Introduction
Lung cancer currently leads new cancer diagnoses
and causes of cancer deaths worldwide, according
to GLOBOCAN 2018 statistics.[] Its most frequent
subtype is non-small cell lung cancer (NSCLC),
which often presents at an advanced stage. Progression
occurs frequently even in local disease that is initially
amenable to local therapy. Activating mutations
in epidermal growth factor receptor (EGFR) gene are
found in 5-15% of Caucasian patients with NSCLC
and sensitize the disease to EGFR tyrosine kinase inhibitors
(TKIs).[,] Among these agents, erlotinib is
a first-generation EGFR TKI which showed superior
efficacy to cisplatin-based chemotherapy in frontline
treatment of stage IIIB-IV NSCLC patients harboring
activating EGFR mutations, as reported in Phase III
trials.[,] Subsequently, it became one of the recommended
first-line options for advanced NSCLC with
activating EGFR mutations.[]
Sarcopenia can be defined as progressive and generalized
muscle loss accompanied by decline in muscle
function and is recognized as an essential component
of cancer cachexia syndrome.[,] As a consequence
in oncology practice, sarcopenia increases drug toxicity,
decreases response to therapy and is a prognostic
indicator of survival in solid tumors.[,] Sarcopenia
has a reported prevalence of more than 50% among
NSCLC patients and was demonstrated to predict
survival independently.[,] Targeted drugs are
increasingly used during management of advanced
NSCLC with actionable mutations and although they
are prescribed at a fixed starting dose, toxicities are
experienced at different levels between individuals.
Given this observation, body composition might also
be a potential factor affecting treatment tolerability in
NSCLC patients receiving targeted agents. Nonetheless,
a few studies have assessed whether sarcopenia
had an impact on outcomes of EGFR-mutant NSCLC
patients receiving TKIs so far. This study aimed to
evaluate the association between pre-existing sarcopenia
and adverse events (AEs), treatment response,
and survival in NSCLC patients harboring an EGFR
mutation who received first-line erlotinib.
Methods
Study Design and Patient Selection
Medical records of patients with histologically proven
NSCLC who were followed up in medical oncology department of our institute between August 2012 and
September 2019 were evaluated retrospectively. Inclusion
criteria were as follows: (1) Confirmed EGFR
mutation in the pathology department of our institute;
(2) receiving erlotinib in first-line treatment for
unresectable stage III or IV NSCLC; (3) 18F-fluorodeoxyglucose
positron emission tomography/computed
tomography (CT) (18F-FDG PET/CT) performed
within 3 months before erlotinib treatment and images
of which were available in nuclear medicine department
of our institute (Fig. 1). Demographic data,
height, weight, and performance status according to
Eastern Cooperative Oncology Group (ECOG) criteria,
comorbidities and smoking history were determined
from patient records. Disease stage (according
to AJCC TNM Staging System, 8th Edition), sites of
distant metastasis and EGFR mutation type were also
recorded. EGFR mutation was detected with real-time
polymerase chain reaction in tissue specimens obtained
before the treatment, using BIO-RAD CFX96®
(Bio-Rad Laboratories, Inc., USA) and Amoy Dx®
EGFR 29 Mutations Detection Kit (Amoy Diagnostics,
China). Body mass index (BMI) was calculated
as weight (kg)/square of height (m2). The Institutional
Ethics Committee granted an approval for this study
and waived the informed patient consent.
Fig 1: Selection of study patients.
NSCLC: Non-small cell lung cancer; EGFR: Epidermal
growth factor receptor; PET/CT: Positron emission tomography/
computed tomography; TKI: Tyrosine kinase inhibitors.
Data Regarding Treatment
All patients had started erlotinib with a standard dose
of 150 mg/day. Information regarding treatment efficacy
and safety was acquired from patient files. Dates of
treatment initiation and discontinuation were recorded.
Toxicities were graded according to Common Terminology
Criteria for Adverse Events Version 5.0. In addition,
it was noted whether dose reduction (to 100 mg/
day), dose interruption, or permanent discontinuation
due to treatment-related AEs had occurred. Treatment
response was assessed using Response Evaluation Criteria
in Solid Tumors Version 1.1 and objective response
rate (ORR) was defined as the percentage of patients
who had either complete or partial response. It was also
determined whether disease had progressed during
or after erlotinib and dates of progression were noted.
Dates of last visit and, if occurred, death were obtained.
18F-FDG PET/CT Scan, Image Analysis and
Assessment of Sarcopenia
All patients had underwent whole-body 18F-FDG PET/
CT (GE Discovery ST; GE Healthcare, Milwaukee, WI,
USA) imaging and multislice CT was performed with
a multidetector ST helical scanner using slip ring technology. All patients fasted for 6 h before PET/CT scan.
After approximately 1 h, a multislice CT scan of areas
from the upper thigh to skull base in shallow breathing
patient was performed using a 16-slice multidetector
scanner (Parameters: 80 mA, 140 kV, table speed
27 mm/rotation, and slice thickness 5.0 mm). A standard
whole-body PET scan was performed in 3D mode
with an acquisition time of 4 min per bed position (five
to seven bed positions) covering the same field as the CT scan. Acquired data were reconstructed using an
iterative algorithm and CT images without contrastenhancement
were acquired for attenuation correction.
Next, acquisition data were transferred to a workstation
(Advantage Windows Server 3.2-Etx. 3.4; GE
Healthcare, Milwaukee, WI, USA) for manual segmentation
and interpretation. CT images were reviewed in
transaxial, coronal and sagittal planes, and evaluated
by two experienced nuclear medicine physicians.
Third lumbar vertebra (L3) was set as the anatomical
landmark to measure cross-sectional total skeletal
muscle area (TMA) because it was demonstrated to accurately
reflect overall muscle mass.[] TMA of each
patient was computed with specific tissue demarcation
of abdominal wall, paraspinal, and psoas muscles at L3
level (Fig. 2). To isolate tissue voxels, thresholding was
applied with Hounsfield unit values between -29 and
+150 for muscles. To assess sarcopenia, skeletal muscle
index (SMI) of each subject was calculated as TMA (in
cm2) divided by square of height (in m2).[] Cutoff
values of SMI for sarcopenia were accepted as per the
definition of Prado et al., which was most commonly
associated with prognosis in solid tumors: <52.4 cm2/
m2 for males and <38.5 cm2/m2 for females.[,]
Fig 2: Graphical representation of the steps of the
manually multi-atlas segmentation method
used by Advantage Windows Workstation 4.5
to segment the muscles. Using transaxial CT
images of FDG PET/CT, the area of muscles
were delineated using a CT-attenuation range
of -29 to 150 HU at the L3 vertebral spine level.
FDG: Fluorodeoxyglucose; PET/CT: Positron emission
tomography/computed tomography; HU: Hounsfield
unit.
Statistical Analysis
Descriptive data were recorded as frequencies and
percentages. Continuous variables were presented as
median values with interquartile ranges. Categorical
variables were compared using Chi-square test. Progression-
free survival (PFS) was defined as the time
interval in months between start of erlotinib treatment
and disease progression, death, or last visit if
the patient was still alive. Overall survival (OS) was
defined as the time interval in months between diagnosis
of metastatic disease and death or last visit
if the patient was still alive. Survival was estimated
with Kaplan-Meier method and log-rank test. Cox
proportional models were conducted to select factors
affecting survival significantly or with a trend toward
significance (p<0.1) in univariate analysis and to determine
independent prognostic indicators in multivariate
analysis using a backward step-wise method.
Confidence interval (CI) was accepted as 95% and
p<0.05 was set for statistical significance. All data
were analyzed with the software "SPSS Version 22"
(IBM Corp. Released 2013. IBM SPSS Statistics for
Windows, Version 22.0. Armonk, NY: IBM Corp.).
Results
Patient Characteristics
Thirty patients were found eligible for the study and
their characteristics are shown in Table 1. Most patients
were female (60%) and median age was 65
(54-71) years. ECOG performance status was 0 or 1
in 23 patients (76.7%), and 22 patients (73.3%) were
unsmoker. Half of the patients had at least one comorbid
disease, with hypertension, diabetes mellitus,
and chronic obstructive lung disease being most common.
Except three patients with stage IIIB disease,
all cases had stage IV disease at the beginning of erlotinib
treatment. Most common sites of metastasis at
baseline were pleura (43.3%), bone (40%), and distant
lymph nodes (26.7%); and rate of brain metastasis
was 20%. Half of patients had two or more metastatic
sites. EGFR exon 19 deletion and exon 21 L858R mutation
were each detected in 14 patients, one patient
had an activating mutation in exon 18 and another
one had an insertion in exon 20.
Table 1: Baseline patient characteristics
Sarcopenia was identified in 11 patients (36.7%).
Among 16 overweight or obese patients (BMI 25-30 kg/m2 or >30 kg/m2), 3 (18.7%) were sarcopenic, whereas
eight out of 14 patients who were underweight (only one
patient) or had normal weight (BMI <18.5 kg/m2 or 18.5-
24.9 kg/m2) had sarcopenia (57.1%). One notable difference
was that sarcopenia was more frequent among patients
with two or more metastatic sites, which had a trend
toward statistical significance (53.3% vs. 20%, p=0.058).
Treatment Tolerability and Response
Median duration of erlotinib exposure was 9.3 (4.9-
14.9) months. Treatment-related AEs of any grade had
occurred in 21 patients (70%). Most frequent toxicities
were rash (60%), fatigue (33.3%) and diarrhea (13.3%).
Four patients (13.3%) had experienced Grade 3 AEs;
two had rash, one had hand-foot syndrome, and one
had conjunctivitis. Due to toxicity, erlotinib dose was
reduced to 100 mg/day in 4 patients (13.3%), interrupted
in one patient and discontinued in one.
Patients with sarcopenia experienced numerically
more treatment-related AEs than non-sarcopenic patients
but the difference was not statistically significant
(81.8% vs. 63.2%, p=0.282). Of Grade 3 toxicities
rash and hand-foot syndrome were seen in sarcopenic
group, while rash and conjunctivitis in non-sarcopenic
group (18.2% vs. 10.5%, p=0.552). Dose was reduced
in three non-sarcopenic and one sarcopenic patient
(15.3% vs. 9.1%, p=0.603).
There was a partial response in 20 (66.7%), progressive
disease in 8 (26.7%), and stable disease in 2 patients (6.7%). The patient with exon 18 deletion had a partial
response, and the subject with exon 20 insertion had
progressive disease. ORR was 66.7% in the whole study
population and was similar in both groups (63.6% in sarcopenic
and 68.4% in non-sarcopenic group, p=0.789).
The presence of any comorbidity was not associated
with all-grade AEs (p=0.690), Grade 3 or 4 AEs (p=0.283),
dose reduction (p=0.283), and ORR (p=0.439).
Survival
At final analysis, 28 patients (93.3%) had progressed
during erlotinib treatment. Median PFS of all patients
was 9.2 months (95% CI, 7.6-10.7). Patients without
sarcopenia had a median PFS of 9.3 months (95% CI,
7.7-10.8) whereas sarcopenic patients had a median PFS
of 7.9 months (95% CI, 1.0-14.9). This PFS difference
was not statistically significant (p=0.561) (Fig. 3). PFS of
patients with and without comorbidity was also statistically
similar (9.3 and 9.2 months, respectively; p=0.707).
Total of 23 patients (76.7%) had died at final analysis.
Median OS of all patients was 21.5 months (95%
CI, 6.8-36.2). Median OS was 30.2 months (95% CI,
9.7-50.8) and 11.8 months (95% CI, 3.6-19.9) in nonsarcopenic
and sarcopenic groups, respectively. As
demonstrated in Fig. 4, the difference in OS was statistically
significant (p=0.023). Univariate Cox regression
model showed that sarcopenia affected OS significantly,
while ECOG performance status showed a trend toward
statistical significance in predicting OS (p=0.029 and 0.054, respectively). In multivariate analysis, sarcopenia
was found as an independent prognostic factor
for OS (Hazard ratio=2.63, p=0.029) (Table 2).
Fig 3: Progression-free survival plots of patients stratified
by sarcopenia status.
Fig 4: Overall survival plots of patients stratified by sarcopenia
status.
Table 2: Univariate and multivariate analyses of prognostic factors for overall survival
Discussion
In oncological practice, muscle loss is an important
and prevalent condition which has been generally
associated with negative treatment outcomes. Our
study revealed that baseline sarcopenia is an independent
prognostic factor in patients with EGFR-mutant
NSCLC receiving erlotinib. Although sarcopenia has
been extensively studied in NSCLC patients so far, our
study is the first report to demonstrate the prognostic
value of pre-treatment sarcopenia in EGFR-mutant
NSCLC treated with erlotinib in first-line setting.
Sarcopenia has been recognized as a significant
prognostic factor in various malignancies, such as colon,
breast, and gastric cancer.[-] As far as lung
cancer is concerned, muscle loss was shown to predict
mortality in both NSCLC and small-cell subtype.[,]
(Table 3). Sarcopenia was also described as a negative prognostic factor in NSCLC patients receiving immune
checkpoint inhibitors.[] However, patients with
EGFR mutation compose a distinct subgroup of NSCLC
and impact of sarcopenia on oncological outcomes has
not been investigated sufficiently in this population. To
date, two studies have addressed this issue. First, Arrieta
et al.[] found a non-significant trend toward shorter
survival in sarcopenic patients with metastatic NSCLC
to whom afatinib was administered after progression
on chemotherapy. Second, Rossi et al.[] showed that
muscle loss was a significant prognostic factor in a retrospective
analysis including 33 patients with metastatic,
EGFR-mutant NSCLC who received gefitinib. In line
with these studies, we demonstrated a remarkable difference
in OS between sarcopenic and non-sarcopenic
NSCLC cohorts who received erlotinib, and sarcopenia
corresponded to an approximately 2.6-fold elevated risk
of death. This outcome is especially interesting because
there was no substantial difference between sarcopenic
and non-sarcopenic groups in terms of response and
PFS. Only two patients in the whole study cohort had
to interrupt or discontinue treatment due to intolerance.
Although sarcopenic patients tended to experience more treatment-related AEs, differences in toxicity
rate and dose reduction were not statistically significant.
As highlighted in baseline characteristics, patients with
more metastatic sites were more likely to have sarcopenia.
After, it can be hypothesized that this association develops
naturally because tumor burden induces muscle
wasting through increased catabolism.[] In the face of
these findings, shorter OS of sarcopenic patients in our
study might be explained by impaired immunity and
increased frailty due to protein degradation along with
systemic inflammation, which have been addressed as
possible mechanisms underlying the prognostic impact
of muscle loss in cancer cachexia.[,,]
Table 3: Studies of sarcopenia in lung cancer patients receiving systemic treatment. These studies were all retrospective
and used CT images to assess sarcopenia
For patients receiving anticancer therapy, pre-existing
sarcopenia is also known to be associated with
treatment-related toxicities. This observation may
be linked to altered body composition, which causes
changes in distribution, metabolism, and clearance of
antineoplastic drugs.[] Previously, sarcopenia was
reported to predict severe toxicities in hepatocellular
or renal cell cancer patients receiving anti-angiogenic TKIs such as sorafenib or sunitinib.[,] One of the
studies focusing on EGFR-mutant NSCLC revealed
that malnourishment and sarcopenia were significant
predictors of severe gastrointestinal and dose-limiting
toxicity during afatinib treatment.[] Sarcopenic patients
also tended to develop more frequent and severe
cutaneous rash related to gefitinib.[] Our research
demonstrated that there was a trend toward increased
all-grade and Grade 3 AEs associated with erlotinib in
sarcopenic patients, which, however, was not statistically
significant. Taking the small sample size into account,
we suggest that this finding might be clinically relevant
and sarcopenic NSCLC patients should be carefully
monitored for toxicity during erlotinib treatment.
Our study is mainly limited by its being done in single-
center and retrospective design, which can cause
selection bias. Furthermore, relatively small sample
size might have precluded numerical differences translating
into statistical significance and thus have complicated
interpretation of the results. We analyzed CT
images at L3 level because it has previously correlated with whole-body muscle mass. However, a major concern
when using SMI for assessment of sarcopenia was
the selection of optimal cutoff values because these
have varied across geographic regions and publications
in the literature. We selected cutoff values that were
most commonly used in the previous studies investigating
sarcopenia in solid tumors.[] Despite all limitations,
we could demonstrate the prognostic value of
sarcopenia in our study.
Conclusion
Pre-treatment sarcopenia is obviously a significant
prognostic marker also in NSCLC patients with
EGFR mutation receiving erlotinib. Nutritional interventions
and countermeasures to ameliorate muscle
loss can therefore help improving long-term survival
in this subpopulation. Our results need to be tested
further in larger studies, which may clarify the prognostic
importance of sarcopenia in NSCLC patients
under erlotinib treatment.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by the
Marmara University Faculty of Medicine Clinical Research
Ethics Committee (no: 09.2020.1107, date: 02/10/2020).
Financial Support: None declared.
Authorship contributions: Concept - N.C.D., T.Ö., P.F.Y.;
Design - N.C.D., T.Ö., P.F.Y.; Supervision - N.C.D., Ö.E.,
F.D., T.Ö., P.F.Y.; Funding ? None; Materials - C.Ö.E., S.Ö.,
T.Ö.; Data collection and/or processing - N.C.D., C.Ö.E.,
T.A.T, T.B., R.A., A.Y., A.Ç., Ö.A., S.I., H.K.; Data analysis
and/or interpretation - N.C.D., Ö.E., F.D., T.Ö, P.F.Y.; Literature
search - N.C.D., P.F.Y.; Writing - N.C.D., T.Ö., P.F.Y.;
Critical review - N.C.D., T.Ö., P.F.Y.
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