Death anxiety is common in patients with metastatic cancer, including those with metastatic non-small cell lung carcinoma (mNSCLC).1 Yet its relationship to brain metastasis and cognitive decline remain unclear.1

Brain Metastasis

The incidence of brain metastases (BM) from solid tumors in the United States is currently 170,000 new cases a year, and approximately 10% to 30 % of adults with cancer will develop BM.2 BM most often originates from cancers of the lung, breast, colon, and the kidney.3 Further, incidence rates continue to increase due to an aging population and medical advances that contribute to cancer patients living longer. The most common location of BM is in the cerebral hemispheres (70%), followed by the cerebellum (15%) and brainstem (5%).2

Among the 220,000 new cases of patients diagnosed with NSCLC annually, an estimated 57% will present with metastatic disease including 20% with BM at diagnosis. In addition, among patients with locally advanced NSCLC treated with multimodal therapy, BM represents a common site of distant relapse in 30% to 55% of patients.4 Patients with BM represent a heterogeneous group, but the median survival of patients with BM has been estimated to be 2 to 6 months.4


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Therapy for BM depends on the size and number of metastases as well as the overall prognosis.3 In cases with multiple BMs, whole brain radiation therapy (WBRT) is administered.1,4 Neurosurgery and/or radiosurgery or hypofractionated stereotactic radiotherapy (hfSRT) is indicated in cases with fewer lesions. Metastatic brain tumors can cause substantial cognitive disability, and moreover, treatment can lead to several adverse effects.4 Though WBRT reduces development of distant BM, presumably due to sterilization of subclinical disease, it comes at the cost of cognitive toxicity. 4 The use of hfSRT results in acceptable local control with less neurocognitive toxicity compared with adjuvant WBRT.4

Areas most affected by chemotherapy treatment include brain hub regions such as prefrontal cortex, and hippocampus.5 However, reports have provided increasing evidence that cancer-related cognitive impairments (CRCI) may be associated with widespread disruption of brain network connectivity, rather than regionally specific effects.5 Consequently, optimal techniques have not yet been defined and emerging trends in the management of BM from NSCLC include clinical trials, which are focused on mitigating cognitive impairments.5

Cancer-related Cognitive Impairments (CRCI)

CRCI is a cause for considerable concern because its development can negatively influence adherence to treatments, impair quality of life (QoL), and lead to long-term cognitive impairments.2,5-6

Areas of cognitive deficits include memory, sustained attention, concentration, and executive function.2,5-6  Studies have shown CRCI have been associated with a reduction in the ability to return to work at all or to a limited capacity.2,5-6  CRCI—specifically executive dysfunction—have also been associated with reduced function in productivity, social role functioning, and community engagement.5 It has also been reported that patients with CRCI may have difficulties driving and reading that interfere with quality of life.5

CRCI is highly prevalent, detected in up to 30% of patients prior to chemotherapy and up to 75% of patients during and post-treatment.5 However, measuring CRCI can be challenging because the extent and type of cognitive dysfunction often varies from patient to patient due to different tumor volumes and location.5 Currently, neuropsychologic tests are used to measure a wide range of cognitive abilities including frontal/executive functioning, verbal memory (immediate and delayed recall, retention, and recognition memory), processing speed, verbal fluency, fine motor control and dexterity.5

Furthermore, the International Cognition and Cancer Task Force recommends several measures (at minimum) be included in assessing cognitive function in cancer patients: the Hopkins Verbal Learning Test-Revised, Trail Making Test, and the Controlled Oral Word Association that is part of the Multilingual Aphasia Examination. However, there is no prefect cognitive test.1,5 Self-report measures of perceived cognitive function correlate with objective assessments, but these correlations are often weak.5 Neuropsychologic assessments are a snapshot in time, consequently their limitations include not being able to detect subtle cognitive changes.5 Ongoing and future research is aimed at better capturing CRCI with combinations of self-report and optimized objective neuropsychologic assessments and methods of analysis.

Death Anxiety

Because the overall prognosis of patients with BM is often very poor, many patients experience a multitude of physical, psychological and psychosomatic symptoms, particularly distress about dying and death which may affect cognition as well.1

Death is a universal human concern that is amplified by mortality salience, wherein patients may be forewarned of their impending death by worsening symptomatology as their disease progresses.6 Such a situation can prompt existential concerns, a unique concern of death awareness known and ‘death anxiety.’6 Psycho-oncology researchers deal with the difficult challenge of ‘double awareness’ for palliative care patients, who aim to balance 2 conflicting views/feelings: remaining engaged and enjoying what remains of their lifespan, while being aware of their near-certain physical deterioration and death.6

Death anxiety can affect people to varying degrees, depending on factors such as age, health, spiritual beliefs and culture.5-6  When not addressed, death anxiety may predispose patients towards hastened requests for euthanasia or physician-assisted suicide.5-6  To measure death anxiety, several scales have been designed, such as the 1970 Death Anxiety Scale , and the more recently clinically validated ‘Death and Dying Distress Scale’ (DADDS).1,5-6  These scales have allowed for further research and evaluation of potential interventions targeted towards those with symptomatic and severe death anxiety.

However, research on death anxiety is scant. It has been argued that previous research has been hindered by a lack of a clear, comprehensive definition of death anxiety.1,5-6 Other reasons hypothesized include difficulties in researching the terminally ill, the lack of tailored measurement tools, and reluctance of researchers to draw attention to death anxiety for fear of harm.1,5-6  A total of 9 studies have been discovered that sought to lessen death anxiety in patients with metastatic cancer.6  The majority of these studies were published within the last 5 years, suggesting that death anxiety is potentially being more widely recognized in recent times. However, this is a low number of studies given the universality of death anxiety in cancer patients, and the relief of existential distress being a specific focus of the ‘whole-person approach’ in palliative medicine.6

Specifically, for patients with NSCLC, death anxiety is a major challenge because it is the most common cancer to metastasize to the brain.1 Despite the overall improved survival, most mNSCLC patients die of the disease.1 Moreover, additional disease-related factors may contribute to death anxiety in these patients.1 The development of BM may trigger death anxiety and fears related to the perceived loss of control, impaired cognition, and changes in personality.1-3,6 However, it is still unclear if death anxiety is associated with brain metastases or cognitive decline, or both.1,6 Improving insight into other relevant contributors to death anxiety could inform preventive and therapeutic interventions directed to reduce death anxiety and existential distress in patients with mNSCLC.1,6   

Death Anxiety in Patients with Metastatic NSCLC With/Without Brain Metastases

Consequently, researchers prospectively assessed psychological, physical and disease-related (including BM, cognitive impairment) factors associated with death anxiety in mNSCLC patients via an exploratory study.1

Between October 2018 and June 2019, a cross-sectional pilot study of 78 patients with mNSCLC outpatients (50% women; median age, 62 years [range: 37- 82years]) were recruited at a comprehensive cancer center in Canada. Median time since mNSCLC diagnosis was 11 months (range, 0-89 months).1 41 patients (53%) had BM; of those 49% were women.1 The patients were asked to complete standardized neuropsychologic tests which included the Hopkins Verbal Learning Test-Revised, and Trail Making Test among others.1 They were also asked to complete validated questionnaires such as DADDS, Rosenberg Self Esteem Scale, and Functional Assessment of Cancer Therapy-Cognitive Function version 3, among others. 1 These tests measured death anxiety, cognitive concerns, illness intrusiveness, depression, demoralization, self-esteem, and common cancer symptoms.1 From this, the researchers constructed a composite for objective cognitive function (mean neuropsychologic tests z-scores).

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The results revealed that 43% of the study participants reported at least moderate death anxiety while 19% reported severe death anxiety.1 Of the participants who reported moderate death anxiety, 49% reported depression and 67% demoralization.1 However, in this pilot cohort, severity of death anxiety did not significantly correlate with patients with and without BM because 44% of patients with BM and 41% without BM reported at least moderate death anxiety.1 Objective cognitive impairment was present in 41% of participants and perceived cognitive impairment in 27%.1 Therefore, death anxiety, objective, and perceived cognitive impairment did not significantly differ between patients with and without BM. 1 However, death anxiety was univariately associated with depression, demoralization, illness intrusiveness, self-esteem, common physical cancer symptoms, and perceived cognitive impairment.1 These factors were entered in the multivariate analysis which demonstrated that demoralization (P < .001) and illness intrusiveness (P = .001) were associated with death anxiety.1

Limitations of the study included the relatively small sample size and cross-sectional design. 1 Furthermore, there was selection bias in recruitment, and heterogeneity in disease and treatment-related factors. 1 Also, the study did not include patients with severe cognitive impairment; this may skew the results because they may have fewer insights into the imminence of the end of life and therefore report less death anxiety.1

The researchers concluded that this pilot study demonstrated that death anxiety is common among patients with mNSCLC, although not necessarily linked to BM or objective cognitive impairment. 1 However, the association of death anxiety with both demoralization and illness intrusiveness in this population highlights the importance of integrated interventions that address physical and psychological well-being.1

Future Directions

More research is needed on all interventions to assist patients with death anxiety and advanced cancer.  Including longitudinal studies to understand the interrelationship over time will provide much needed insights and bring greater awareness the need to investigate, identify, treat and support all terminally ill patients who suffer existential issues.1,6 With continued research, education and training, the capability to offer even the most existentially distraught patients a positive death will hopefully be seen as a challenge rather than an impossibility.1,6

References

1. Eggen AC, Reyners AKL, Shen G, Bosma I, Jalving M, Leighl NB, et al. Death anxiety in patients with metastatic non-small cell lung cancer with and without brain metastases [published online March 4, 2020]. J Pain Symptom Manage. doi:10.1016/j.jpainsymman.2020.02.023

2. Gerstenecker A, Nabors LB, Meneses K, Fiveash JB, Marson DC, Cutter G, et al. Cognition in patients with newly diagnosed brain metastasis: profiles and implications. J Neurooncol. 2014;120:179–185.

3. Cordes M-C, Scherwath A, Ahmad T, Cole Am, Ernst G, Oppitz K, et al. Distress, anxiety and depression in patients with brain metastases before and after radiotherapy. BMC Cancer. 2014;14:731–742.

4. Churilla TM, Weiss SE. Emerging Trends in the Management of Brain Metastases from Non-small Cell Lung Cancer. Curr Oncol Rep. 2018;20:54–63.

5. Janelsins MC, Kesler SR, Ahles TA, Morrow GR. Prevalence, mechanisms, and management of cancer-related cognitive impairment. Int Rev Psychiatry. 2014;26:102–113.

6. Grossman CH, Brooker J, Michael N, Kissane D. Death anxiety interventions in patients with advanced cancer: a systematic review. Palliat Med. 2018;32:172–184.