Prognostic Factors in Patients with Terminal
Stage Lung Cancer
Ryo Matsunuma, MD,1Yuichi Tanbo, MD,1Nobuhiro Asai, MD,4Yoshihiro Ohkuni, MD,4Satoshi Watanabe, MD,3
Shinya Murakami, MD, PhD,2Yukimitsu Kawaura, MD, PhD,2and Kazuo Kasahara, MD, PhD3
Background: Lung cancer is the leading cause of cancer-related death.1Accurate prediction of survival in the
terminal stage is important, because it may help patients make a rational decision. Although several prognostic
scores have been described as effective indicators of outcome, these scores were intended for patients with other
types of cancers. There is no prognostic score for patients with terminal-stage lung cancer.
Objective: The aim of this study was to determine prognostic factors for patients with terminal-stage lung
Setting/Subjects: Patients in our palliative care unit (PCU) were selected retrospectively and divided into two
independent groups, training and testing. Univariate and multivariate analyses were performed on data from the
training group to detect independent prognostic factors, while data from patients in the testing group were
analyzed to validate whether these prognostic factors predicted near-term death.
Results: Ninety-three patients (69 in the training group and 24 in the testing group) were included in the
analyses. Multivariate analysis showed that fatigue, anorexia, desaturation, hyponatremia, and hypoalbumi-
nemia were independent prognostic factors in the training group. Mean survival time in patients who had more
than three of these five factors was 9.2–2.6 days (p=0.012). In the testing group, the presence of more than
three of these five factors predicted death within two weeks, with a sensitivity of 100% and specificity of 75%.
Conclusions: This study revealed that fatigue, anorexia, desaturation, hyponatremia, and hypoalbuminemia
may be short-term prognostic factors in terminally ill lung cancer patients. In particular, the presence of more
than three of these factors predicted death within two weeks.
death.1It is estimated that about 70,000 patients died
from lung cancer in Japan in 2011.1In addition, since ter-
minally ill lung cancer patients commonly present with
symptoms such as dyspnea, cough, sputum, and malaise,2
these patients are generally thought to need palliative care. In
Japan, patients with cancer sometimes receive care at palli-
ative care units (PCUs). These units are staffed by special
doctors and nurses who have expert training in palliative
care.3As a result, terminally ill patients suffering from sev-
eral cancer-related symptoms receive special treatment in
PCUs, compared with care provided in general hospitals. A
research study reported that about 40% of Japanese patients
hope to receive various care in PCU in the terminal stage of
ung cancer is the leading cause of cancer-related
their disease.4However, there is a shortage of beds in PCUs,
because there are only a few specialists and nurses for pal-
liative care in Japan.1Indeed, the number of patients who die
from lung cancer every year in Japan is approximately
500,000, whereas there are only 5000 PCU beds in the
country.5Accordingly, more and more home care doctors
have begun to take care of patients at home, and physicians
who do not specialize in oncology or pulmonology are re-
quired to care for patients with lung cancer.
Accurate prediction of survival in terminally ill lung can-
cer patients is important for physicians, since it may help
them make a rational decision about the best location for care
(i.e., home care, hospice, or PCU). Several studies have
treatment with opioids and/or glucocorticoids,6poor Kar-
nofsky performance status (KPS),7
and poor Eastern
1Department of Respiratory Medicine,2Department of Surgery, The Komatsu Municipal Hospital, Komatsu City, Japan.
3Department of Respiratory Medicine, The University of Kanazawa, Kanazawa, Japan.
4Department of Pulmonology, Kameda Medical Center, Kamogawa, Japan.
Accepted October 3, 2013.
JOURNAL OF PALLIATIVE MEDICINE
Volume 17, Number 2, 2014
ª Mary Ann Liebert, Inc.
Cooperative Oncology Group (ECOG) performance status
patients. In particular, general symptoms, psychosocial well-
being,10and quality of life11–14have been suggested as
prognostic factors in patients with lung cancer. Moreover,
prognostic scores such as the palliative prognostic score
(PaP)15and the palliative prognostic index (PPI)16have been
reported tobe effectiveindicators of prognosis.These studies
included patients with a variety of cancers and focused on
determining appropriate prognostic factors for cancer pa-
ill cancer patients. However, there are no predictive prog-
nostic scores for patients with lung cancer in the terminal
Therefore, the aim of this study was to investigate factors
in patients with lung cancer in the terminal stage in order to
establish lung cancer specific prognostic factors.
This retrospective study was performed at Komatsu
Municipal Hospital, a 364-bed community hospital in Ko-
matsu City, Ishikawa, Japan. This hospital is the only fa-
cility treating lung cancer in this area of 230,000 people. In
2012, 367 patients were newly diagnosed with lung cancer
at this hospital, while only 31 patients (8.4%) were admitted
to the PCU. Patients who met the following inclusion cri-
teria were included in the study: (1) lung cancer confirmed
pathologically or clinically and (2) admission to the PCU in
the hospital from April 2009 to June 2012 (training group)
and from July 2012 to June 2013 (testing group). In our
PCU, patients with malignancy who had not received any
specific anticancer therapy at the time of admission except
for palliative chemotherapy and radiation therapy were
admitted voluntarily. This study protocol was approved
by the institutional review board of Komatsu Municipal
Factors of analysis
Clinical data were collected by review of electronic
medical records. Twenty-six candidate predictors were cho-
sen from published clinical studies as potential predictive
factors.6–9,15,16All of the patients were examined at the time
of admission to the PCU. In addition to laboratory parame-
ters, several scales designed specifically for measurement of
physical status were measured. The EPS uses a scale from 0
to 5, with 0 denoting perfect health and 5 death.17The KPS is
prognosis in the PCU were calculated: the PaP score and the
PPI score. The PaP score includes anorexia, dyspnea, total
white blood count, and lymphocyte percentage in conjunc-
tion with the KPS and expert clinical prediction of survival.15
The PPI, originally defined by the Palliative Performance
Scale (PPS), also includes measurements of oral intake,
edema, dyspnea at rest, and delirium.16Blood examination
data were collected within one week from the registration.
Continuous variables of the factors were divided into two
categories as follows: age (<70, ‡70); KPS (<50, ‡50);
EPS17(<4, ‡4); PaP (<11, ‡11); PPI (<6, ‡6); body
temperature (BT) (<37.1, ‡37.1?C); oxygen saturation
(SpO2; <93%, ‡93%); white blood cell (WBC) (<8500,
‡8500 cells/lL); lymphocyte (Lym) (<20%,
C-reactive protein (CRP) (<0.03, ‡0.03mg/dL); lactase
dehydrogenase (LDH) (<230, ‡230IU); sodium (Na; <135,
‡135mEq/L); calcium (Ca; <8.6, ‡8.6mg/dL); blood urea
nitrogen (BUN; <17, ‡17mg/dL); and albumin (Alb; <2.7,
‡2.7g/dL). The cut-off points for BT, SpO2, WBC, CRP,
LDH, Na, Ca, and BUN were set at the value that demarcated
the normal and abnormal ranges, whereas Alb was based on
the median value.
To identify factors correlated with survival, the log rank
test was performed using the 26 candidate predictors in the
training set. Factors that were significantly related with
survival were extracted, and multivariate analysis was
performed for these factors using the Cox proportional
hazards regression model. Finally, to determine the number
of factors predicting short-term death, patients were divided
into groups categorized by the number of factors that were
estimated to be independent prognostic factors in multi-
variate analysis. The appropriate number of the factors was
defined as the cut-off point in our study. The validity of the
prediction was then examined on all assessments in the
testing set. In addition, to determine sensitivity and speci-
ficity, and the positive predictive value (PPV) and negative
predictive value (NPV) in this study, the PaP and PPI scores
were compared in order to measure the accuracy of pre-
dicting short-term death.
Differences were assumed to be significant when the
p-value was <0.05. Continuous variables with a normal
distribution were compared using Student’s t-test and the
Wilcoxon rank-sum test for nonnormally distributed vari-
ables. The v2 statistic or Fisher’s exact test were used to
compare categorical variables. Survival rates were analyzed
using the Kaplan-Meier method. Overall survival time (OS)
was calculated from admission until death and included data
from other facilities. All the analyses were performed using
SPSS 20.0.0 (SPSS, Armonk, NY).
Patient characteristics are shown in Table 1. A total of 69
patients were eligible for participation in the training group
and included 38 men (51%) and 31 women (49%). Twenty-
two of the 69 patients (32%) died within two weeks, and the
remaining 47 (68%) survived for longer than two weeks. The
mean age of patients in the training group was 75–10 years.
Fifty-one (74%) patients had received antitumor therapy
common histologic type (n=35, 51%). The median overall
survival forall 69patients was 30days.The characteristics of
the patients in the testing group are summarized in Table 1.
This shows that the mean age of the patients was 73–7.9
years, 8 patients (33%) were female, and 17 patients (71%)
had received antitumor therapy. The median survival time of
patients in the testing group was 26 days. The patient char-
acteristics in the two groups were not significantly different
(see Table 1).
2MATSUNUMA ET AL.
Analysis of prognostic factors
The results of univariate analysis using the log rank test in
patients in the training group are shown in Table 2. Eight
of 26 parameters were associated significantly with survival,
namely the PaP (p<0.0001), desaturation (p<0.0001),
supplemental oxygen (p=0.002), anorexia (p=0.002), fa-
tigue (p=0.003), dyspnea (p=0.031), hypoalbuminemia
(p=0.0015), and hyponatremia (p=0.014). Multivariate
analysis was then used to analyze the prognostic significance
of these eight factors (see Table 3). Multivariate analysis
showed that fatigue (p=0.001, hazard ratio [HR]: 5.90, 95%
confidence interval [CI]: 2.04–17.0); anorexia (p=0.023,
HR: 2.57, 95% CI: 1.14–5.88); desaturation (p=0.005, HR:
3.30, 95% CI: 1.42–7.65); hyponatremia (p=0.049, HR:
2.17, 95% CI: 1.01–4.68); and hypoalbuminemia (p=0.037,
HR: 2.37, 95% CI: 1.05–5.36) were considered independent
factors predicting short-term prognosis.
We divided the patients into two groups having either 0–2
of these factors (0–2 group) or >3 of these factors (3–5
group). The mean survival time of the two groups was ana-
lyzed using the Kaplan-Meier method. As shown in Figure 1,
9.2–2.6 days in the 3–5 group.
These results indicate clearly that more than three of these
five factors predicted death within two weeks in patients with
terminal lung cancer. We then analyzed the sensitivity,
specificity, PPV, and NPV to predict death within two weeks
in the training group. When more than three items were used,
the sensitivity was 59%, specificity 94%, PPV 77%, and
In the testing group, the presence of more than three of the
five factors predicted death within two weeks with a sensi-
tivity of100% andspecificity of75%.Incomparison, thePaP
predicted death within three weeks with a sensitivity of 21%
and specificity of 100%, while the PPI predicted death within
four weeks with a sensitivity of 66% and specificity of 100%
(see Table 4).
This study revealed that suffering from fatigue, anorexia,
desaturation, hyponatremia, and hypoalbuminemia may be
prognostic factors in terminally ill lung cancer patients. In
particular, the presence of more than three of these factors
could be used to predict death within two weeks. These
factors may also be useful for untrained personnel in PCUs
Table 1. General Characteristics of the Patients
in the Training and Testing Sets
Age, years (mean–SD)
Female sex (n)
Antitumor therapy, n (%)
Survival days (median)
2 weeks death, n (%)
Adenocarcinoma, n (%)
carcinoma, n (%)
carcinoma, n (%)
LCNEC, n (%)
Others, n (%)
Not detected, n (%)
7 (10)5 (21)0.29
EPS, Eastern Cooperative Oncology Group performance status;
KPS, Karnofsky performance status; LCNEC, large cell neuroen-
docrine carcinoma; SD, standard deviation.
Table 2. Univariate Analysis of Predictors
for Survival According to Patients’ Backgrounds,
Symptoms, Treatments, and Laboratory Findings
PaP score (‡11)
Alb, albumin; BT, body temperature; BUN, blood urea nitrogen;
CRP, C-reactive protein; EPS, Eastern Cooperative Oncology
Group performance status; KPS, Karnofsky performance status;
LDH, lactate dehydrogenase; Lym, lymphocytes; PPI, palliative
prognostic index; PPS, palliative prognostic score; WBC, white
Table 3. Multivariate Analysis
of Factors Predicting Survival
Serum sodium (<134mEq/L)
Serum albumin (<2.6g/dL)
CI, confidence interval.
PROGNOSTIC FACTORS FOR LUNG CANCER PATIENTS3
because the factors were either categorical variables (i.e.,
positive or negative) or continuous measured values.
MacEachern and colleagues stated that experienced phy-
of 48%–64% and a specificity of 73%–91%.19Therefore, the
values obtained in the present study (100% sensitivity and
75% specificity in the testing group) were acceptable for
predicting death within two weeks using a cut-off point of
three of the identified factors.
Desaturation, i.e., low blood oxygen concentrations, was
also correlated with prognosis in this study. Generally, pa-
tients with chronic hypoxia, such as those with chronic ob-
structive pulmonary disease (COPD), suffer from anorexia.20
Adaptation to low oxygen tension (hypoxia) in cells and
tissues is regulated by hypoxia-inducible factor-1 (HIF-1)
and leads to the transcriptional induction of a series of genes
that participate in angiogenesis, iron metabolism, glucose
metabolism, and cell proliferation/survival.20,21HIF-1 in-
duced by hypoxia in COPD patients is assumed to be re-
sponsible for changes in various metabolism factors that
result in anorexia and body weight loss. This suggests that
hypoxemia could be correlated to anorexia in terminally ill
lung cancer patients as well, although the relationship be-
tween anorexia and HIF-1 in these patients is not yet clear.
Hypoalbuminemia was also related to mortality in our
study. Hypoalbuminemia is generally seen in terminal cancer
patients due to the presence of anorexia and chronic inflam-
mation in association with cachexia. In addition, hypoalbu-
minemia is related to malnutrition, and both of these
characteristics are common in patients with lung cancer.22
Malnutrition has been associated with a number of clinical
consequences, including deterioratedquality oflife, decreased
have found that higher serum albumin levels are associated
with better survival in multivariate analyses.26,27In this
two weeks; indeed, the presence of anorexia may be related
to hypoalbuminemia. In a similar fashion, malnutrition and
anorexia were correlated with hyponatremia, also an in-
dependent prognostic factor for survival. Deficiencies in
sodium intake caused by anorexia seem to bring about hy-
ponatremia.Similarly, Castillo and colleagues demonstrated
that hyponatremia is an independent risk factor for poor
outcomes in patients with small-cell lung cancer.28
The PaP15and the PPI16are prognostic predicting scores
used in terminally ill patients. In contrast to our study, which
only investigated lung cancer patients, studies describing the
PaP and PPI15,16have included patients with various types of
cancer, such as lung, stomach, breast, pancreas, colorectal,
and bladder cancer, among others. Moreover, anorexia is
common to the PPS and the PPI, while fatigue, hyponatremia,
and hypoalbuminemia are not included in the PPS and PPI.
Morita and colleagues suggested that although the effects of
disease-related pathology and psychosocialfactors onsurvival
are controversial, some clinical symptoms, such as perfor-
mance status, nutritional disturbance (e.g., anorexia, lowered
oral intake, weight loss, edema, dysphagia), dyspnea espe-
cially at rest, and delirium are useful prognostic indicators.
Therefore, lowered oral intake, edema, dyspnea, and delirium
detail, these clinical factors (lowered oral intake, edema,
dyspnea) may be appropriate symptoms due to their associa-
tionwithcachexiainprognosticscores. Similarly inour study,
the presence of cachexia indicated a poor prognosis and pre-
dicted short-term survival. Unlike anorexia, desaturation dif-
fered between the PaP and PPI. Hypoxemia is a common
symptom in patients with advanced cancer, estimated as a
moderate or severe problem in 46% of those admitted to a
palliative care program, and is thought to affect 70% of hos-
pice inpatients.29This hypoxemia is likely due to the presence
of pleural effusion, constriction of trachea, atelectasis, lym-
phangitis, pulmonary embolism, and pneumonia, which could
lead to dyspnea, a condition commonly seen in advanced
cancer patients.30,31In particular, most terminally ill lung
cancer patients need oxygen supplementation due to their
desaturation.2Therefore, desaturation is a characteristic factor
in terminal patients with lung cancer, and oncologists and
stages of the disease to give insight into predicted survival.
analysis that included a very small population. Second, we
did not use an objective tool to evaluate the symptoms of
terminally ill cancer patients. Third, only patients who were
Survival curves of the 0–2 and 3–5 groups in the
Table 4. The Sensitivity, Specificity, Positive
Predictive Value, and Negative Predictive
Value for Pap And PPI in this Study
PaP, palliative prognostic score; PPI, palliative prognostic index.
JPM-2013-0448-ver9-Matsunuma_2P.3d01/15/146:38am Page 4
4 MATSUNUMA ET AL.
admitted to our PCU were evaluated in our study. In the real
world, many terminal lung cancer patients die in hospitals,
nursing homes, and their own homes in Japan. Finally, since
this was a retrospective study, it is possible that some se-
lection bias was present. Therefore, further prospective
studies using objective tools and more patients will be re-
quired to confirm and expand upon these results.
This study revealed that fatigue, anorexia, desaturation,
hyponatremia, and hypoalbuminemia may be factors pre-
dicting prognosis in terminally ill lung cancer patients. In
particular, the presence of more than three of these factors
predicted death within two weeks with a high degree of
specificity and sensitivity. Since the number of lung cancer
patients is estimated to increase year by year, clinicians who
do not specialize in oncology or pulmonology will be re-
quired to treat these terminally ill patients. Therefore, these
findings may be helpful for clinicians to make decisions.
Further prospective studies to confirm the significance of
these results are warranted.
We are grateful for the diligent and thorough critical
reading of our manuscript by John Wocher, executive vice
president and director, International Affairs/International
Patient Services, Kameda Medical Center (Japan). We also
appreciate the expert assistance with the statistical analyses
in the study provided by Kazuki Yoshida, research fellow,
Division of Rheumatology, Immunology and Allergy, Brig-
ham and Women’s Hospital (United States).
Author Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Ryo Matsunuma, MD
60 Ho Mukaimotoori-machi
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