Lung Cancer xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Lung Cancer
journal homepage: www.elsevier.com/locate/lungcan

Newly diagnosed patients with advanced non-small cell lung cancer: A

clinical description of those with moderate to severe depressive symptoms
B.L. Andersena,*, T.R. Valentinea, S.B. Loa, D.P. Carboneb, C.J. Presleyb, P.G. Shieldsb
a
Department of Psychology, The Ohio State University, United States
b
Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center and The James Cancer Hospital/Solove Research
Institute, United States

A R T I C LE I N FO A B S T R A C T

Keywords: Objectives: The aims of this observational study were to 1) accrue newly diagnosed patients with advanced-stage
Lung cancer non-small cell lung cancer (NSCLC) awaiting the start of first-line treatment and identify those with moderate to
Depression severe depressive symptoms and, 2) provide a clinical description of the multiple, co-occurring psychological
Anxiety and behavioral difficulties and physical symptoms that potentially exacerbate and maintain depressive symp-
Quality of life
toms.
Illness perceptions
Materials and methods: Patients with stage IV NSCLC (N = 186) were enrolled in an observational study
(ClinicalTrials.gov Identifier: NCT03199651) and completed the American Society of Clinical Oncology-re-
commended screening measure for depression (Patient Health Questionnaire-9 [PHQ-9]). Individuals with none/
mild (n = 119; 64 %), moderate (n = 52; 28 %), and severe (n = 15; 8 %) depressive symptoms were identified.
Patients also completed measures of hopelessness, generalized anxiety disorder (GAD) symptoms, stress, illness
perceptions, functional status, and symptoms.
Results: Patients with severe depressive symptoms reported concomitant feelings of hopelessness (elevating risk
for suicidal behavior), anxiety symptoms suggestive of GAD, and traumatic, cancer-specific stress. They per-
ceived lung cancer as consequential for their lives and not controllable with treatment. Pain and multiple severe
symptoms were present along with substantial functional impairment. Patients with moderate depressive
symptoms had generally lower levels of disturbance, though still substantial. The most salient differences were
low GAD symptom severity and fewer functional impairments for those with moderate symptoms.
Conclusions: Depressive symptoms of moderate to severe levels co-occur in a matrix of clinical levels of anxiety
symptoms, traumatic stress, impaired functional status, and pain and other physical symptoms. All of the latter
factors have been shown, individually and collectively, to contribute to the maintenance or exacerbation of
depressive symptoms. As life-extending targeted and immunotherapy use expands, prompt identification of
patients with moderate to severe depressive symptoms, referral for evaluation, and psychological/behavioral
treatment are key to maximizing treatment outcomes and quality of life for individuals with advanced NSCLC.

1. Introduction highest of all cancer types, 5.74 (95 % CI = 5.30–6.22), with hazard
ratios of 6.04 (95 % CI = 5.54–6.57) for men and 4.18 (95 %
Many facts about lung cancer are well-known: lung cancer persists CI = 3.27–5.27) for women [5].
as the number one cause of all cancer-related mortality worldwide [1]. Studies comparing patients with cancer find that those with lung
The most prevalent type, non-small cell lung cancer (NSCLC), accounts cancer have the greatest prevalence of mood disorders (est. 18 %) and
for 85 % of all cases, and many individuals present with stage IV disease anxiety disorders (est. 19 %) [6–8]. Studies assessing only patients with
(44 %), with a 5-year survival estimate of 4.2 % [2]. What may be less advanced NSCLC at diagnosis/prior to treatment find estimates of
well-known is that the case is compelling for patients with lung cancer “probable cases” of depression to be 9 % in a patient sample (N = 461)
being the most psychologically disabled of all cancer groups [3,4]. In fact, from the United Kingdom [9], 17.9 % in a Canadian sample (N = 597;
SEER registry data (3.5 million patients; 1973–2002) show the stan- all types/stages) [6], and 32.9 % in a sample (N = 82) from Mexico
dardized suicide mortality ratio for patients with lung cancer is the [10]. Additional cases of “sub-clinical” or “borderline” symptom levels

⁎
Corresponding author at: Department of Psychology, 1835 Neil Avenue, The Ohio State University, Columbus, OH, 43210-1222, United States.
E-mail address: Andersen.1@osu.edu (B.L. Andersen).

https://doi.org/10.1016/j.lungcan.2019.11.015
Received 28 June 2019; Received in revised form 19 November 2019; Accepted 20 November 2019
0169-5002/ © 2019 Elsevier B.V. All rights reserved.

Please cite this article as: B.L. Andersen, et al., Lung Cancer, https://doi.org/10.1016/j.lungcan.2019.11.015
B.L. Andersen, et al. Lung Cancer xxx (xxxx) xxx–xxx

have ranged from 13 % [9] to 35.3 % [6]. Studies from the United
States have predominantly assessed patients with lung cancer in the
early weeks of treatment or thereafter and reveal estimates similar to
those when patients are assessed at diagnosis. In them, rates of “severe”
depressive symptoms have ranged from 14 % [11] to 41 % [12,13].
Irrespective of the occurrence of depressive symptoms, the days of
diagnosis and awaiting treatment are unique. Reliably, cancer stress
peaks during this period [14,15] and is associated with biobehavioral
processes relevant to disease course, such as immunosuppression [16]
and inflammation [17–19]. A meta-analytic study revealed stress as-
sessed at some time after lung cancer diagnosis to heighten risk for
premature cancer death (n = 23 studies; hazard ratio = 1.17; 95 %
CI = 1.03–1.34) [20]. Potential contributors to the latter effects are the
covariation of heightened stress with physical symptom exacerbation
[21–26] and depressive symptoms [23,27].
With foundational data such as these, the American Society of
Clinical Oncology (ASCO) recommended screening as the primary
mechanism to determine the level/classification of symptom severity
and asserted that screening should begin at diagnosis or start of treat- Fig. 1. Flow diagram for the current observational study.
ment [28]. To date, the implementation of screening and use of the
ASCO-recommended measures among patients with NSCLC is un- 2.1. Eligibility criteria
known. A comprehensive look at the characteristics of those with
moderate to severe psychological symptoms among patients with Inclusion criteria were as follows: newly diagnosed stage IV NSCLC
NSCLC is needed. Even when patients are screened “positive,” the with pathological confirmation; any ECOG performance status and with
complete picture of difficulties and impairments that are likely to ac- any comorbidity; age > 18 years; English-speaking; and willing to
company moderate to severe depressive symptoms is not clear. Re- provide access to medical records, provide biospecimens, and respond
search with other cancer types would suggest that there are co-occur- to self-report measures either in-person or by telephone interview.
ring stressors and cognitive and behavioral disruptors, and they too Exclusion criteria were as follows: patients to be treated with definitive
may impede cancer patients’ coping with the diagnosis and decision- chemo-radiotherapy; individuals age < 18 years; receiving treatment
making as do depressive symptoms [29–32]. for advanced lung cancer for over one month before enrollment; and
For this observational study, there were two aims. First, newly di- presence of disabling hearing, vision, or psychiatric impairments pre-
agnosed patients with advanced-stage NSCLC who were awaiting the venting consent or completion of self-report measures in English.
determination and start of treatment were accrued and administered
the ASCO-recommended screening measure for depression (Patient
Health Questionnaire-9 [PHQ-9] [28,33]) and supplementary mea- 2.2. Variables and measures
sures. Individuals with symptoms of moderate (scores 15–19) and se-
vere (scores 20–27) depressive levels were identified. Having identified 2.2.1. Psychological symptoms
these patients, the preeminent aim was to detail and discuss the co- Three measures were used. 1) The Patient Health Questionnaire-9
occurring negative emotions (stress), impairments (quality of life, (PHQ-9 [33]) is a 9-item self-report scale that assesses the frequency of
functional status, symptoms), and negative perceptions of one’s life and symptoms of major depressive disorder, as defined by the Diagnostic
illness that co-occurred. To do this was significant because the latter and Statistical Manual of Mental Disorders 4th edition (DSM-IV [40]).
factors foster the maintenance of depressive symptoms and, conversely, Referencing the past two weeks, items were rated on a 4-point Likert
depressive symptoms increase the frequency/severity of these sources scale (0=not at all to 3=nearly every day) and summed for a total
of impairment and disability [31,32,34–38]. Moving beyond PHQ-9 score ranging from 0 to 27, with higher scores indicating higher de-
classification, the goal was provision of clinical descriptions for provi- pressive symptom severity. Cut-off values for the PHQ-9 are none/
ders and researchers alike of the common psychological, behavioral, mild = 1–7, moderate = 8–14, moderate to severe = 15–19, and se-
and symptom comorbidities experienced by such individuals, ones that, vere = 20–27. (Note: In this manuscript, moderate to severe and severe
along with depressive symptoms, may impair patients’ coping and groups are combined and labeled “severe”). Internal consistency relia-
functioning when they are to make choices and begin lung cancer bility was α = .806. Responses to two items were considered: a)
treatment [39]. number of individuals endorsing the suicidal ideation item (thinking
one would be better off dead; thoughts of hurting oneself); b) score on
an item assessing the impact of the depressive symptoms on working,
2. Materials & methods home activities, and getting along with other people, rated from 0 (not
difficult) to 3 (extremely difficult).
From June 2017 to August 2019, individuals were accrued from the 2) The Beck Hopelessness Scale (BHS [41]) was included, as it is a
Thoracic Oncology clinics of an NCI-designated Comprehensive Cancer correlate of suicide [42,43]. Using 20 true–false items, the BHS assesses
Center (CCC) for participation in an observational study feelings and expectations about one’s future life and loss of motivation.
(ClinicalTrials.gov Identifier: NCT03199651; see Fig. 1 for study flow). Scores range from 0 to 20, with the following cut-offs: normal = 0–3,
Consent was completed face-to-face by research personnel in the clinic mild = 4–8, moderate = 9–14, and severe = 15–20. Normative data
at the time of first appointment with a thoracic oncologist. Within two suggest a mean of 3.1 in non-illness samples [44], and scores ≥ 9 are
weeks of enrollment, patients were contacted by telephone by trained associated with suicidal risk [42]. Internal consistency reliability was
interviewers who conducted the assessment of patient-reported out- α=0.805.
comes (see below). Patients were also given a “hard copy” measure 3) The Generalized Anxiety Disorder-7 (GAD-7 [45]) is a 7-item
booklet to follow along with the interview and item responses. Each measure that assesses the frequency of symptoms of generalized anxiety
patient received $15 for participation. disorder (GAD) as defined by the DSM-IV [40]. Items were rated on a 4-
point Likert scale (0=not at all to 3=nearly every day) and summed for

2
B.L. Andersen, et al. Lung Cancer xxx (xxxx) xxx–xxx

a total score ranging from 0 to 21 with the following cutoffs: none/ 2.3. Statistical analysis
mild = 0–9, moderate = 10–14, and moderate to severe/se-
vere = 15–21. Internal consistency reliability was α = .874. A final Descriptive statistics, including frequencies, means, standard de-
item assessed the impact of the symptoms on working, home activities, viations, and ranges, were used to summarize all sociodemographic and
and getting along with other people, rated from 0 (not difficult at all) to disease-related characteristics and measure responses. To determine
3 (extremely difficult). depressive symptom severity groups, established cut-offs for the PHQ-9
were used [33]: none/mild (1–7), moderate (8–14), and severe (15–27).
Analyses tested the hypothesis that overall group differences would be
2.2.2. Cancer stress and perceptions of lung cancer found, with negative functioning/symptoms outcomes ordered such
Two measures were used. 1) The Impact of Events Scale-Revised that severe > moderate > none/mild. Analysis of variance for con-
(IES-R [46]), a 22-item measure, is widely used to assess subjective tinuous measures was used to test for overall group differences, and
stress caused by traumatic events and has been adapted to measure when significant, Tukey’s tests were used for follow-up tests [55]. χ2
cancer-specific stress [17,47]. Patients rate the frequency of intrusive tests adjusted by Holm method were used to compare group differences
thoughts (8 items; e.g., “Other things kept making me think about for categorical measures [56].
cancer”), avoidant thoughts and behaviors (8 items; e.g., “I tried not to
talk about it”), and hyperarousal symptoms (6 items; e.g., “I felt irri-
table and angry”) over the past seven days on a 5-point Likert scale 3. Results
(0=not at all to 4=often). Total scores range 0–88, with higher scores
indicating more cancer-specific stress. Internal consistency reliability Two hundred and forty-two patients were enrolled in the study, 191
was α = .902. completed the baseline questionnaires (79 %), and 5 subsequently
2) The Brief Illness Perception Questionnaire (BIPQ [48]) is a self- withdrew consent and were excluded from the analyses, yielding a final
report measure used to assess eight mental representations of one’s sample of 186 patients (77 % of total enrolled; see Fig. 1 for study flow).
illness (identity [symptoms], consequences, timeline, personal control, Sociodemographic and clinical characteristics of the sample are pro-
treatment control, coherence [understanding], concern, and emotional vided in Table 1. The sample was primarily older (M age = 63 years,
response), with one question for each. Patients responded to each item SD = 12, range = 27–92), male (55 %), Caucasian (85 %), at least high
using a 0- to 10-point Likert scale, with higher scores reflecting stronger school-educated (87 %), and married (58 %). Patients were diagnosed a
endorsement of the illness representation. As there are no cut-off va- median of 32 days before completing their baseline questionnaire,
lues, scores were summarized by tertiles, with scores 0.00–3.33 viewed predominantly with adenocarcinoma (73 %). The depressive symptom
as low, 3.34–6.66 as moderate, and 6.67–10.00 as high. (PHQ-9) severity groups included 119 (64 %) patients with none/mild
depressive symptoms, 52 (28 %) with moderate depressive symptoms,

2.2.3. Physical symptoms Table 1

Two measures were used. 1) The lung cancer-specific EORTC Sociodemographic and clinical characteristics of sample (N = 186).
Quality of Life Questionnaire (QLQ-LC13 [49]) was used to assess
n (%); Mean ± SD
health-related quality of life [50,51]. The QLQ-LC13 contains nine
items that assess individual symptoms (e.g., pain, coughing) and one Sociodemographic:
three-item symptom scale that assesses dyspnea. Items are rated on a 4- Age (years) 62.5 ± 11.7
point Likert scale (1=not at all to 4=very much), and each is trans- Gender (male) 103 (55.4 %)
Race:
formed to a score ranging 0–100, with lower scores indicating better
Caucasian/White 158 (84.9 %)
health-related quality of life and lower symptoms. 2) Additionally, 20 African American/Black 10 (5.4 %)
common symptoms and treatment side effects (e.g., nausea, infection) Other 1 (0.5 %)
were assessed. Rating scales were adapted from the QLQ-LC13, with Multiracial 17 (9.1 %)
items rated on a 4-point Likert scale (1=not at all to 4=very much). Hispanic 3 (1.6 %)
Education:
Scoring and interpretation are identical to the QLQ-LC13.
< High school 25 (13.4 %)
High school 69 (37.1 %)
> High school 92 (49.5 %)
2.2.4. Functional status and health evaluation Married 107 (57.5 %)
The EQ-5D [52] assesses five health status categories, with three Employed 45 (24.2 %)
relevant to functional status, i.e., mobility, self-care, and engagement in Income ≤ $25,000 (below Ohio poverty line for family of 4) 40 (21.5 %)

usual activities, with each rated on a 5-point Likert scale of perfor-

Clinical:
mance difficulty (1=none, 2=slight, 3=moderate, 4=severe, 5=un- Lung cancer diagnosis:
able to perform). Population norms for the US have been published for Adenocarcinoma 135 (72.6 %)
the EQ-5D, and indicate that adults similar in age (55–64 years) have at Squamous 28 (15.1 %)
Not otherwise specified 11 (5.9 %)
least some problems with mobility = 26.4 %, self-care = 5.9 %, usual
Large cell 4 (2.2 %)
activities = 27.0 %, pain/discomfort = 58.8 %, and anxiety/depres- Adenosquamous 2 (1.1 %)
sion = 31.3 % [53]. For health evaluation, the EQ VAS [52] is a single Missing/unknown 6 (3.2 %)
item asking the patient to rate his/her overall health, with anchors of 0 Prior psychiatric diagnosis 24 (12.9 %)
(the worst health you can imagine) and 100 (the best health you can Prior psychological treatment for psychological distress 58 (31.2 %)
Prior medical treatment for psychological distress 107 (57.5 %)
imagine). The mean EQ VAS for adults aged 55–64 is 76.9 ± 21.0 [53].
Smoking status:
Never 16 (8.6 %)
Former 137 (73.7 %)
2.2.5. Social connections Current 33 (17.7 %)
The Social Network Index (SNI [54]) is a 16-item measure of social Alcohol use:
contacts and involvement. Scores range from 1 to 12, with higher scores Never 99 (53.2 %)
Monthly or less 37 (19.9 %)
indicating more social connection; alternatively, social connection ca-
2-4 times a month 17 (9.1 %)
tegories can be used: low (1), medium (2–5), medium-high (6–7), and ≥ 2–3 times a week 33 (17.7 %)
high (8–12) social connectedness.

3
B.L. Andersen, et al. Lung Cancer xxx (xxxx) xxx–xxx

Table 2
Psychological and health characteristics by depressive symptom (PHQ-9) severity.
Group 1: None/Mild Group 2: Moderate Group 3: Severe (n = 15) Range Comparisons of PHQ-9 severity
(n = 119) (n = 52) groups:a

Depression:
PHQ-9 score 3.4 ± 2.3 10.0 ± 1.9 18.9 ± 3.4 0-24 1<2<3
≥ Some difficulties with function due to 32 (26.9 %) 32 (61.5 %) 14 (93.3 %) 1<2<3
depression
Suicidal ideation 0 (0.0 %) 2 (3.8 %) 5 (33.3 %) 1,2 < 3; 1 = 2
Hopelessness 3.4 ± 2.8 5.1 ± 3.0 8.1 ± 4.2 1-17 1<2<3
Hopelessness ≥ 9 7 (5.9 %) 9 (17.3 %) 7 (46.7 %) 1<2<3

Anxiety:
GAD-7 score 3.4 ± 3.5 7.2 ± 4.7 15.5 ± 5.2 0-21 1<2<3
Moderate to severe/severe GAD symptoms 2 (1.7 %) 6 (11.5 %) 11 (73.3 %) 1<2<3
≥ Some difficulties with function due to 24 (20.2 %) 29 (55.8 %) 13 (86.7 %) 1<2<3
anxiety

Cancer stress:
Cancer stress (IES) 11.1 ± 10.0 21.8 ± 12.8 44.1 ± 16.4 0-80 1<2<3

Perceptions of
lung cancer:
Consequences 5.5 ± 2.8 6.3 ± 2.9 8.7 ± 2.7 0-10 1,2 < 3; 1 = 2
Timeline 6.4 ± 3.0 6.3 ± 2.6 7.2 ± 2.3 0-10 1=2=3
Personal control 5.5 ± 2.8 5.1 ± 2.9 3.0 ± 1.7 0-10 1,2 > 3; 1 = 2
Treatment control 8.4 ± 2.0 8.7 ± 1.6 6.9 ± 2.9 0-10 1,2 > 3; 1 = 2
Identity 3.7 ± 2.6 5.6 ± 2.9 8.7 ± 1.4 0-10 1<2<3
Concern 7.4 ± 2.9 8.1 ± 2.6 9.7 ± 0.7 0-10 1 < 3; 2 = 1,3
Coherence 8.1 ± 2.1 7.7 ± 2.5 7.4 ± 2.1 0-10 1=2=3
Emotional response 3.7 ± 2.3 5.7 ± 3.1 8.1 ± 2.0 0-10 1<2<3

Functional status:b
Mobility 22 (18.5 %) 17 (32.7 %) 11 (73.3 %) 1>2>3
Self-care 2 (1.7 %) 4 (7.7 %) 5 (33.3 %) 1 < 3; 2 = 1,3
Usual activities 28 (23.5 %) 20 (38.5 %) 15 (100.0 %) 1,2 > 3; 1 = 2
Pain & discomfort 35 (29.4 %) 28 (53.8 %) 10 (66.7 %) 1 < 2,3; 2 = 3
Anxiety/depression 10 (8.4 %) 11 (21.2 %) 11 (73.3 %) 1>2>3

Health evaluation:
Perception of health 66.9 ± 22.9 58.8 ± 21.9 40.1 ± 16.5 0-100 1,2 > 3; 1 = 2

a
Multiple comparisons were completed with Tukey’s test and χ2 tests adjusted by Holm method for continuous and categorical measures respectively.
b
≥ moderate problems with functional area.

and 15 (8 %) with severe depressive symptoms. Table 2 provides A large majority of patients with severe depressive symptoms (73.3 %)
summary statistics for the psychological, behavioral, and symptom also had moderate to severe/severe anxiety comorbidity (GAD-7
measures for each depressive symptom severity group, with significant M = 15.5, SD = 5.2). Additionally, most (86.7 %) reported that their
differences between groups noted. Fig. 2 provides a graphical depiction anxiety symptoms interfered with their occupational, household, and/
of the percentage of patients in each severity group endorsing common or social functioning.
symptoms/signs (depressive, pain, respiratory, eye/ear, gastro-
intestinal/thoracic, nervous system, skin/general), with group differ- 3.1.2. Cancer stress and perceptions of lung cancer
ences again noted. Patients with newly diagnosed NSCLC and severe depressive
symptoms reported extreme levels of cancer-related stress (M = 44.1,
3.1. Patients with severe depressive symptoms (n = 15) SD = 16.4). Patients with severe depressive symptoms, relative to all
others, perceived the highest level of symptom burden (identity;
3.1.1. Psychological symptoms M = 8.7, SD = 1.4), the greatest consequences for their lives (M = 8.7,
Fifteen patients (8.1 %) with newly diagnosed NSCLC scored at the SD = 2.7), the greatest emotional impact (emotional response;
severe depressive symptom level on the PHQ-9 (scores 15–27 of 27 M = 8.1, SD = 2.0), the least personal control over their cancer
possible; M = 18.9, SD = 3.4; see Table 2). Of them, all (100 %) re- (M = 3.0, SD = 1.7), and the least confidence that treatment would
ported depressed mood and 80.0 % reported anhedonia more days than help (treatment control; M = 6.9, SD = 2.9). They reported the highest
not in the preceding two weeks. Patients’ responses on the QLQ-LC13 possible level of concern about their cancer (M = 9.7, SD = 0.7). These
symptom questionnaire showed a majority reported experiencing ve- patients were no different than those with moderate and none/mild
getative and cognitive symptoms at level/frequency of “quite a bit” or depressive symptoms in believing that they have a high level of un-
“very much” (see Fig. 2), including 93.3 % with fatigue, 86.7 % with derstanding of their cancer (coherence; M = 7.4, SD = 2.1) and that
weakness, 73.3 % with appetite change, 66.7 % with insomnia, and their illness would last a long time (M = 7.2, SD = 2.3).
60.0 % with concentration impairment. Nearly all (93.3 %) reported
that their depressive symptoms made it difficult to do their work, take 3.1.3. Physical symptoms
care of things at home, and/or get along with other people. Patients Patients with newly diagnosed NSCLC and severe depressive
with severe depressive symptoms also exhibited high levels of hope- symptoms reported multiple physical symptoms of high intensity (see
lessness (M = 8.1, SD = 4.2), with 46.7 % endorsing moderate or se- Fig. 2), including “quite a bit” or “very much” pain (73.3 %), loss of
vere levels (scores 9–20). One third (33.3 %) reported suicidal ideation. taste (53.3 %), dyspnea (53.3 %), and/or cough (46.7 %).

4
B.L. Andersen, et al. Lung Cancer xxx (xxxx) xxx–xxx

Fig. 2. Percentage of patients by depressive symptom (PHQ-9) severity groups (none/mild, moderate, severe) reporting symptoms/signs occurring quite a bit/very
often in the last week.
Note: † Indicates significant difference (p < .05) between none/mild group and others;
‡
Indicates significant difference (p < .05) between moderate group and severe group.

3.1.4. Functional status and health evaluation household, and/or social functioning. Patients in this group had lower
Functional status was significantly impaired for those with severe hopelessness scores (M = 5.1, SD = 3.0) than patients with severe de-
depressive symptoms. The percentage reporting moderate or severe pressive symptoms, but still a substantial percentage (17.3 %) had
functional issues was 100 % for usual activities (e.g., work, study, moderate to severe levels. Two individuals reported suicidal ideation.
housework, family or leisure activities), 73.3 % for mobility, and 33.3 Of clinical importance, depression-anxiety comorbidity was notably
% for self-care. In line with this level of disability, patients’ average self- lower, with only 11.5 % endorsing moderate to severe/severe anxiety
rated health evaluation was 40.1 ± 16.5. symptoms (M = 7.2, SD = 4.7), although approximately half (55.8 %)
reported anxiety-related impairment.
3.1.5. Social connections and other resources
These patients with severe depressive symptoms reported medium 3.2.2. Cancer stress and perceptions of lung cancer
social connectedness (M = 2.5, SD = 2.7). Also, 46.7 % reported being Though lower than the extreme scores of those with severe de-
unmarried. These patients reported limited financial resources, with pressive symptoms, patients with moderate depressive symptoms en-
33.3 % earning an average annual income below the state poverty dorsed a high level of cancer-related stress (M = 21.8, SD = 12.8).
threshold for a family of four in the state they resided. Additionally, Patients with moderate depressive symptoms had similar illness per-
only 13.3 % were employed at the time of diagnosis. ceptions to those with none/mild depressive symptoms in viewing their
illness as moderately consequential for their lives (M = 6.3, SD = 2.9)
3.2. Patients with moderate depressive symptoms (n = 52) and perceiving a moderate level of personal control over their cancer
(M = 5.1, SD = 2.9) and a high level of treatment control (M = 8.7,
3.2.1. Psychological symptoms SD = 1.6). However, they differed significantly from the none/mild
Fifty-two patients (28 %) scored at the level of moderate depressive depressive symptom group by reporting greater symptom burden
symptoms on the PHQ-9 (scores 8–14 of 27 possible; M = 10.0, (identity; M = 5.6, SD = 2.9) and viewing their lung cancer as having a
SD = 1.9; see Table 2). Within this group, 15.4 % reported depressed greater emotional impact (emotional response; M = 5.7, SD = 3.1).
mood and 34.6 % reported anhedonia more days than not in the pre- They had a high level of concern about their cancer (M = 8.1,
ceding two weeks. Like those with severe depressive symptoms, pa- SD = 2.6).
tients in this group reported fatigue as their most common vegetative/
cognitive depressive symptom (see Fig. 2), with 61.5 % reporting that 3.2.3. Physical symptoms
this symptom affected them “quite a bit” or “very much.” Rates for Relative to those with severe depressive symptoms, patients with
other vegetative and cognitive symptoms of depression were 42.3 % for moderate depressive symptoms reported less intense (although still
insomnia, 38.5 % for weakness, 26.9 % for appetite change, and 21.2 % troublesome) physical symptoms (see Fig. 2), with fewer individuals
for concentration impairment. The majority (61.5 %) reported that endorsing “quite a bit” or “very much” pain (59.6 %), cough (32.7 %),
their depressive symptoms led to difficulties with occupational, and loss of taste (25.0 %). The groups differed substantially in their

5
B.L. Andersen, et al. Lung Cancer xxx (xxxx) xxx–xxx

reports of dyspnea: 7.7 %, versus 53.3 % for those with severe de- added vulnerabilities of the patients with severe symptom levels. These
pressive symptoms. are vulnerabilities found previously to worsen and/or maintain de-
pressive symptoms, even in the context of depression treatment.
3.2.4. Functional status and health evaluation First, more than 70 % of patients with newly diagnosed NSCLC and
Functional impairment was also a noteworthy problem for patients severe depressive symptoms also had moderate to severe/severe GAD
with moderate depressive symptoms, but the levels of impairments symptoms. Depressive symptoms are known to co-occur with anxiety,
were lower than those reported by the severely depressed group. with the majority (60 %) of those with a depressive disorder also having
Among those with moderate depressive symptoms, 38.5 % reported at an anxiety disorder [69]. GAD worry or fear can be particularly toxic
least moderate impairment in usual activities, 32.7 % in mobility, and for lung cancer patients, as severe anxiety can worsen dyspnea and
7.7 % in self-care. These patients rated their overall health as sig- induce panic [70–72], and GAD can impede decision-making and par-
nificantly better than that of the severe depressive symptom group ticipation in or continuation of treatment [10,73].
(M = 58.8; SD = 21.9). Second, the level of cancer-specific stress patients with severe de-
pressive symptoms reported was extraordinary, far exceeding the IES-R
3.2.5. Social connections and other resources cutoff of 24 for likely diagnosis of post-traumatic stress disorder (PTSD)
Patients with moderate depressive symptoms reported a medium [74], and so high that a search of the IES-R literature assessing patients
level of social connection (M = 3.9, SD = 2.5). More of these patients with cancer at diagnosis (e.g., chronic lymphocytic leukemia, M = 13.6
(51.9 %) were unmarried. Average annual income was similar, with [18]) found none comparable [75–79]. Likely contributing to their
28.8 % reporting levels below the state poverty threshold for a family of stress [80,81], patients with severe depressive symptoms, relative to all
four, despite a higher rate of employment (25.0 %) at the time of as- others, also endorsed the most negative perceptions of their illness.
sessment. Appreciating patients’ illness perceptions at the time of diagnosis is
important, as negative illness perceptions are associated with patients
4. Discussion coping less effectively, especially when having to make treatment
choices [82,83]. Patients with negative illness perceptions are more
The American Society of Clinical Oncology (ASCO [28]) re- likely to delay seeking treatment [84], or conversely, pursue aggressive
commends that all patients with cancer be evaluated for symptoms of therapies at end of life that have detrimental effects on quality of life
depression and anxiety at diagnosis/start of treatment. This study is an [85].
exemplar of the guideline’s edicts, i.e., using the recommended self- Third, while it is well-known that advanced-stage patients often
report measures to identify patients with moderate to severe depressive experience significant physical symptoms [86], these data demonstrate
symptom levels. Beyond that, the aim was to expand providers’ and that patients with severe depressive symptoms are particularly bur-
researchers’ perspective on the co-occurring difficulties and impair- dened, reporting their health status (M = 40.1) to be nearly two stan-
ments that newly diagnosed advanced NSCLC patients with moderate to dard deviations below the US population norm (M = 76.9) for those of
severe depressive symptoms are experiencing. That is, these patients’ similar age (55–64) [53]. These patients reported the highest levels of
depressive symptoms co-occur in a matrix which included clinical levels dyspnea and cough—known correlates of poor quality of life [87] and
of anxiety symptoms, traumatic stress, impaired functional status, and functional impairment [88,89] in lung cancer patients. Upwards of 70
significant pain and other physical symptoms. All of the latter factors % of the patients reported one or more type of pain, suggesting a sig-
have been shown—individually and collectively—to contribute to the nificant need for pain management (or referral for) at the point of di-
exacerbation and/or maintenance of depressive symptoms. As a group, agnosis. Further, the co-occurrence of fatigue, weakness, and appetite
cancer patients’ stress declines and moods improve with the start of changes for more than 70 % of the patients may be suggestive of ca-
treatment [14,15,57,58], and this general observation would likely chexia. Oncology providers may not fully appreciate patients’ symptom
apply to the majority of the sample (64 %). However, its applicability to experiences, as other data suggest a strikingly low concordance (i.e., 38
the patients described here, as discussed below, is limited. % agreement) between physician-rated and patient-reported lung
Much evidence points to the likelihood that the patients reporting a cancer symptom burden [87,90].
severe level of depressive symptoms (n = 15) would be diagnosed with Fourth, more than 30 % of these patients with severe depressive
major depressive disorder (MDD). Positive responses to PHQ-9 items symptoms came with self-care impairments. Considering all the func-
are endorsements of the DSM criteria symptoms for MDD [33,59]. tional impairment data, the likelihood of additional patients becoming
Uniformly, patients endorsed depressed mood and/or anhedonia (the self-care impaired in the short term would be high. Functional status
presence of either is necessary for a diagnosis of MDD [40]) as well as has obvious implications for day-to-day quality of life, but is ad-
vegetative/cognitive symptoms at high rates (appetite changes [73 %], ditionally a prognostic factor in patients with lung cancer, predicting
trouble sleeping [67 %], and trouble concentrating [60 %]). Virtually relative risk of death [91]. Data such as these illustrate the importance
all patients in this group (93 %) felt their depressive symptoms made it of determining patients’ functional status early and following with in-
difficult to work, take care of things at home, and/or get along with terventions, e.g., occupational therapy, to prevent further decline and
other people. Additionally, these patients’ levels of hopelessness were disability [92,93].
notably higher than those found in non-illness comparison samples Lastly, patients with severe depressive symptoms reported limited
[60]. Nearly half (47 %) reported moderate or severe hopelessness, access to social and financial resources. Their level of social con-
signified by BHS scores ≥ 9; for comparison, Overholser et al. [61] and nectedness (M = 2.5 of 12 possible), combined with the fact that nearly
Fisher et al. [62] reported mean BHS scores of 10–11 among depressed half identified as unmarried, is concerning given the need for adequate
psychiatric patients. Hopelessness is a particularly important reponse in social support when coping with cancer. Indeed, lower levels of social
this cancer group, as it predicts depressive symptoms throughout the support from family and friends are associated with worse emotional
disease trajectory [63] and suicidal ideation [64]. Indeed, a substantial and physical aspects of quality of life for patients with lung cancer [94],
proportion—one third—of patients with severe depressive symptoms in and unmarried patients are known to die earlier than married patients
the sample reported suicidal ideation. [95]. Of additional concern, one third of these patients with severe
Importantly, once diagnosed, MDD is a psychiatric disorder which depressive symptoms reported income levels below the state poverty
continues for months and may not remit [65–67]. Even with psy- threshold for a family of four. The financial burden imposed by cancer
chotherapy and/or pharmacotherapy, significant symptom remission is is significant, with patients with cancer spending an estimated $976 to
not typically observed until after 2–3 months of continuous treatment $1170 more on out-of-pocket treatment-related expenses in a given
[68]. Quick resolution of symptoms is also unlikely because of the year than patients without cancer [81]. Moreover, in lung cancer

6
B.L. Andersen, et al. Lung Cancer xxx (xxxx) xxx–xxx

specifically, financial strain is associated with higher symptom burden, Carbone: Resources, Writing - review & editing, Supervision, Funding
reduced quality of life, and earlier mortality [96,97]. acquisition. C.J. Presley: Resources, Writing - review & editing,
Patients having a moderate severity of depressive symptoms were, Supervision, Project administration. P.G. Shields: Resources, Writing -
as expected, less symptomatic than those with severe depressive review & editing, Supervision, Project administration, Funding acqui-
symptoms in the majority of the areas assessed. As noted above, 15.4% sition.
reported depressed mood and 34.6% reported anhedonia more days Barbara L. Andersen, Stephen B. Lo, and Peter G. Shields received
than not in the preceding two weeks on the first two PHQ-9 items. If funding from The Ohio State University Comprehensive Cancer Center
only these two items were used as a screen [33] rather than the full Pelotonia. In addition to Peletonia, David P. Carbone reports personal
measure, the majority of patients in the moderate group—roughly fees from Abbvie, Adaptimmune, Agenus, Amgen, Ariad, AstraZeneca,
70%—would have been missed. In other respects, there were two Boehringer-Ingelheim, EMD Serono, Inc., Foundation Medicine,
striking differences between the moderate and severe groups. First was Genentech/Roche, Gritstone, Guardant Health, Helsinn, Incyte, Inivata,
that of GAD symptom severity, with 11.5 % of patients in the moderate Inovio, Janssen, Kyowa Kirin, Loxo Oncology, Merck, MSD, Nexus
depressive symptom group having a moderate to severe/severe GAD Oncology, Novartis, Palobiofarma, Pfizer, prIME Oncology, Stemcentrx,
score versus 73.3 % of patients in the severe depressive symptom group. and Takeda Oncology, and research funding and personal fees from
Second, many fewer of the patients with moderate depressive symp- Bristol Myers-Squibb (BMS). Carolyn J. Presley received funding from
toms had impairments in self-care (7.7 % vs. 33.3 %), mobility (32.7 % the National Cancer Institute through The Ohio State University K12
vs. 73.3 %), and usual activities (38.5 % vs. 100.0 %). Considering the Training Grant for Clinical Faculty Investigators (K12CA133250).
general observation of patients emotionally improving once cancer Thomas R. Valentine has no declarations of interest.
treatment begins, that may be more likely for individuals at the mod-
erate depressive symptom level, though not certain, due to their co- Declaration of Competing Interest
occurring problems.
Aspects of study design and method are noted. This is a single in- Barbara L. Andersen, Stephen B. Lo, and Peter G. Shields received
stitution study, but the case could be made that no single or even multi- funding from The Ohio State University Comprehensive Cancer Center
institutional study is sufficiently generalizable. There may be differ- Pelotonia. In addition to Peletonia, David P. Carbone reports personal
ences across the United States, but lung cancer patients share common fees from Abbvie, Adaptimmune, Agenus, Amgen, Ariad, AstraZeneca,
features, namely, it is largely a disease of smoking and aging. The state Boehringer-Ingelheim, EMD Serono, Inc., Foundation Medicine,
from which these patients came has among the highest smoking rates in Genentech/Roche, Gritstone, Guardant Health, Helsinn, Incyte, Inivata,
the U.S. (21.1 % vs. 14 %) and is the 44th lowest in the nation for lung Inovio, Janssen, Kyowa Kirin, Loxo Oncology, Merck, MSD, Nexus
cancer mortality. Also, 50 % of the patients were from rural Appalachia Oncology, Novartis, Palobiofarma, Pfizer, prIME Oncology, Stemcentrx,
counties. Unlike the majority of lung clinical trials [98], there were no and Takeda Oncology, and research funding and personal fees from
age or functional status exclusions. Regarding the method, diagnostic Bristol Myers-Squibb (BMS). Carolyn J. Presley received funding from
interviews for depression and anxiety were not used. Yet, the items for the National Cancer Institute through The Ohio State University K12
both the PHQ-9 and GAD-7 are those of the DSM criteria and both have Training Grant for Clinical Faculty Investigators (K12CA133250).
extensive literatures showing their convergence with interview de- Thomas R. Valentine has no declarations of interest.
terminations of MDD and GAD [33,45,99–101]. Supplementing mea-
sures for conceptually similar (though not overlapping) con- Acknowledgements
structs—hopelessness and traumatic stress—added description and
enhanced the validity of grouping patients into moderate and severe This work was supported by The Ohio State University
symptom groups. The remaining measures provided descriptive breadth Comprehensive Cancer Center Pelotonia (BLA, SBL, DPC, PGS), the
to the difficult circumstances of these patients. National Cancer Institute through The Ohio State University K12
Training Grant for Clinical Faculty Investigators (CJP, K12CA133250),
5. Conclusions and the Beating Lung Cancer in Ohio study. We thank the patients for
their participation.
The present data speak to the immediate struggles facing patients
with advanced NSCLC in the days of diagnosis and the critical im- References
portance of screening for depressive symptoms during this period.
Patients with significant depressive symptoms display a constellation of [1] J. Ferlay, I. Soerjomataram, R. Dikshit, S. Eser, C. Mathers, M. Rebelo,
anxiety symptoms, traumatic stress, impaired functional status, and D.M. Parkin, D. Forman, F. Bray, Cancer incidence and mortality worldwide:
sources, methods and major patterns in GLOBOCAN 2012, Int. J. Cancer 136
physical symptoms—factors that may further exacerbate and/or (2015) E359–E386, https://doi.org/10.1002/ijc.29210.
maintain depression. Given the survival benefits of targeted and im- [2] K.A. Cronin, A.J. Lake, S. Scott, R.L. Sherman, A.-M. Noone, N. Howlader,
munotherapies, it is crucially important to provide referral and follow- S.J. Henley, R.N. Anderson, A.U. Firth, J. Ma, B.A. Kohler, A. Jemal, Annual
Report to the Nation on the Status of Cancer, part I: National cancer statistics,
up mental health care to improve the quality of life of patients with Cancer 124 (2018) 2785–2800, https://doi.org/10.1002/cncr.31551.
depression and aid them to engage in and benefit from new therapies. [3] L.E. Carlson, M. Angen, J. Cullum, E. Goodey, J. Koopmans, L. Lamont,
Without appropriate referral and care, patients’ understanding of their J.H. MacRae, M. Martin, G. Pelletier, J. Robinson, J.S.A. Simpson, M. Speca,
L. Tillotson, B.D. Bultz, High levels of untreated distress and fatigue in cancer
disease will be suboptimal, decision-making and engagement in treat-
patients, Br. J. Cancer 90 (2004) 2297–2304, https://doi.org/10.1038/sj.bjc.
ment will be impaired [10,102], tolerance of symptoms and treatment 6601887.
side effects will be lowered, and motivation and efforts to maintain [4] J. Zabora, K. BrintzenhofeSzoc, B. Curbow, C. Hooker, S. Piantadosi, The pre-
valence of psychological distress by cancer site, Psychooncology 10 (2001) 19–28,
functional status will decline [9,10,103,104].
https://doi.org/10.1002/1099-1611(200101/02)10:1<19::AID-PON501>3.0.
CO;2-6.
CRediT authorship contribution statement [5] S. Misono, N.S. Weiss, J.R. Fann, M. Redman, B. Yueh, Incidence of suicide in
persons with cancer, J. Clin. Oncol. 26 (2008) 4731–4738, https://doi.org/10.
1200/JCO.2007.13.8941.
B.L. Andersen: Conceptualization, Methodology, Resources, [6] W. Linden, A. Vodermaier, R. Mackenzie, D. Greig, Anxiety and depression after
Writing - original draft, Supervision, Project administration. T.R. cancer diagnosis: prevalence rates by cancer type, gender, and age, J. Affect.
Valentine: Conceptualization, Methodology, Validation, Formal ana- Disord. 141 (2012) 343–351, https://doi.org/10.1016/j.jad.2012.03.025.
[7] D.R. Sullivan, C.W. Forsberg, L. Ganzini, D.H. Au, M.K. Gould, D. Provenzale,
lysis, Writing - original draft. S.B. Lo: Conceptualization, Methodology, C.G. Slatore, Longitudinal changes in depression symptoms and survival among
Validation, Formal analysis, Writing - original draft, Visualization. D.P.

7
B.L. Andersen, et al. Lung Cancer xxx (xxxx) xxx–xxx

patients with lung cancer: a national cohort assessment, J. Clin. Oncol. 34 (2016) [30] E. Kolva, L. Hoffecker, E. Cox-Martin, Suicidal ideation in patients with cancer: a
3984–3991, https://doi.org/10.1200/JCO.2016.66.8459. systematic review of prevalence, risk factors, intervention and assessment, Palliat.
[8] K.M. Brintzenhofe-Szoc, T.T. Levin, Y. Li, D.W. Kissane, J.R. Zabora, Mixed an- Support. Care (2019) 1–14, https://doi.org/10.1017/S1478951519000610.
xiety/depression symptoms in a large cancer cohort: prevalence by cancer type, [31] M. Dempster, D. Howell, N.K. McCorry, Illness perceptions and coping in physical
Psychosomatics 50 (2009) 383–391, https://doi.org/10.1176/appi.psy.50.4.383. health conditions: a meta-analysis, J. Psychosom. Res. 79 (2015) 506–513,
[9] P. Hopwood, R.J. Stephens, Depression in patients with lung cancer: prevalence https://doi.org/10.1016/j.jpsychores.2015.10.006.
and risk factors derived from quality-of-life data, J. Clin. Oncol. 18 (2000) 893, [32] M.P.J. Schellekens, M.D.J. Wolvers, M.J. Schroevers, T.I. Bootsma, A.O.J. Cramer,
https://doi.org/10.1200/JCO.2000.18.4.893. M.L. van der Lee, Exploring the interconnectedness of fatigue, depression, anxiety
[10] O. Arrieta, L.P. Angulo, C. Nunez-Valencia, Y. Dorantes-Gallareta, E.O. Macedo, and potential risk and protective factors in cancer patients: a network approach, J.
D. Martinez-Lopez, S. Alvarado, J.F. Corona-Cruz, L.F. Onate-Ocana, Association Behav. Med. (2019), https://doi.org/10.1007/s10865-019-00084-7.
of depression and anxiety on quality of life, treatment adherence, and prognosis in [33] K. Kroenke, R.L. Spitzer, J.B. Williams, The PHQ-9, Validity of a brief depression
patients with advanced non-small cell lung cancer, Ann. Surg. Oncol. 20 (2013) severity measure, J. Gen. Intern. Med. 16 (2001) 606–613, https://doi.org/10.
1941–1948, https://doi.org/10.1245/s10434-012-2793-5. 1046/j.1525-1497.2001.016009606.x.
[11] W.F. Pirl, J.A. Greer, L. Traeger, V. Jackson, I.T. Lennes, E.R. Gallagher, P. Perez- [34] C.-M. Chen, J. Mullan, Y.-Y. Su, D. Griffiths, I.A. Kreis, H.-C. Chiu, The long-
Cruz, R.S. Heist, J.S. Temel, Depression and survival in metastatic non-small-cell itudinal relationship between depressive symptoms and disability for older adults:
lung cancer: effects of early palliative care, J. Clin. Oncol. 30 (2012) 1310–1315, a population-based study, J. Gerontol. A Biol. Sci. Med. Sci. 67 (2012) 1059–1067,
https://doi.org/10.1200/jco.2011.38.3166. https://doi.org/10.1093/gerona/gls074.
[12] M.E. Kurtz, J.C. Kurtz, M. Stommel, C.W. Given, B. Given, Predictors of depressive [35] S. Dauchy, S. Dolbeault, M. Reich, Depression in cancer patients, EJC Suppl. 11
symptomatology of geriatric patients with lung cancer - A longitudinal analysis, (2013) 205–215, https://doi.org/10.1016/j.ejcsup.2013.07.006.
Psychooncology 11 (2002) 12–22, https://doi.org/10.1002/pon.545. [36] J. Ormel, F.V. Rijsdijk, M. Sullivan, E. van Sonderen, G.I.J.M. Kempen, Temporal
[13] D.R. Sullivan, C.W. Forsberg, L. Ganzini, D.H. Au, M.K. Gould, D. Provenzale, and reciprocal relationship between IADL/ADL disability and depressive symp-
K.S. Lyons, C.G. Slatore, Depression symptom trends and health domains among toms in late life, J. Gerontol. B Psychol. Sci. Soc. Sci. 57 (2002) P338–347, https://
lung cancer patients in the CanCORS study, Lung Cancer 100 (2016) 102–109, doi.org/10.1093/geronb/57.4.p338.
https://doi.org/10.1016/j.lungcan.2016.08.008. [37] K.S. Grotmol, H.C. Lie, M.J. Hjermstad, N. Aass, D. Currow, S. Kaasa, T.Å. Moum,
[14] B.L. Andersen, N.G. Goyal, T.D. Westbrook, B. Bishop, W.E. Carson, Trajectories of A. Pigni, J.H. Loge, European Palliative Care Research Collaborative (EPCRC),
stress, depressive symptoms, and immunity in cancer survivors: diagnosis to 5 Depression - A major contributor to poor quality of life in patients with advanced
years, Clin. Cancer Res. 23 (2017) 52–61, https://doi.org/10.1158/1078-0432. cancer, J. Pain Symptom Manage. 54 (2017) 889–897, https://doi.org/10.1016/j.
CCR-16-0574. jpainsymman.2017.04.010.
[15] I. Henselmans, V.S. Helgeson, H. Seltman, J. de Vries, R. Sanderman, [38] S. Wen, H. Xiao, Y. Yang, The risk factors for depression in cancer patients un-
A.V. Ranchor, Identification and prediction of distress trajectories in the first year dergoing chemotherapy: a systematic review, Support. Care Cancer 27 (2019)
after a breast cancer diagnosis, Health Psychol. 29 (2010) 160–168, https://doi. 57–67, https://doi.org/10.1007/s00520-018-4466-9.
org/10.1037/a0017806. [39] C. McKay, T. Burke, X. Cao, A.P. Abernethy, D.P. Carbone, Treatment patterns for
[16] N. Kawamura, Y. Kim, N. Asukai, Suppression of cellular immunity in men with a advanced non-small-cell lung cancer after platinum-containing therapy in U.S.
past history of posttraumatic stress disorder, Am. J. Psychiatry 158 (2001) community oncology clinical practice, Clin. Lung Cancer 17 (2016) 449–460,
484–486, https://doi.org/10.1176/appi.ajp.158.3.484. https://doi.org/10.1016/j.cllc.2016.03.008 e7.
[17] B.L. Andersen, W.B. Farrar, D.M. Golden-Kreutz, L.A. Kutz, R.M. MacCallum, [40] American Psychiatric Association, Diagnostic and Statistical Manual of Mental
M.E. Courtney, R. Glaser, Stress and immune responses after surgical treatment for Disorders, 5th ed., American Psychiatric Publishing, Arlington, VA, 2013.
regional breast cancer, J. Natl. Cancer Inst. 90 (1998) 30–36, https://doi.org/10. [41] A.T. Beck, A. Weissman, D. Lester, L. Trexler, The measurement of pessimism: the
1093/jnci/90.1.30. hopelessness scale, J. Consult. Clin. Psychol. 42 (1974) 861–865, https://doi.org/
[18] B.L. Andersen, N.G. Goyal, D.M. Weiss, T.D. Westbrook, K.J. Maddocks, J.C. Byrd, 10.1037/h0037562.
A.J. Johnson, Cells, cytokines, chemokines, and cancer stress: a biobehavioral [42] A.T. Beck, G. Brown, R.J. Berchick, B.L. Stewart, R.A. Steer, Relationship between
study of patients with chronic lymphocytic leukemia, Cancer. 124 (2018) hopelessness and ultimate suicide: a replication with psychiatric outpatients, Am.
3240–3248, https://doi.org/10.1002/cncr.31538. J. Psychiatry 147 (1990) 190–195, https://doi.org/10.1176/ajp.147.2.190.
[19] B.L. Andersen, J.K. Kiecolt-Glaser, R. Glaser, A biobehavioral model of cancer [43] A.T. Beck, R.A. Steer, J.S. Beck, C.F. Newman, Hopelessness, depression, suicidal
stress and disease course, Am. Psychol. 49 (1994) 389–404, https://doi.org/10. ideation, and clinical diagnosis of depression, Suicide Life, Threat. Behav. 23
1037/0003-066X.49.5.389. (1993) 139–145, https://doi.org/10.1111/j.1943-278X.1993.tb00378.x.
[20] Y. Chida, M. Hamer, J. Wardle, A. Steptoe, Do stress-related psychosocial factors [44] D.J.A. Dozois, R. Covin, J.K. Brinker, Normative data on cognitive measures of
contribute to cancer incidence and survival? Nat. Clin. Pract. Oncol. 5 (2008) depression, J. Consult. Clin. Psychol. 71 (2003) 71–80, https://doi.org/10.1037/
466–475, https://doi.org/10.1038/ncponc1134. 0022-006X.71.1.71.
[21] K. Mystakidou, E. Parpa, E. Tsilika, C. Gennatas, A. Galanos, L. Vlahos, How is [45] R.L. Spitzer, K. Kroenke, J.B. Williams, B. Lowe, A brief measure for assessing
sleep quality affected by the psychological and symptom distress of advanced generalized anxiety disorder: the GAD-7, Arch. Intern. Med. 166 (2006)
cancer patients? Palliat. Med. 23 (2009) 46–53, https://doi.org/10.1177/ 1092–1097, https://doi.org/10.1001/archinte.166.10.1092.
0269216308098088. [46] D.S. Weiss, The impact of event scale: revised, Cross-Cult. Assess. Psychol. Trauma
[22] A. Mykletun, A.A. Dahl, C.F. Haaland, R. Bremnes, O. Dahl, O. Klepp, E. Wist, PTSD, Springer Science + Business Media, New York, NY, US, 2007, pp. 219–238,
S.D. Fosså, Side effects and cancer-related stress determine quality of life in long- https://doi.org/10.1007/978-0-387-70990-1_10.
term survivors of testicular cancer, J. Clin. Oncol. 23 (2005) 3061–3068, https:// [47] K. Mystakidou, E. Tsilika, E. Parpa, A. Galanos, L. Vlahos, Psychometric properties
doi.org/10.1200/JCO.2005.08.048. of the Impact of Event Scale in Greek cancer patients, J. Pain Symptom Manage. 33
[23] D.-H. Kang, N.-J. Park, T. McArdle, Cancer-specific stress and mood disturbance: (2007) 454–461, https://doi.org/10.1016/j.jpainsymman.2006.09.023.
implications for symptom perception, quality of life, and immune response in [48] E. Broadbent, K.J. Petrie, J. Main, J. Weinman, The brief illness perception
women shortly after diagnosis of breast cancer, ISRN Nurs. 2012 (2012) 608039, , questionnaire, J. Psychosom. Res. 60 (2006) 631–637, https://doi.org/10.1016/j.
https://doi.org/10.5402/2012/608039. jpsychores.2005.10.020.
[24] S.M. Thekdi, K. Milbury, A. Spelman, Q. Wei, C. Wood, S.F. Matin, N. Tannir, [49] B. Bergman, N.K. Aaronson, S. Ahmedzai, S. Kaasa, M. Sullivan, The EORTC QLQ-
E. Jonasch, L. Pisters, L. Cohen, Posttraumatic stress and depressive symptoms in LC13: a modular supplement to the EORTC Core Quality of Life Questionnaire
renal cell carcinoma: association with quality of life and utility of single-item (QLQ-C30) for use in lung cancer clinical trials, Eur. J. Cancer 30 (1994) 635–642,
distress screening, Psychooncology 24 (2015) 1477–1484, https://doi.org/10. https://doi.org/10.1016/0959-8049(94)90535-5.
1002/pon.3758. [50] M. Koller, S. Warncke, M.J. Hjermstad, J. Arraras, C. Pompili, A. Harle,
[25] E.J. Morrison, J.M. Flynn, J. Jones, J.C. Byrd, B.L. Andersen, Individual differ- C.D. Johnson, W.-C. Chie, C. Schulz, F. Zeman, J.P. van Meerbeeck, D. Kuliś,
ences in physical symptom burden and psychological responses in individuals with A. Bottomley, Use of the lung cancer–specific Quality of Life Questionnaire EORTC
chronic lymphocytic leukemia, Ann. Hematol. 95 (2016) 1989–1997, https://doi. QLQ-LC13 in clinical trials: a systematic review of the literature 20 years after its
org/10.1007/s00277-016-2790-z. development, Cancer 121 (2015) 4300–4323, https://doi.org/10.1002/cncr.
[26] M. Mazor, S.M. Paul, M.A. Chesney, L.-M. Chen, B. Smoot, K. Topp, Y.P. Conley, 29682.
J.D. Levine, C. Miaskowski, Perceived stress is associated with a higher symptom [51] N. Salvo, S. Hadi, J. Napolskikh, P. Goh, E. Sinclair, E. Chow, Quality of life
burden in cancer survivors, Cancer (2019), https://doi.org/10.1002/cncr.32477. measurement in cancer patients receiving palliative radiotherapy for symptomatic
[27] T.R. Norton, S.L. Manne, S. Rubin, J. Carlson, E. Hernandez, M.I. Edelson, lung cancer: a literature review, Curr. Oncol. 16 (2009) 16–28, https://doi.org/10.
N. Rosenblum, D. Warshal, C. Bergman, Prevalence and predictors of psycholo- 3747/co.v16i2.376.
gical distress among women with ovarian cancer, J. Clin. Oncol. 22 (2004) [52] M. Herdman, C. Gudex, A. Lloyd, M. Janssen, P. Kind, D. Parkin, G. Bonsel,
919–926, https://doi.org/10.1200/JCO.2004.07.028. X. Badia, Development and preliminary testing of the new five-level version of EQ-
[28] B.L. Andersen, R.J. DeRubeis, B.S. Berman, J. Gruman, V.L. Champion, 5D (EQ-5D-5L), Qual. Life Res. 20 (2011) 1727–1736, https://doi.org/10.1007/
M.J. Massie, J.C. Holland, A.H. Partridge, K. Bak, M.R. Somerfield, J.H. Rowland, s11136-011-9903-x.
Screening, assessment, and care of anxiety and depressive symptoms in adults with [53] B. Janssen, A. Szende, Population norms for the EQ-5D, in: A. Szende, B. Janssen,
cancer: An American Society of Clinical Oncology Guideline adaptation, J. Clin. J. Cabases (Eds.), Self-Rep. Popul. Health Int. Perspect. Based EQ-5D, Springer,
Oncol. 32 (2014) 1605–1619, https://doi.org/10.1200/JCO.2013.52.4611. Dordrecht, 2014(accessed April 7, 2019), http://www.ncbi.nlm.nih.gov/books/
[29] E. Parpa, E. Tsilika, A. Galanos, M. Nikoloudi, K. Mystakidou, Depression as NBK500364/.
mediator and or moderator on the relationship between hopelessness and patients’ [54] S. Cohen, W.J. Doyle, D.P. Skoner, B.S. Rabin, J.M. Gwaltney, Social ties and
desire for hastened death, Support. Care Cancer 27 (2019), https://doi.org/10. susceptibility to the common cold, JAMA 277 (1997) 1940–1944, https://doi.org/
1007/s00520-019-04715-2. 10.1001/jama.1997.03540480040036.

8
B.L. Andersen, et al. Lung Cancer xxx (xxxx) xxx–xxx

[55] J.W. Tukey, Comparing individual means in the analysis of variance, Biometrics 5 T. Banerjee, D. Spiegel, Traumatic stress symptoms among women with recently
(1949) 99–114, https://doi.org/10.2307/3001913. diagnosed primary breast cancer, J. Trauma. Stress 15 (2002) 277–287, https://
[56] S. Holm, A simple sequentially rejective multiple test procedure, Scand. Stat. doi.org/10.1023/a:1016295610660.
Theory Appl. 6 (1979) 65–70, https://doi.org/10.2307/4615733. [79] S. Phipps, A. Long, M. Hudson, S.N. Rai, Symptoms of post-traumatic stress in
[57] V. Meraner, E.-M. Gamper, A. Grahmann, J.M. Giesinger, P. Wiesbauer, children with cancer and their parents: effects of informant and time from diag-
M. Sztankay, A.G. Zeimet, B. Sperner-Unterweger, B. Holzner, Monitoring physical nosis, Pediatr. Blood Cancer 45 (2005) 952–959, https://doi.org/10.1002/pbc.
and psychosocial symptom trajectories in ovarian cancer patients receiving che- 20373.
motherapy, BMC Cancer 12 (2012) 77, https://doi.org/10.1186/1471-2407- [80] T.D. Westbrook, K. Maddocks, B.L. Andersen, The relation of illness perceptions to
12-77. stress, depression, and fatigue in patients with chronic lymphocytic leukaemia,
[58] A. Schneider, G. Kotronoulas, C. Papadopoulou, L. McCann, M. Miller, J. McBride, Psychol. Health 31 (2016) 891–902, https://doi.org/10.1080/08870446.2016.
Z. Polly, S. Bettles, A. Whitehouse, N. Kearney, R. Maguire, Trajectories and 1158259.
predictors of state and trait anxiety in patients receiving chemotherapy for breast [81] J. Miceli, D. Geller, A. Tsung, C.L. Hecht, Y. Wang, R. Pathak, H. Cheng, W. Marsh,
and colorectal cancer: results from a longitudinal study, Eur. J. Oncol. Nurs. 24 M. Antoni, F. Penedo, L. Burke, K. Ell, S. Shen, J. Steel, Illness perceptions and
(2016) 1–7, https://doi.org/10.1016/j.ejon.2016.07.001. perceived stress in patients with advanced gastrointestinal cancer,
[59] American Psychiatric Association, Diagnostic and Statistical Manual of Mental Psychooncology 28 (2019) 1513–1519, https://doi.org/10.1002/pon.5108.
Disorders, 4th ed., (1994) Washington, DC. [82] H. Leventhal, I. Brissette, E.A. Leventhal, The common-sense model of self-reg-
[60] D.J.A. Dozois, R. Covin, J.K. Brinker, Normative data on cognitive measures of ulation of health and illness, in: L.D. Cameron, H. Leventhal (Eds.), Self-Regul.
depression, J. Consult. Clin. Psychol. 71 (2003) 71–80, https://doi.org/10.1037/ Health Illn. Behav. Routledge, New York, NY, US, 2003, pp. 42–65.
0022-006X.71.1.71. [83] E.M. Richardson, N. Schüz, K. Sanderson, J.L. Scott, B. Schüz, Illness representa-
[61] J. Overholser, L. Fisher, A. Braden, N. Peak, Despair beyond repair? Severity of tions, coping, and illness outcomes in people with cancer: a systematic review and
hopelessness in depressed psychiatric inpatients, J. Depress. Ther. 1 (2015) 1–10, meta-analysis, Psychooncology 26 (2017) 724–737, https://doi.org/10.1002/pon.
https://doi.org/10.14302/issn.2476-1710.jdt-14-567. 4213.
[62] L.B. Fisher, J.C. Overholser, J. Ridley, A. Braden, C. Rosoff, From the outside [84] S.M. Attari, G. Ozgoli, M. Solhi, H. Alavi Majd, Study of relationship between
looking in: sense of belonging, depression, and suicide risk, Psychiatry 78 (2015) illness perception and delay in seeking help for breast cancer patients based on
29–41, https://doi.org/10.1080/00332747.2015.1015867. Leventhal’s Self-Regulation Model, Asian Pac. J. Cancer Prev. 17 (2016) 167–174,
[63] C. Lo, C. Zimmermann, A. Rydall, A. Walsh, J.M. Jones, M.J. Moore, https://doi.org/10.7314/apjcp.2016.17.s3.167.
F.A. Shepherd, L. Gagliese, G. Rodin, Longitudinal study of depressive symptoms [85] J.S. Temel, J.A. Greer, S. Admane, E.R. Gallagher, V.A. Jackson, T.J. Lynch,
in patients with metastatic gastrointestinal and lung cancer, J. Clin. Oncol. 28 I.T. Lennes, C.M. Dahlin, W.F. Pirl, Longitudinal perceptions of prognosis and
(2010) 3084–3089, https://doi.org/10.1200/JCO.2009.26.9712. goals of therapy in patients with metastatic non-small-cell lung cancer: results of a
[64] H.M. Chochinov, K.G. Wilson, M. Enns, S. Lander, Depression, hopelessness, and randomized study of early palliative care, J. Clin. Oncol. 29 (2011) 2319–2326,
suicidal ideation in the terminally ill, Psychosomatics 39 (1998) 366–370, https:// https://doi.org/10.1200/JCO.2010.32.4459.
doi.org/10.1016/S0033-3182(98)71325-8. [86] T.R. Mendoza, K.L. Kehl, O. Bamidele, L.A. Williams, Q. Shi, C.S. Cleeland,
[65] A.J. Ferrari, F.J. Charlson, R.E. Norman, A.D. Flaxman, S.B. Patten, T. Vos, G. Simon, Assessment of baseline symptom burden in treatment-naïve patients
H.A. Whiteford, The epidemiological modelling of major depressive disorder: with lung cancer: an observational study, Support. Care Cancer (2019), https://
application for the Global Burden of Disease Study 2010, PLoS One 8 (2013) doi.org/10.1007/s00520-018-4632-0.
e69637, , https://doi.org/10.1371/journal.pone.0069637. [87] S. Iyer, A. Roughley, A. Rider, G. Taylor-Stokes, The symptom burden of non-small
[66] J. Spijker, R. de Graaf, R.V. Bijl, A.T.F. Beekman, J. Ormel, W.A. Nolen, Duration cell lung cancer in the USA: a real-world cross-sectional study, Support. Care
of major depressive episodes in the general population: results from the Cancer 22 (2014) 181–187, https://doi.org/10.1007/s00520-013-1959-4.
Netherlands Mental Health Survey and Incidence Study (NEMESIS), Br. J. [88] A.S.M. Harle, F.H. Blackhall, A. Molassiotis, J. Yorke, R. Dockry, K.J. Holt,
Psychiatry J. Ment. Sci. 181 (2002) 208–213, https://doi.org/10.1192/bjp.181.3. D. Yuill, K. Baker, J.A. Smith, Cough in patients with lung cancer: a longitudinal
208. observational study of characterization and clinical associations, Chest 155 (2019)
[67] W.W. Eaton, H. Shao, G. Nestadt, B.H. Lee, O.J. Bienvenu, P. Zandi, Population- 103–113, https://doi.org/10.1016/j.chest.2018.10.003.
based study of first onset and chronicity in major depressive disorder, Arch. Gen. [89] K. Tanaka, T. Akechi, T. Okuyama, Y. Nishiwaki, Y. Uchitomi, Impact of dyspnea,
Psychiatry 65 (2008) 513–520, https://doi.org/10.1001/archpsyc.65.5.513. pain, and fatigue on daily life activities in ambulatory patients with advanced lung
[68] E. Frank, G.B. Cassano, P. Rucci, W.K. Thompson, H.C. Kraemer, A. Fagiolini, cancer, J. Pain Symptom Manage. 23 (2002) 417–423, https://doi.org/10.1016/
L. Maggi, D.J. Kupfer, M.K. Shear, P.R. Houck, S. Calugi, V.J. Grochocinski, S0885-3924(02)00376-7.
P. Scocco, J. Buttenfield, R.N. Forgione, Predictors and moderators of time to [90] J.R. Landis, G.G. Koch, The measurement of observer agreement for categorical
remission of major depression with interpersonal psychotherapy and SSRI phar- data, Biometrics 33 (1977) 159–174, https://doi.org/10.2307/2529310.
macotherapy, Psychol. Med. 41 (2011) 151–162, https://doi.org/10.1017/ [91] E. Radzikowska, P. Glaz, K. Roszkowski, Lung cancer in women: age, smoking,
S0033291710000553. histology, performance status, stage, initial treatment and survival. Population-
[69] R.C. Kessler, P. Berglund, O. Demler, R. Jin, D. Koretz, K.R. Merikangas, A.J. Rush, based study of 20 561 cases, Ann. Oncol. 13 (2002) 1087–1093, https://doi.org/
E.E. Walters, P.S. Wang, National comorbidity survey replication, the epide- 10.1093/annonc/mdf187.
miology of major depressive disorder: results from the national comorbidity [92] R. Bentley, A. Hussain, M. Maddocks, A. Wilcock, Occupational therapy needs of
survey replication (NCS-R), JAMA 289 (2003) 3095–3105, https://doi.org/10. patients with thoracic cancer at the time of diagnosis: findings of a dedicated
1001/jama.289.23.3095. rehabilitation service, Support. Care Cancer 21 (2013) 1519–1524, https://doi.
[70] E. Bruera, B. Schmitz, J. Pither, C.M. Neumann, J. Hanson, The frequency and org/10.1007/s00520-012-1687-1.
correlates of dyspnea in patients with advanced cancer, J. Pain Symptom Manage. [93] M. Pergolotti, G.R. Williams, C. Campbell, L.A. Munoz, H.B. Muss, Occupational
19 (2000) 357–362, https://doi.org/10.1016/S0885-3924(00)00126-3. therapy for adults with cancer: why it matters, Oncologist 21 (2016) 314–319,
[71] D.J. Dudgeon, M. Lertzman, G.R. Askew, Physiological changes and clinical cor- https://doi.org/10.1634/theoncologist.2015-0335.
relations of dyspnea in cancer outpatients, J. Pain Symptom Manage. 21 (2001) [94] A. Luszczynska, I. Pawlowska, R. Cieslak, N. Knoll, U. Scholz, Social support and
373–379, https://doi.org/10.1016/S0885-3924(01)00278-0. quality of life among lung cancer patients: a systematic review, Psychooncology 22
[72] J.A. Shin, J.D. Kosiba, L. Traeger, J.A. Greer, J.S. Temel, W.F. Pirl, Dyspnea and (2013) 2160–2168, https://doi.org/10.1002/pon.3218.
panic among patients with newly diagnosed non-small cell lung cancer, J. Pain [95] Y. Wu, Z. Ai, G. Xu, Marital status and survival in patients with non-small cell lung
Symptom Manage. 48 (2014) 465–470, https://doi.org/10.1016/j.jpainsymman. cancer: an analysis of 70006 patients in the SEER database, Oncotarget 8 (2017)
2013.10.021. 103518–103534, https://doi.org/10.18632/oncotarget.21568.
[73] J.A. Greer, W.F. Pirl, E.R. Park, T.J. Lynch, J.S. Temel, Behavioral and psycholo- [96] C.S. Lathan, A. Cronin, R. Tucker-Seeley, S.Y. Zafar, J.Z. Ayanian, D. Schrag,
gical predictors of chemotherapy adherence in patients with advanced non-small Association of financial strain with symptom burden and quality of life for patients
cell lung cancer, J. Psychosom. Res. 65 (2008) 549–552, https://doi.org/10.1016/ with lung or colorectal cancer, J. Clin. Oncol. 34 (2016) 1732–1740, https://doi.
j.jpsychores.2008.03.005. org/10.1200/JCO.2015.63.2232.
[74] N. Asukai, H. Kato, N. Kawamura, Y. Kim, K. Yamamoto, J. Kishimoto, Y. Miyake, [97] S.D. Ramsey, A. Bansal, C.R. Fedorenko, D.K. Blough, K.A. Overstreet,
A. Nishizono-Maher, Reliability and validity of the Japanese-language version of V. Shankaran, P. Newcomb, Financial insolvency as a risk factor for early mortality
the Impact of Event Scale-Revised (IES-R-J): four studies of different traumatic among patients with cancer, J. Clin. Oncol. 34 (2016) 980–986, https://doi.org/
events, J. Nerv. Ment. Dis. 190 (2002) 175–182, https://doi.org/10.1097/ 10.1200/JCO.2015.64.6620.
00005053-200203000-00006. [98] K. Al-Baimani, H. Jonker, T. Zhang, G.D. Goss, S.A. Laurie, G. Nicholas,
[75] S.K. Chambers, L. Zajdlewicz, D.R. Youlden, J.C. Holland, J. Dunn, The validity of P. Wheatley-Price, Are clinical trial eligibility criteria an accurate reflection of a
the Distress Thermometer in prostate cancer populations, Psychooncology 23 real-world population of advanced non-small-cell lung cancer patients? Curr.
(2014) 195–203, https://doi.org/10.1002/pon.3391. Oncol. 25 (2018) e291–e297, https://doi.org/10.3747/co.25.3978.
[76] D.M. Golden-Kreutz, L.M. Thornton, S. Wells-Di Gregorio, G.M. Frierson, H.S. Jim, [99] B. Wild, A. Eckl, W. Herzog, D. Niehoff, S. Lechner, I. Maatouk, D. Schellberg,
K.M. Carpenter, R.A. Shelby, B.L. Andersen, Traumatic stress, perceived global H. Brenner, H. Müller, B. Löwe, Assessing generalized anxiety disorder in elderly
stress, and life events: prospectively predicting quality of life in breast cancer people using the GAD-7 and GAD-2 scales: results of a validation study, Am. J.
patients, Health Psychol. 24 (2005) 288–296, https://doi.org/10.1037/0278- Geriatr. Psychiatry 22 (2014) 1029–1038, https://doi.org/10.1016/j.jagp.2013.
6133.24.3.288. 01.076.
[77] M. Kangas, J.L. Henry, R.A. Bryant, Posttraumatic stress disorder following cancer: [100] B. Löwe, R.L. Spitzer, K. Gräfe, K. Kroenke, A. Quenter, S. Zipfel, C. Buchholz,
a conceptual and empirical review, Clin. Psychol. Rev. 22 (2002) 499–524, S. Witte, W. Herzog, Comparative validity of three screening questionnaires for
https://doi.org/10.1016/S0272-7358(01)00118-0. DSM-IV depressive disorders and physicians’ diagnoses, J. Affect. Disord. 78
[78] C. Koopman, L.D. Butler, C. Classen, J. Giese-Davis, G.R. Morrow, J. Westendorf, (2004) 131–140, https://doi.org/10.1016/S0165-0327(02)00237-9.

9
B.L. Andersen, et al. Lung Cancer xxx (xxxx) xxx–xxx

[101] B. Löwe, K. Kroenke, W. Herzog, K. Gräfe, Measuring depression outcome with a function, the systemic inflammatory response, and psychological distress in pa-
brief self-report instrument: sensitivity to change of the Patient Health tients with advanced lung cancer, Cancer 103 (2005) 377–382, https://doi.org/
Questionnaire (PHQ-9), J. Affect. Disord. 81 (2004) 61–66, https://doi.org/10. 10.1002/cncr.20777.
1016/S0165-0327(03)00198-8. [104] A. Vodermaier, S. Lucas, W. Linden, R. Olson, Anxiety after diagnosis predicts lung
[102] S.A. Cook, P. Salmon, G. Hayes, A. Byrne, P.L. Fisher, Predictors of emotional cancer-specific and overall survival in patients with stage III non-small cell lung
distress a year or more after diagnosis of cancer: a systematic review of the lit- cancer: a population-based cohort study, J. Pain Symptom Manage. 53 (2017)
erature, Psychooncology 27 (2018) 791–801, https://doi.org/10.1002/pon.4601. 1057–1065, https://doi.org/10.1016/j.jpainsymman.2016.12.338.
[103] D.J.F. Brown, D.C. McMillan, R. Milroy, The correlation between fatigue, physical

10