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J Pain Symptom Manage. 2011 August ; 42(2): 202–212. doi:10.1016/j.jpainsymman.2010.10.257.
Fatigue, Dyspnea, and Cough Comprise a Persistent Symptom

Cluster Up to Five Years After Diagnosis with Lung Cancer
Andrea L. Cheville, MD MSCE, Paul J. Novotny, MS, Jeffrey A. Sloan, PhD, Jeffrey R.
Basford, MD, PhD, Jason A. Wampfler, MS, Yolanda I. Garces, MD, Aminah Jatoi, MD, and
Ping Yang, MD, PhD
Departments of Physical Medicine and Rehabilitation (A.L.C., JR.B.), Health Sciences Research
(P.J.N., J.A.S., J.A.W., P.Y.), Radiation Oncology (Y.I.G.), and Medical Oncology (A.J.), Mayo
Clinic, Rochester, Minnesota, USA
Abstract
Context—Aggregates of concurrent symptoms, known as symptom clusters (SxCls), have been
described in predominantly cross-sectional samples of lung cancer patients undergoing treatment.
Objectives—The objective of this study was to delineate symptom clusters in lung cancer
survivors up to five years following diagnosis, investigate their stability over time, and identify
determinants of SxCl development and resolution.
Methods—A sensitivity approach involving multiple exploratory and confirmatory analyses was
applied to an eight-year prospective cohort study that annually assessed 2405 patients with lung
cancer for symptom burden with the Lung Cancer Symptom Scale (LCSS) and Linear Analogue
Self-Assessment (LASA).
Results—A single robust SxCl of fatigue, cough, and dyspnea was identified in 14.6%, 12.9%,
14.1%, 14.6%, and 15.4% of participants at years 1-5 after diagnosis, respectively. Participants
with the SxCl (SxCl (+)) were more likely to die than those without it but this tendency
diminished over time. SxCl persistence varied, with >40% of surviving patients annually
transitioning to or from the SxCl(+) state until year 4, after which the SxCl became increasingly
stable. The SxCl was more likely to develop among male survivors who underwent surgery,
received radiation, and were current smokers.
Conclusion—A single SxCl comprised of dyspnea, fatigue, and cough has a stable prevalence
among lung cancer survivors up to five years following diagnosis but is not stable among
individuals. Initially following diagnosis, the SxCl is associated with a greater risk of death;
however, after year 2 the SxCl becomes increasingly stable and provides a marker for
parenchymal lung injury.
Keywords
Symptom cluster; lung cancer; fatigue; employment; survival; quality of life
© 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Address correspondence to: Andrea L. Cheville, MD, MSCE Department of Physical Medicine and Rehabilitation Mayo Clinic 200
First Street SW Rochester, MN 55905, USA Cheville.andrea@mayo.edu.
Disclosures The authors declare no conflicts of interest.
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Cheville et al. Page 2
Introduction
Physicians typically confine consideration of symptoms to their role as diagnostic clues or as

indicators of the need to initiate or change treatment. However, there is growing interest in
the idea that a more encompassing consideration of symptoms, specifically as groups or
clusters of symptoms, may provide benefits in the form of improved prognostication,
screening and treatment optimization.1-3 Although, a number of researchers have found
empirical links between specific clusters of symptoms and adverse outcomes such as death,
explanatory mechanisms remain speculative and the clinical relevance of symptom clusters
(SxCl) is unclear.4
Lung cancer (LC) engenders a uniquely high symptom burden and, as such, has already
received some attention from investigators in this area.5-7 Previous authors have identified a
number of symptom clusters such as anxiety, fatigue, and dyspnea8-11 that were associated
with poor patient performance. These studies, however, have been primarily cross sectional
in nature and limited to patients on active treatment.9-11 Understanding of the persistence of
symptom clusters with time is much more limited. Persistence has emerged as an important
issue in light of recent reports that symptoms remain problematic throughout the course of
LC treatment and continue long into post-treatment survivorship. 8, 12
Given the potential long-term relevance of SxCl to patients with LC, we utilized several
complementary analytic techniques to identify SxCls in a cohort of 2405 LC survivors
followed longitudinally over eight years. In addition to identifying SxCls using differing
analytic approaches, we also examined their stability over time, as well as demographic,
disease-based, and treatment-based factors associated with their persistence.
Methods
Subject Recruitment
The Epidemiology and Genetics of Lung Cancer research program maintains a database of
all patients with a pathologically confirmed diagnosis of LC who have been evaluated at the
Mayo Clinic, Rochester, Minnesota, since January 1, 1999. As of December 31, 2008, this
data base contained entries for 2500 subjects who consented to be followed annually. Data
collection involved sending patients who agreed to participate a mailed self-report study
instrument within six months of their diagnosis and subsequently on a yearly basis.
Additional details have been outlined in previous publications.13, 14 Patients contacted study
personnel with questions but otherwise had no interaction with study personnel. The study
was approved by the Mayo Clinic Institutional Review Board.
Study Questionnaire Components Utilized in This Study

The Lung Cancer Symptom Scale (LCSS) is a validated, disease-specific measure of
symptom intensity and functionality that emphasizes symptoms related to LC.15, 16
Although the LCSS includes two parts, this study confined analyses to six self-report items
that assess appetite, fatigue, coughing, dyspnea, hemoptysis, and pain. The intensity of
patient responses is measured by 11-point visual analogue scales, with responses converted
to a range extending from 0 (worst symptoms/highest burden) to 10 (least symptoms/lowest
burden).
Linear Analogue Self-Assessment (LASA) consisted of five items that were rated on a scale
from 0 (as bad as it can be) to 100 (as good as it can be). Items included ratings of cognitive,
emotional, and social well-being, as well as sleep quality and overall quality of life. Single-
item LASAs to assess cancer-related symptoms have been widely utilized in oncology
research and evidence strongly suggests that they are valid and reliable.17-19
Tobacco use at each assessment point was queried with questions regarding current and/or
previous use, duration, average number of cigarettes smoked per day, and years since the
patient quit smoking.
Information from Electronic Medical Records

Information regarding patients’ demographics, LC histology, staging, location,
comorbidities, and treatment was abstracted from their electronic medical records by a
research nurse. Copies of LC-related medical records for patients who received all or a
portion of their treatment outside the Mayo Clinic were reviewed. 20-22 The occurrence of
disease progression, recurrent disease, and a second primary LC were all captured with a
binary “active disease” variable.23
Vital Status
Patients’ vital status was verified annually through death certificates, the Mayo Clinic’s
electronic medical notes and registration database, and next-of-kin reports, as well as
through the Mayo Clinic Tumor Registry and Social Security Death Index website.
Statistical Analysis
Analysis extended from the point of entry into the data base until December 31, 2008 or the
time of death. Data obtained six months and one year after study enrollment were combined
to generate a single score, with scores averaged as appropriate. Separate symptom clusters
were created at each evaluation point (less than or equal to one year, two years, three years,
four years, and five years).
Three methods were used to construct and validate the symptom clusters. The clusters were
identified using variable clustering based on principal components. Cluster and factor
analytic methods were based on the correlation matrix of the symptom variables as
described by Barsevick et al.24 Exploratory cluster analysis was performed including all
available symptom data (poor appetite, fatigue, coughing, dyspnea, hemoptysis, pain, poor
sleep quality and subjective cognitive, emotional, and social well-being) at each time point.
The clustering criteria used was Euclidean distance and we followed the analytical approach
suggested by Romesburg.25 Variables were combined and dendrograms created based on the
percent of variation explained by the variables. Factor analysis with varimax rotation was
used to determine the variables in each cluster. Factors were selected if their eigenvalues
were greater than one and they explained at least 10% of the variation, and the number of
factors was verified using scree plots. Individual variables were considered to be part of a
factor if their rotated factor loadings were greater than 0.50. The factors were then verified
using bootstrapped factor analysis with 5000 replications. Variables with factor loadings
over 0.50 in at least 70% of the samples were considered to be validated for that factor.26
The final SxCls were then validated using latent trait analyses and the categorical
classification described in the next paragraph.27 Latent trait analysis is a special form of
structural equation models wherein categorical variables are used to identify underlying
relationships among continuous variables. Like other structural equation models, latent trait
analysis involves a detailed modeling of the covariance structure of the variables being
studied to identify correlational patterns that suggest pooling of individual observable
variables into unobservable latent variables. We followed the methods of Bollen 28 in
carrying out the latent trait modeling processes. These latent trait analyses were created
using PROC CALIS in SAS (SAS Institute Inc., Cary, NC).29 For this latent trait analysis,
the number of clusters and the variables in each cluster were based on the results of the
factor analysis and cluster analysis. All three modeling methods used the raw variables.
Following SxCl identification, each patient was subsequently classified as experiencing the
symptoms included in the delineated cluster at a problematic intensity or not. A patient was
considered to be in a cluster if he/she had scores of 5 or less (on a 0 to 10 scale) on each of
the variables in the cluster. A score of 5 was used as the threshold for inclusion in the SxCl
subgroup given extensive evidence that a score of 5 or lower on an 11-point numeric rating
scale (NRS) indicates a problematic symptom intensity level, and the alignment of this
criterion with precedents in the cancer symptom control literature.30, 31 Patients were
classified, using this scoring algorithm, as either rating all symptoms within the cluster at
<5, SxCl(+), or not, SxCl(−). A separate classification category was used to represent death.
Examination of the relative likelihood of transitioning among the three mutually exclusive
states was accomplished using simple percentage summary statistics.
Markov Chain Monte Carlo—The relative likelihood of transitioning among the three
mutually exclusive states was explored using Markov Chain Monte Carlo (MCMC).
Separate MCMC models were created for transitioning from SxCl(−) to SxCl(+),
transitioning from SxCl(−) to death, from SxCl(+) to SxCl(−), and from SxCl(+) to death.
These models treated the proportion of patients transitioned as a Bernoulli process. The
models were each run using PROC MCMC in SAS, with 500,000 iterations and 10,000
burn-in iterations. These models adjusted for age at diagnosis, smoking pack years, gender,
race, marital status, education, stage of disease, treatment, chronic obstructive pulmonary
disease (COPD) status, and whether or not the patient had prior recurrences.
Results
Subjects
Of 3162 patients sent invitations to participate, 65 (2%) died before responding, 208 (7%)
refused, 389 (12%) did not respond, and 2500 (79%) consented and returned questionnaires.
Among the 2500 patients who returned questionnaires at >1 assessment point, 95 (4%)
provided insufficient data for analysis. Therefore, 2405 (76% of eligible subjects) were
included in the analyses. The left two columns of Table 1 describe the demographics, LC
characteristics and comorbidities of the 2405 patients who were, and the 757 who were not,
included in the analyses. Subjects who provided data were more likely to be never or former
smokers (P<0.001), to be married (P = 0.011), to have post-high school education (P
<0.0001), to have greater medical morbidity and to have been diagnosed with stage I LC (P
<0.0001). The number of patients returning questionnaires diminished at each assessment
point following diagnosis because of mortality. Data were available for years <1, 2, 3, 4, and
5 from 1828, 1244, 941, 738, and 482 subjects, respectively.
Symptom Cluster Delineation

Cluster Analyses—Non-parametric cluster analysis revealed the existence of a single
SxCl comprised of dyspnea, cough, and fatigue at each of the first five years after LC
diagnosis. Figure 1 presents a dendrogram of the year 1 cluster analysis. Cluster analyses for
years 2-5 were very similar. In each year, fatigue and dyspnea combined first, and,
excepting year 5 when cough first combined with pain, cough joined the fatigue/dyspnea
cluster before any other variables combined.
Factor Analyses—Exploratory factor analyses were performed for years 1-5 which
yielded the integrated scree plot in Fig. 2. The percentage of explained variance, factor
loadings, and eigenvalues of all factors identified by the year < 1 analysis are listed in Table
2. Year 2-5 factor analyses yielded similar results. A single dominant factor representing the
SxCl of fatigue, dyspnea, and cough was present at each year, with eigenvalues ranging
from 2.11 to 2.52. A second factor comprising emotional disturbance and either pain or
sleep also was detected in years 1 through 4. However the eigenvalue for this factor was
low, 0.28 to 0.49, and this factor did not differentiate substantially from other factors, as
depicted in Fig. 2. To further assess the consistency of the SxCl across years following lung
cancer diagnosis, 5000 bootstrapped factor analyses were performed with data from each
year. Using a factor loading threshold of >0.50, the percentages of bootstrapped samples that
yielded a factor containing the SxCl variables are listed in Table 3.
Latent Trait Analyses—The latent trait analysis confirmed the existence of two factors,
as depicted in Fig. 3. The first factor comprised fatigue, shortness of breath, and cough while
the second factor comprised emotional well-being and sleep items. The observed
coefficients within each factor are between 0.5 and 0.84 indicating that the linkages among
the variables within each factor are strong. The two factors are modestly correlated
(coefficient of −0.34). These results were consistent with those obtained through factor
analysis and cluster analysis.
Prevalence of the Symptom Cluster

As outlined in the Methods section, inclusion in the SxCl subgroup was based on rating all
three symptoms at an intensity level < 5. The percentage of patients experiencing the SxCl
remained stable after diagnosis and was 14.6%, 12.9%, 14.1%, 14.6%, and 15.4%, in years
1-5, respectively. The right-hand columns of Table 1 list characteristics of the 1828 subjects
with data at < year 1 who did (n=266) and did not (n=1562) experience the SxCl. Patients
with the SxCl were significantly more likely to be male (P <0.0001), have greater tobacco
exposure (P = 0.021) and to be current smokers (P = 0.004). They were also more likely to
have had radiation (43% versus 33%, P = 0.001) and a history of stroke (P = 0.02). Similar
patterns were noted in the SxCl(+) and SxCl(−) patients in years 2-5.
Transitions Between SxCl Defined States Over Time

Changes in the transition rates between the states of SxCl(+), SxCl(−), and death fluctuated
over time as depicted in panels A-D of Fig. 4 and were most marked in the transition
between years 1 and 2. The percentage of patients who died was highest between years 1
and 2 (49.8% for those that were SxCl(+) and 34.9% for those that were SxCl(−)) and fell
sharply thereafter, as depicted in Fig. 5, panel A. On an overall basis, more patients
transitioned from SxCl(+) to death than from SxCl(−) to death.
SxCl stability, as reflected by a lack of in between-year “inter-state” transitions increased

steadily over time, most markedly for the SxCl(+) state (Fig. 5, panel B). Between years 1
and 2, 18.8% of patients remained SxCl(+). In contrast, between years 4 and 5, 49.2% of
patients remained SxCl(+). The decrease in intra-state transitions over time was less
pronounced for the SxCl(−) state yet still notable. Between years 1 and 2, 58.0% of patients
remained SxCl(−), in contrast to the interval between years 4 and 5 when the percentage of
patients remaining SxCl(−) increased to 81.1%. . The rates of inter-state transitions, i.e., to
or from SxCl(+), were remarkably stable over time, as illustrated in Fig. 5, panel C. The
percentage of patients transitioning from SxCl(−) to SxCl(+) was consistently low, ranging
from 7.1% to 8.6%. Although higher, transition rates from SxCl(+) to SxCl(−) also remained
constant over time, ranging from 31.5% to 37.8%.
Determinants of State Transitions

The results of Markov Chain Monte Carlo models of “to death” and inter-state transitions
are listed in Table 4. Examining specific transitions between SxCl-defined states across all
study years revealed that undergoing surgery significantly lowered a patient’s probability of
dying but increased their probability of inter-state transitions, both SxCl(+) to SxCl(−) and
visa versa. Male survivors had a higher probability of transitioning to the SxCl(+) state and,
if SxCl (+), a lower probability of transitioning to the SxCl(−) state. Being married
significantly increased the probability of transitioning from the SxCl(+) state and reduced
the probability of death among SxCl(−) patients. Receipt of radiation and current smoking
increased the probability of transitions to the SxCl(+) state. Older age and the presence of
Stage IV lung cancer increased participants’ probability of dying. Lung cancer recurrence
significantly increased the probability of death among SxCl(−) patients.
Discussion
This study identified a SxCl of fatigue, dyspnea and cough that persisted across cluster,
factor, and latent trait analyses, and characterized its persistence over time in an eight-year
cohort of LC survivors. In so doing, the study yielded a number of observations with
potentially important implications for clinical practice and research. First, while presence of
the SxCl was not necessarily stable in an individual over time, transition rates between
SxCl(+) and SxCl(−) states in the group as a whole remained constant throughout the study
period and, after year 4, the SxCl was less likely to resolve in surviving patients. Second,
developing the SxCl was more likely among male survivors who underwent surgery,
received radiation, and were current smokers. The latter characteristics implicate pulmonary
injury as a sustaining factor for the SxCl.
Our results accord with reports of poor prognoses in LC patients manifesting SxCls during
the first year. 8, 11, 12, 32 A symptom cluster of fatigue, dyspnea, and cough has been
previously identified through quantitative32 and qualitative methods33 among patients with
LC up to 12 months following their diagnoses. Our findings add to this work by
demonstrating this SxCl’s strong association with death during the first one to two years
following a lung cancer diagnosis, as well as its increasing stability and diminishing
association with death over time. In addition, our findings may allow more precise
estimation of the SxCl’s association with demographics, disease characteristics, treatment
and medical comorbidities because our study cohort was not only followed longer but is also
significantly larger, n=2405, and more extensively characterized than previously described
LC cohorts.
While our analyses suggested that other clusters, e.g., pain or sleep disturbance with
emotional disturbance, might be present, these clusters did not meet our a priori criteria of
an eigenvalue >1. We assessed survivors for the symptoms described by prior authors, e.g.,
appetite disturbance, mood, pain, yet failed to detect previously identified clusters.10, 12 This
may be, in part, because our first sampling point occurred farther along in the LC trajectory
than the sampling time frame utilized by many investigators, and many of our participants
had completed cancer treatments prior to enrollment. This may suggest that some SxCls
resolve following active LC treatment.
Despite a remarkably stable prevalence of roughly 15% among LC survivors in this study,
the SxCl was not stable over time and frequent transitions occurred between SxCl-defined
states. High transition rates between the SxCl(+) and SxCl(−) states are not surprising given
the fact that patients’ LC treatments were frequently changing, particularly after year 1 when
some patients recovered from aggressive cure-oriented therapies. Additionally, patients’
disease burden changed over time, with some experiencing disease progression. Given these
dynamic processes, the stability of transition rates between the SxCl(+) and SxCl(−) states
(collectively 40% - 45% of survivors each year) across all study years is notable and
contrasts with the decreasing rates of “to dead” and increasing rates of intra-state transitions.
The patterns and determinants of “to dead” and inter-state transitions may shed some light
on the etiology of the SxCl. The fall in the “to dead” transitions and the rise in state stability
among both SxCl(+) and SxCl(−) patients with time (see Fig. 5, panels A and B) may
indicate that patients with greater disease burden are more likely to die in the first years
following diagnosis, which accords with current survival estimates. 34, 35 However, the
proportion of SxCl (+) patients who died dropped markedly after year 2 and still further after
year 4. This finding suggests that the SxCl may indicate a transitional phase prior to LC
death experienced by patients with worse prognoses in the first years following an LC
diagnosis. However, over time the SxCl becomes increasingly stable, possibly in association
with chronic pulmonary compromise. This inference is supported by the increased
prevalence of COPD among SxCl(+) patients, as well as the higher proportion of current
smokers, radiation recipients, and lung resection patients transitioning to the SxCl(+) state.
For clinicians, the implication would be that this SxCl suggests a poor prognosis in the near-
term but, with extended survival, the SxCl(+) is increasingly likely to arise from chronic
lung injury and that appropriate work-up and therapies should be initiated.
Limitations
Symptom clusters are an evolving construct and there are no specified, optimal analytic
methods for their discovery and validation.36 Hence, we adopted a sensitivity approach,
running multiple exploratory and confirmatory models to test the consistency of our results
in the presence of varying model assumptions. Each approach served overlapping analytic
purposes; however, model structures varied substantially. Reassuringly, all yielded

consistent results and overwhelmingly support the presence of a single SxCl.
Our 79% response rate was high. Nonetheless, participants who provided symptom data
differed in their demographics, tobacco use, LC characteristics and co-morbidities from
those eligible subjects who did not. This is a common occurrence in quality of life studies.37
The fact that non-participants were more likely to have higher stage LC and to be current
smokers suggests that those who did not provide data may have had greater symptom
burden. In this case, our data could underreport the impact of the SxCl. One could argue,
however, that patients who were too ill to complete a questionnaire would be readily
identified without the need for a complex identification of SxCl, making the present sample
more relevant and useful to potential applications in clinical practice. Additionally, our
requirement that a symptom be rated at an intensity of 5/10 is admittedly stringent. Prior
authors have utilized lower threshold ratings.9 Our results must be interpreted in light of the
fact that SxCl(+) survivors were severely burdened by their symptoms.
Conclusions
A single SxCl comprised of dyspnea, fatigue, and cough has a stable roughly 15%
prevalence among LC survivors up to five years following diagnosis but is not stable among
individuals, with the SxCl resolving in approximately 35% and developing in approximately
7% of survivors each year. In the first one to two years following a LC diagnosis, the SxCl
appears to be a marker for sicker patients at greater risk of death; however, after year 2 the
SxCl becomes increasingly stable and a marker for parenchymal lung injury.
Acknowledgments
This work was supported by the National Cancer Institute of the National Institutes of Health (grant numbers
R01-80127, R01-80354, R01-80115857).
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Figure 1.
Dendrogram of <1 cluster analysis.
Figure 2.
Cumulative scree plots for factor analyses of data from years <1 through 5.
Figure 3.
Latent variable structure derived from the modeled data.
Figure 4.
Frequencies of transitions between symptom cluster-defined states and death over the first
five years following lung cancer diagnosis. SxCl = symptom cluster.
Figure 5.
Alterations over time first five years following lung cancer diagnosis in the probability of
dying and transitioning between symptom cluster-defined states. SxCl = symptom cluster.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Table 1
Characteristics of Patients Who Did and Did Not Provide Symptom Data and of Patients with and without the Symptom Cluster at Year ≤1 After Lung
Cancer Diagnosis
Subjects Invited to Participate in Long-term Subjects with Symptom Data at ≤ 1 Year

Cheville et al.
Lung Cancer Follow-up Study after Diagnosis with Lung Cancer

Data Data
P value SxCl (+) SxCl (−) P value*
available Unvailable
N = 2405 N = 757 N = 266 N = 1562
Demographics
Age mean (SD) 67.4 (10.7) 66.6 (10.8) 0.148 67.3 (9.6) 65.7 (11.0) 0.042
Gender, % Female 47.7 51.5 0.069 32 49.9 <0.001
Race, % Caucasian 93.6 92.8 0.445 92.9 94.5 0.102
Marital status, % 0.011 0.672
Married 79.2 72.8 79.8 80
Single 3.8 4.1 2.7 3.7
Divorced 6.9 10.8 9 6.7
Widowed 10 12.2 8.5 9.5
Education beyond high school, % 51.5 42.2 <0.001 42.3 49.7 0.086
Tobacco Exposure
Status at study intake, % <0.001 0.004
Current smoker 29.9 37.2 35.3 27.3
Former smoker 53.2 41.7 52.6 54.1
Never smoker 16.9 21.2 12 18.6
Pack years mean (SD) 48.6 (30.6) 50.8 (30.6) 0.155 53.1 (31.4) 47.5 (29.5) 0.021
Lung Cancer Characteristics and
Treatment
Stage, % <0.001 0.005
I NSCLC 41.2 29.3 31.4 41.2
II NSCLC 8.8 10.2 7.8 7.4
III NSCLC/Limited SCLC 28.2 34.6 37.1 27.6
IV NSCLC/Extensive SCLC 21.8 28.7 21.2 23.4
Cell Type, % 0.057 0.056
Adenocarcinoma 50.8 47.9 42.9 51.9
Page 15
Subjects Invited to Participate in Long-term Subjects with Symptom Data at ≤ 1 Year

Lung Cancer Follow-up Study after Diagnosis with Lung Cancer
Data Data
P value SxCl (+) SxCl (−) P value*
available Unvailable
N = 2405 N = 757 N = 266 N = 1562
Cheville et al.
Squamous cell carcinoma 22.0 19.9 29.3 21.4

Large cell carcinoma 2.6 2.6 2.6 2.0
Adenosquamous carcinoma 1.3 1.5 1.5 1.5
NSCLC unspecified 8.2 12.8 9.4 8.1
Small cell lung cancer 7.6 9.5 9.0 8.0
Surgery, % 64.1 59.0 0.030 57.1 62.4 0.104
Received chemotherapy, % 54.3 42.6 <0.001 58.3 55.3 0.361
Received radiation therapy, % 35.2 31.5 0.116 42.9 32.5 0.001
Medical Comorbidity
Asthma, % 4.9 4.4 0.568 0.4 3.3 0.009
COPD, % 19.8 12.5 <0.001 10.5 9.5 0.615
Stroke, % 0.7 0.1 0.067 3.8 1.6 0.018
Diabetes, % 1.5 0.5 0.038 1.1 2.2 0.24
Heart disase, % 3.5 0.5 <0.001 4.9 5 0.941
Hypertension, % 6.0 1.7 <0.001 4.9 6.6 0.291
SxCl = symptom cluster; NSCLC = non-small cell lung cancer; SCLC = small cell lung cancer.
a
P-values represent the results of t-tests for continuous variables and Chi-square tests for categorical variables. COMP: PLS REPLACE ASTERISKS IN TABLE WITH SUPERSCRIPT ITALIC a.
Page 16
Table 2
Results of Year ≤ 1 Exploratory Factor Analysis Including Factor Loadings > 0.5, Eigenvalues, and
Percentage of Variance Explained
Variable Factor 1 Factor 2 Factor 3 Factor 4

Fatigue 0.68
SOB 0.67
Cough 0.5
Sleep 0.51
Emotional −0.54
Pain
Cognitive Thinking
Appetite
Eigen value 2.11 0.34 0.1 0.04
Percentage of
variance explained by 82% 13% 4% 2%
the factor
Table 3
Percentage of Times That Specific Symptoms with Loadings ≥ 0.5 Were Included in the Dominant Factor (Factor 1), Based on 5000 Bootstrapped
Samples with Varimax Rotation
<=1 Year 2nd Year 3rd Year 4th Year 5th Year
Cheville et al.
Fatigue 91% 98% 95% 91% 98%

Dyspnea 84% 91% 91% 85% 97%
Cough 49% 91% 92% 80% 66%
Pain 26% 21% 17% 12% 30%
Sleep 15% 6% 7% 15% 2%
Emotional Disturbance 0% 0% 0% 0% 0%
Appetite 0% 0% 0% 0% 0%
Cognitive 0% 0% 0% 0% 0%
Page 18
Table 4
Odds Ratios and 95% Confidence Intervals of Demographic, Disease and Treatment Characteristics for
Transitions Between Symptom Cluster-Defined States and Death, Based on 500,000 Markov Chain Monte
Carlo Replications
Variable SxCl(+) → SxCl(−) SxCl(+) → Dead SxCl(−) → SxCl(+) SxCl(−) → Dead

Any Surgery 4.69 (1.62-11.91) 0.16 (0.05-0.33) 2.91 (1.44-5.09) 0.15 (0.10-0.22)
Stage IV* 0.34 (0.08-0.93) 4.05 (1.21-10.02) 1.34 (0.64-1.74) 5.17 (3.08-7.92)
Male 0.42 (0.18-0.82) 1.63 (0.69-3.28) 1.69 (1.15-2.46) 1.15 (0.84-1.52)

Married 2.44 (1.03-5.06) 0.76 (0.29-1.75) 0.98 (0.63-1.51) 0.70 (0.49-0.99)
Age at Diagnosis† 1.00 (0.97-1.03) 1.05 (1.01-1.09) 1.02 (0.99-1.04) 1.03 (1.02-1.05)
Any Chemotherapy 1.19 (0.46-2.58) 2.84 (1.06-6.63) 1.14 (0.64-1.81) 1.14 (0.74-1.64)
Any Radiation 1.12 (0.47-2.25) 0.99 (0.39-2.04) 2.05 (1.27-3.20) 1.00 (0.66-1.43)
Caucasian Ethnicity 2.09 (0.47-6.62) 1.31 (0.26-4.42) 3.17 (1.10-8.37) 1.98 (0.86-4.09)
Current Smoker 0.99 (0.40-2.05) 1.23 (0.43-2.69) 2.46 (1.34-3.97) 0.89 (0.52-1.38)
Recurrent Lung Cancer 0.69 (0.26-1.42) 1.41 (0.52-3.20) 0.69 (0.37-1.15) 3.93 (2.60-5.84)
Beyond High School Education 1.53 (0.81-2.75) 0.82 (0.52-3.20) 0.81 (0.56-1.13) 0.94 (0.71-1.24)
Pack Years† 1.00 (0.99-1.01) 1.00 (0.99-1.01) 1.01 (1.00-1.01) 1.00 (0.99-1.01)
Stage III* 0.61 (0.25-1.29) 2.15 (0.86-4.63) 1.10 (0.64-1.74) 1.55 (0.99-2.30)
*
Relative to Stage I non-small cell lung cancer.
†
Continuous variables.
COMP: PLS REPLACE ASTERISK and DAGGER IN TABLE & LEGEND WITH SUPERSCRIPT ITALIC a and b.

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J Pain Symptom Manage. 2011 August ; 42(2): 202–212. doi:10.1016/j.jpainsymman.2010.10.257.

Fatigue, Dyspnea, and Cough Comprise a Persistent Symptom

Physicians typically confine consideration of symptoms to their role as diagnostic clues or as

Study Questionnaire Components Utilized in This Study

Information from Electronic Medical Records

5 from 1828, 1244, 941, 738, and 482 subjects, respectively.

Symptom Cluster Delineation

Prevalence of the Symptom Cluster

Transitions Between SxCl Defined States Over Time

SxCl stability, as reflected by a lack of in between-year “inter-state” transitions increased

Determinants of State Transitions

injury as a sustaining factor for the SxCl.

purposes; however, model structures varied substantially. Reassuringly, all yielded

different impact on quality-of-life outcomes. J Pain Symptom Manage. 2008; 35(2):162–170.

606–612. [PubMed: 170482]

Cancer Nurs. 2008; 31(5):E1–10. [PubMed: 18772651]

Subjects Invited to Participate in Long-term Subjects with Symptom Data at ≤ 1 Year

Lung Cancer Follow-up Study after Diagnosis with Lung Cancer

Subjects Invited to Participate in Long-term Subjects with Symptom Data at ≤ 1 Year

Squamous cell carcinoma 22.0 19.9 29.3 21.4

Percentage of Variance Explained

Variable Factor 1 Factor 2 Factor 3 Factor 4

Fatigue 91% 98% 95% 91% 98%

Variable SxCl(+) → SxCl(−) SxCl(+) → Dead SxCl(−) → SxCl(+) SxCl(−) → Dead

Male 0.42 (0.18-0.82) 1.63 (0.69-3.28) 1.69 (1.15-2.46) 1.15 (0.84-1.52)

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