prevalent symptom.
Although anxiety and depression are correlated, they represent distinct symptom patterns, which should be studied separately. For example, anxiety can be a more volatile syndrome in cancer patients compared with depression,
A longitudinal study on anxiety, depressive and adjustment disorder, suicide ideation and symptoms of emotional distress in patients with cancer undergoing radiotherapy.
Given the scarcity of studies on lung cancer and anxiety and inconsistency of findings with regard to depression, the present study tested associations between anxiety and depression on lung-cancer–specific and all-cause mortality in a defined sample of patients with Stage III non–small cell lung cancer awaiting upfront radiotherapy. We hypothesized that both anxiety and depression were associated with shorter length of survival, possibly because distressed lung cancer patients also tend to continue smoking despite their cancer diagnosis.
In 2004, a routine screening program for emotional distress was started, where every newly diagnosed cancer patient attending two major cancer centers in Metro Vancouver (BC Cancer Agency Vancouver and BC Cancer Agency Surrey) was asked to complete a psychological screening questionnaire, the Psychosocial Screen for Cancer (PSSCAN
), with resulting findings being added to the patient's chart. The study used a retrospective cohort design and collected additional information from the provincial Cancer Agency Information System (CAIS). Approval was obtained from the University of British Columbia–BC Cancer Agency (BCCA) Research Ethics Board.
Participant Selection
To maximize homogeneity and representativeness of the sample, Stage III non–small cell lung cancer (NSCLC) patients were selected as upfront radiotherapy (RT) is the predominant treatment modality in these patients and RT is only delivered at the BCCA within British Columbia. Thus, a high proportion of Stage III patients are referred to BCCA. In British Columbia, more than 80% of Stage III lung cancer patients are referred to BCCA for consideration of radiotherapy.
In contrast, only a fraction of patients with Stage I and Stage II lung cancer are referred to BCCA because these rarely require RT, whereas a large proportion of these patients may have received adjuvant chemotherapy through community hospitals instead. Thus, inclusion of patients with early-stage lung cancer would have led to a significant selection bias. Likewise, only a fraction of Stage IV lung cancer patients are referred to the BCCA, and inclusion of this stage would have also increased the selection bias. All patients with Stage III NSCLC referred to two Greater Vancouver cancer centers between 2002 and 2010 were identified.
Patients were excluded if PSSCAN scores in the chart were missing or incomplete. PSSCAN scores and other characteristics of interest were manually extracted from the patients' paper charts. These psychosocial variables were merged with electronically archived demographic and biomedical data from the CAIS system. The resulting database was then merged with censored data regarding the patients' survival status. Survival data were retrieved from BC Vital Statistics, the Provincial Vital Statistics Agency, who provides complete death lists for all deceased British Columbians on a monthly basis. Survival data had been extracted in May 2012.
Nonpsychological Variables Collected
Age, sex, marital status, ethnicity, employment status, performance status (measured by the Eastern Cooperative Oncology Group performance status), stage, histology, and the use of definitive surgery, radiation, and/or initial chemotherapy were abstracted from CAIS. The Eastern Cooperative Oncology Group performance status
assesses anxiety and depressive symptoms, perceived social support, desired social support, and quality of life via self-report. Only the anxiety and depression subscales were analyzed in this study. These consist of five questions each asking for the patients' level of anxiety and depression, respectively. The answer format is a five-point rating scale, with scores ranging from “Not at All” (Score 1) to “Very Much So” (Score 5). The sum of the five items of each subscale represents the subscale score.
The PSSCAN was specifically developed for use with cancer patients, meets multiple criteria for reliability in cancer patients and healthy individuals, and also possesses content, concurrent, and construct validity.
The validation process also included a control group of healthy individuals. Furthermore, comparisons of the PSSCAN anxiety and depression subscales against the extensively validated HADS scale
demonstrated very good sensitivity (92% and 100%) and specificity (98% and 86%). Cutoffs for each subscale are 8 for subclinical symptoms and 11 for clinical symptoms.
Statistical Methods
To test the effect of anxiety and depression on mortality, Cox proportional hazards regression analysis was used for survival analysis adjusting for relevant demographic, biomedical, and treatment variables.
The censor date, which is the most recent date for which death information was available, contains complete information on all patients in the registry, and all cases are censored at that same date. Censored cases were defined by nonreceipt of information about a patient's death and death date at the time of retrieval of survival data. Thus, patients for whom data on survival status were missing were categorized as censored. In this process, the censoring mechanism is not related to the outcome and the assumption of noninformative and right censoring is satisfied.
Survival time was calculated by subtracting the date of death or censoring from the date of diagnosis. Analyses were conducted for death resulting from any cause (i.e., all-cause mortality) and death resulting from lung cancer (i.e., lung cancer–specific mortality).
Cox proportional hazards regression analysis uses the likelihood ratio statistic and calculates the overall chi-square. Parameter estimates for each variable in the model represent hazard ratios. Analyses were controlling for the effects of age, sex, marital status, ethnicity, employment status, performance status, stage, histology, and treatment variables (i.e., surgery, radiation, chemotherapy).
In a first step, proportionality of hazards was examined by testing the time dependency of each control or predictor variable separately. The respective variable was entered together with its interaction with time in a Cox regression model. If the variable × time interaction turned out to be significant, this respective variable demonstrates time-dependent changes in hazards, and a variable × time interaction, therefore, needs to be included in the multivariate model.
Next, a forced entry hierarchical model was chosen where demographic variables were entered in a first step, biomedical (i.e., performance status, stage, histology) entered second, treatment variables (surgery, radiation, chemotherapy) entered third, and either anxiety or depression entered fourth.
Age was entered as continuous, mean-centered variable into the Cox regression equation model. All other control variables were entered as categorical variables. Predictor variables were tested separately in its effects on survival and were entered as continuous variables because analyzing variables as continuous variables in contrast with analyzes of categorized variables is not associated with a loss of information.
Significant effects were visualized by plotting Kaplan-Meier curves with the subclinical threshold used as the cutoff.
All statistical tests were two-tailed and a P-value of less than 0.05 was considered statistically significant. Confidence intervals are also reported as an alternative indicator of significance, indicating that the population mean will fall within the respective range in 95% of samples. Statistical analyses were conducted with IBM SPSS Statistics, version 23.
Results
One thousand eighty patients were identified with Stage III NSCLC and 756 provided complete PSSCAN data. Missing biomedical and treatment data further reduced the sample number to 684 (To retain as many patients as possible for analyzes, categorical control variables included an “unknown” category. This strategy, however, cannot be applied to continuous variables.). Characteristics of the study cohort are presented in Table 1. Patients were 68 years on average and equally distributed by sex; 65.2% of the sample were married or lived in a common law relationship and 78.9% were white. Only 12.0% of patients were still in the work force. About two-third of patients had Stage IIIA disease. Among histologic subtypes, non–small cell carcinoma not otherwise specified (NOS) was with 43.7% the most prevalent, followed by squamous cell carcinoma (24.4%) and adenocarcinoma (23.4%). Only 15.8% of patients had undergone surgery, whereas 83.2% received upfront radiation treatment; 36.5% underwent upfront chemotherapy. Mean anxiety and depression scores reached the subclinical threshold. At the time of analysis, 553 of 684 subjects had died, of which 489 had died of lung cancer. Median overall survival was 12.5 months.
Anxiety and depression were moderately to strongly positively correlated at ρ = 0.64. Anxiety and depression were also modestly positively correlated with performance status (ρ = 0.11 for anxiety; ρ = 0.20, for depression). Age at diagnosis exhibited small negative correlations with anxiety (ρ = −0.14) and depression (ρ = −0.10) and was positively associated with performance status (ρ = 0.18).
Unadjusted analyses showed both significant associations between anxiety and all-cause mortality (χ2(1) = 4.31; P = 0.038) and between depression and lung cancer–specific (χ2(1) = 8.79; P = 0.003) and all-cause mortality (χ2(1) = 7.38; P = 0.007). Kaplan-Meier curves of these unadjusted effects are displayed in Fig. 1a and 1b for anxiety and in Fig. 2a and 2b for depression, respectively.
Fig. 1a) Anxiety and lung cancer–specific survival. b) Anxiety and overall survival.
Adjusted analyses demonstrated significant associations between anxiety on lung cancer–specific (hazard ratio [HR] 1.04; 95% confidence interval [CI] 1.01–1.07; P = 0.035) and all-cause mortality (HR 1.04; 95% CI 1.01–1.07; P = 0.005) (Table 2), whereas no significant effect of depression on mortality emerged (Table 3). Accounting for the significant intercorrelation of depression with performance status and a potential confounder effect of performance status on the outcome, analyzes were rerun while omitting performance status as a predictor. As a result, depression was significantly associated with lung cancer–specific (HR 1.03; 95% CI 1.01–1.06; P = 0.008) and all-cause mortality (HR 1.04; 95% CI 1.01–1.06; P = 0.003).
Table 2Results of Cox Proportional-Hazards Regression Analyses: Anxiety
Patients with Stage III NSCLC who reported greater anxiety after diagnosis had a greater hazard of lung cancer–specific and all-cause mortality at follow-up. In unadjusted analyses, both anxiety and depression predicted shorter length of survival. However, associations between depression after diagnosis and mortality did not reach significance in multivariate analyses, whereas the effect of anxiety on mortality remained. Given that depression was more strongly correlated with performance status than anxiety, this evident discrepancy raises the question of overlapping variances. The fact that a significant effect emerged again after exclusion of performance status from analyses indicates a potential confounder effect of performance status. Because relations between depression and performance status are bidirectional, a mediational pathway cannot be presumed: patients with poor performance status often report functional limitations and pain and, thus, are more likely to feel depressed. Conversely, depressed patients likewise report functional impairment, which can result as a consequence of reduced energy and of cognitive distortions, both core symptoms of depression.
Although widely examined in other cancer types, studies that tested associations between emotional distress and mortality in patients with lung cancer are scarce to date, and many of these are based on nonrepresentative small sample sizes and lack biomedical and treatment prognosticators. The present study, therefore, provides evidence that anxiety and eventually depression influence length of survival in advanced lung cancer. Nevertheless, the effects observed are small. It has been hypothesized previously that psychosocial factors may not play a role in more aggressive types of cancer,
but this observation may have arisen from studies with smaller samples and less statistical power.
Limitations of the study include the lack of information about smoking habits after lung cancer, a well-known moderator of mortality in this patient group and on biochemical measures (albumin, lactate dehydrogenase), weight loss, and mediastinal node (N2) status,
Advance lung cancer inflammation index (ALI) at diagnosis is a prognostic marker in patients with metastatic non-small cell lung cancer (NSCLC): a retrospective review.
Ideally, anxiety and depression could have been assessed via use of Structured Clinical Interviews, which compared with questionnaire assessments reflect a superior method. A disadvantage of interview assessments are a) its time intensity, which is difficult to establish in routine medical care, where the data of this study had been collected, and b) it would have omitted the consideration of subclinical symptom levels, which can involve dysfunctional health behavior including continued smoking, potentially influencing the course of the disease. Furthermore, anxiety and depression scores were only recorded once, and the potential impact of varying trajectories of distress and its effects on survival, therefore, could not be investigated. Similarly, physician-rated performance status was only assessed once and is likewise a construct whose parameter values can change across time.
Despite these limitations, this study's strengths include a large, representative patient sample within a well-defined tumor type and stage, allowing for accurate control of many relevant biomedical prognostic factors.
No information was available on whether lung cancer patients continued smoking after diagnosis. It is well known that a significant proportion of lung cancer patients continue smoking or fail smoking cessation attempts.
Consequently, psychological interventions should target these correlates of continued smoking to ultimately improve patients' quality of life and eventual length of survival.
Disclosures and Acknowledgments
This research received no specific funding/grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors declare no conflicts of interest.
References
Govindan R.
Page N.
Morgensztern D.
et al.
Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database.
Epidemiology of lung cancer: diagnosis and management of lung cancer, 3rd ed.: American College of Chest Physicians evidence-based clinical practice guidelines.
A longitudinal study on anxiety, depressive and adjustment disorder, suicide ideation and symptoms of emotional distress in patients with cancer undergoing radiotherapy.
Advance lung cancer inflammation index (ALI) at diagnosis is a prognostic marker in patients with metastatic non-small cell lung cancer (NSCLC): a retrospective review.
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