Early childhood adversity in adult patients with metastatic lung cancer: Cross-sectional analysis of symptom burden and inflammation

Highlights

• Early childhood adversity (ECA) leads to inflammation and adult psychopathology.

• Psychological and physical symptom burden may be worsened by ECA in cancer.

• In lung cancer patients, depression was explained by ECA and inflammation.

• Depression appears to mediate the impact of ECA on physical symptoms.

• ECA may identify patients at risk for greater psychological and physical symptoms.

Abstract

Objective

Psychological and physical symptoms commonly occur in patients with metastatic lung cancer and are associated with reduced quality of life and decreased survival. Previous work has associated these symptoms with inflammation. The experience of Early Childhood Adversity (ECA) is linked to chronic inflammation and may identify adult cancer patients who are at-risk for psychological and physical symptoms. We thus hypothesized that ECA in lung cancer patients would be associated with increased psychological symptoms (distress, anxiety, and depression) and physical symptoms and that this relationship would be explained by inflammation.

Methods

Patients with metastatic lung cancer (n = 92) were evaluated for ECA using the Risky Families Questionnaire. Concomitant assessments were made of distress (Distress Thermometer and Problem List [DT&PL]), anxiety (Generalized Anxiety Disorder-7), depression (Patient Hospital Questionniare-9), physical symptoms (DT&PL), and inflammation (C-reactive protein [CRP]). Multivariate models were created to explain associations of ECA with depression, anxiety, distress, number of physical problems, and inflammation.

Results

ECA was associated with distress (r = 0.24, p = .03), anxiety (r = 0.30, p = .004), depression (r = 0.35, p = .001), greater physical problems (r = 0.25, p = .03), younger age (r = -0.29, p = .006), and elevated CRP (r = 0.22, p = .04). Multivariate analyses of outcomes found that depression severity was independently explained by both ECA and inflammation (β = 0.37, p = .001) but not distress or anxiety, while controlling for age and sex. Number of physical problems were also associated with ECA (β = 0.35, p = .004) but not inflammation. The association between ECA and physical problems was not significant after controlling for depression.

Conclusion

ECA is associated with increased depression and physical symptoms independent of inflammation. Moreover, depression appears to mediate the impact of ECA on physical symptoms. ECA may identify patients at risk for psychological and physical symptoms.

Introduction

The prevalence of depression, distress, and anxiety in patients with lung cancer is significant and considered to be among the highest in comparison to other cancer subtypes (Walker et al., 2014). In addition, patients with lung cancer experience high rates of physical symptoms that are associated with psychological symptoms (McFarland et al., 2020). Depression may also contribute to worsened overall survival in patients with cancer and in lung cancer patients in particular (Sullivan et al., 2016, Pinquart and Duberstein, 2010). Depression is also more prominent in advanced disease and the majority of lung cancer is advanced (Grotmol et al., 2018).

We previously reported an association between inflammation as measured by C-reactive protein (CRP) and symptom burden (psychological and physical) experienced by patients with metastatic lung cancer (McFarland et al., 2020, McFarland et al., 2019). Associations between inflammation and depression are similarly reported in patients with various cancer types (e.g., breast, lung, gastrointestinal, gynecologic, hematologic) (Jehn et al., 2012, Du et al., 2013, Steel et al., 2007, Breitbart et al., 2014, Lutgendorf et al., 2008, Loh et al., 2020) and in various stages (e.g., early localized versus advanced metastatic) (Jehn et al., 2012, Pertl et al., 2013) and settings (e.g., receiving radiation, systemic treatments, or prior to surgery) (McFarland et al., 2019, Xu et al., 2016, Bower et al., 2009). These findings have been replicated in medically healthy patients and also have bearing on depression treatment effects (Strawbridge et al., 2015, Valkanova et al., 2013). This relationship between inflammation and depression is highly applicable to patients with cancer since rates of co-morbid physical and psychological symptom burden are high and inflammation has been termed the seventh hallmark of cancer (Colotta et al., 2009).

Patients with lung cancer have multiple reasons for increased inflammation which may include smoking, obesity, and medical co-morbidities in addition to cancer and its treatments (O'Connor et al., 2009). These factors may help explain some of the variability in physical and psychological symptom burden related to inflammation among patients lung cancer. An additional and important source of chronic inflammation and its long term effects may be Early Childhood Adversity (ECA).

ECA has been characterized by marked elevation in chronic Inflammation represented by CRP, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in adult survivors of childhood abuse (Kiecolt-Glaser et al., 2011, Fagundes et al., 2013). Along with inflammatory markers, ECA in adults is associated with psychological processes such as chronic stress, poor coping, and behaviors such as alcohol and tobacco use, which may also increase inflammation. There is a graded relationship between ECA and risky behaviors, substance abuse, smoking, smoking-related illness such as COPD, and risk of cancer and specifically lung cancer in adulthood (Cronholm et al., 2015, Anda et al., 2008, Brown et al., 2010, Holman et al., 2016). In addition to cancers, adults who experienced abuse, neglect, or traumatic environments as children are also more likely to develop psychiatric disorders (Nanni et al., 2012). Indeed, ECA or maltreatment is a particularly potent risk factor for depression in adults and may be especially potent when individuals encounter stressful life events, such as cancer (Slavich and Irwin, 2014). Importantly, ECA is associated with greater episodes of recurrent and treatment-resistant depression (Akil et al., 2018). However, the relationship between ECA and anxiety or depression may be related to the same chronic inflammation that appears to be associated with ECA and mood symptoms throughout adulthood (Witek Janusek et al., 2013, Young et al., 1997). This may have particular relevance for patients with lung cancer who are particularly prone to chronic inflammatory states even independently of mood symptoms (Jafri et al., 2013).

Thus, behavioral consequences of ECA appear to be mediated by higher levels of chronic inflammation as an adult. The same inflammatory markers (e.g., IL-6, TNF-α, and CRP) that are increased in patients with ECA20, (Fagundes et al., 2013), are similarly elevated in patients with lung cancer and depression (McFarland et al., 2019, Du et al., 2013). But, the effects of ECA in adulthood are far reaching and likely affect physical symptoms given their close relationship with psychological symptom burden (Hughes et al., 2017). That is, ECA may be associated with physical symptoms experienced by patients with lung cancer who are undergoing various systemic treatments and may be dealing with psychological symptoms. Our group previously found that the number of endorsed physical problems was linked to the presence of ECA in other cancer populations (McFarland et al., 2016, McFarland et al., 2017). A multitude of physical symptoms are highly prevalent in patients with advanced disease and lung cancer (LeBlanc et al., 2015). The presence and refractoriness of these symptoms increases in patients with depression (Fitzgerald et al., 2015). Therefore, this study also evaluated the presence of physical symptoms and their relationship with psychological issues and ECA.

The presence of physical and psychological symptoms in cancer settings is associated with reduced survival in addition to poor quality of life (Pinquart and Duberstein, 2010). In fact, the survival implications of depression are most severe in patients with early localized and curable lung cancer (Sullivan et al., 2016). In addition, pro-actively addressing physical symptoms (by screening instead of waiting for the patient to present with symptoms) has been associated with improved survival (Basch et al., 2017). Similarly, remission of depression in patients with lung cancer is associated with survival rates that are similar to patients who were not ever depressed during their cancer trajectory (Sullivan et al., 2016). Early detection and treatment of symptoms appears to have significant benefit in patients with cancer, which may be facilitated by the identification of ECA.

The relationship between ECA and symptom burden (psychological and physical) in patients with lung cancer has not been reported previously. We hypothesized that patients with lung cancer who experienced ECA would report higher psychological and physical symptom burden. We also hypothesized that inflammation would explain these relationships given documented associations between inflammation and ECA in addition to the relationship between inflammation and psychological and physical symptoms. This study evaluated the presence of ECA in patients with metastatic lung cancer along with inflammation, psychological symptoms (distress, anxiety, and depression), and physical symptoms.