Introduction
Lung cancer is still one of the leading cancer-related
deaths worldwide.[] Small-cell lung cancer (SCLC)
constitutes approximately 15% of all lung cancer cases.
The proportion of patients who can be diagnosed in
the limited stage is very low, accounting for only onethird
of cases.[] Definitive chemoradiotherapy (CRT)
and chemotherapy are the accepted standard treatment
modalities in limited-stage SCLC.[,] In responding
cases, prophylactic cranial irradiation (PCI) is routinely
added to standard therapy, especially since it contributes
to survival.[,]
Despite the treatments applied in SCLC, which has
the potential for early metastatic spread and has an
aggressive course, the survival rates cannot be as high
as desired.[] Therefore, there is a need for prognostic
markers that can identify high-risk patients and predict
survival. Prognostic markers related to survival
have been examined in many studies to date, age, gender,
performance status, tumor stage, the timing of radiotherapy
(RT), PCI, lactate dehydrogenase (LDH),
and C-reactive protein (CRP) are some of these
markers.[-] The most important prognostic factor
among these is the stage. Although SCLC has traditionally
been staged according to the Veterans Affairs
classification, the tumor-node-metastasis (TNM)
classification has also been found to be prognostic for
survival and direct correlation between both T and
N stage and survival has been demonstrated.[] In
addition, it is known that the prognosis worsens as
the tumor volume increases.[] Previous data have
explained that good performance status, younger age,
and female gender are associated with improved prognosis.[-] Other prognostic factors are timing of RT
and administration of PCI.[-] The early timing
of RT with the first or second cycle of chemotherapy
is superior to delayed RT, with significant results on
survival.[-] In two consecutive meta-analyses
published before the 2000s, PCI was shown to reduce
the frequency of brain metastases and also improve
survival.[,] In addition to patient- and treatment-
related factors, several routine laboratory tests
have been associated with survival, including LDH,
CRP, albumin, sodium, creatinine, and bilirubin, and
pre-treatment evaluation with these laboratory tests is
useful in predicting survival.[,]
In this retrospective study, we aimed to examine the
survival outcomes in limited-stage SCLC treated with
definitive CRT and to evaluate the prognostic factors
that may affect survival.
Methods
Study Design and Patient Characteristics
Patients with limited-stage SCLC who underwent definitive
CRT at the Health Sciences University Samsun Training
and Research Hospital Radiation Oncology Clinic
between January 2012 and December 2020 were included
in the study. Patients who are older than 18 years of age,
have a pathological diagnosis, have undergone definitive
CRT, and have an Eastern Cooperative Oncology Group
performance status of 0-1 are inclusion criteria. Patients
with extensive-stage SCLC, patients who did not receive
concomitant chemotherapy, and patients who could not
complete RT were not included in the study.
98 patients diagnosed with limited-stage SCLC were
identified, and 83 patients were included in the study after
excluding 15 patients who did not receive concomitant
chemotherapy and received consolidation RT alone.
The demographic and clinical characteristics of patients
are displayed in Table 1. The majority of the patients were
male (84.3%) and the median age was 61 (36-84). 31.9%
of the patients were in the T4 stage and 74.3% were in the
N2 stage. According to the American Joint Committee
on Cancer (AJCC), the majority of patients were stage 3
(81.9%). Median 60 Gy (50-66 Gy) RT was applied. Thoracic
RT was given with 1st or 2nd chemotherapy in 68.7%
of the patients, and it was applied sequentially in 31.3%
of the patients. PCI was applied to 45.9% of the patients.
PCI was not performed in 38.5% of the patients due to
progression and/or brain metastasis. PCI could not be
performed in 15.6% of the patients due to patient preference
or not being referred by the physician.
Table 1: Patient characteristics
Approval was obtained from the ethics committee
of our hospital for our study, data were collected
in accordance with the Declaration of Helsinki, and
informed consent was not obtained because it was a
retrospective study.
Data Collection
Demographic features, clinical information, and laboratory
data of the patients were accessed through the
patient archive files and electronic medical records system.
Hemoglobin (Hb) level, LDH, CRP, and albumin
levels were recorded. Hb level <12 was defined as anemia,
LDH >225 U/L as elevated LDH, CRP >5 mg/L as
elevated CRP, and albumin <35 g/L as hypoalbuminemia,
and the values were categorized.
Staging and Treatment
Thorax computed tomography (CT) and CT of the
whole abdomen were performed in all patients for diagnosis and staging. Positron emission tomography/
CT (PET CT) was performed in some of the patients
for distant metastasis screening. Brain magnetic resonance
imaging (MRI) was performed to scan for brain
metastasis. The patients were classically staged according
to the Veterans Affairs Lung Study Group, and
TNM stages were also noted according to the 8th edition
of the AJCC.
Definitive CRT was applied concurrently with the
first or second chemotherapy in the majority of the
patients, and sequential CRT was applied in some of
the patients because the tolerance doses of the critical
organs due to the high treatment volume could not be
achieved. Thoracic RT was administered with a threedimensional
conformal technique, with a median of 60
Gy (50-66) at 1.8-2 Gy/fraction. Gross tumor volume
was drawn by drawing the primary mass and involved
lymph nodes. In patients who received chemotherapy,
the target volumes were determined according to the
post-chemotherapy volumes. The clinical target volume
was formed with the volume created by expanding this
defined volume by 0.5-0.8 cm. To prevent possible setup
errors and changes due to respiratory movements,
the planning target volume was created by giving this
volume a margin of 1-2 cm, depending on the location
of the primary mass. Position accuracy was ensured by
the kV imaging taken during the treatment. Concurrently with RT, cisplatin 75 mg/m2 (1 days), etoposide
100 mg/m2 (1-3 days) 1 or 2 cycles of chemotherapy
were administered at 21-day intervals. PCI was administered
with a three-dimensional conformal technique,
with a total dose of 25 Gy in 10 fractions.
Follow-up
The first evaluation with thorax CT was performed 1
month after the completion of CRT. Patients who completed
chemotherapy courses and achieved complete or
partial response were re-evaluated with brain MRI, and
PCI was applied to patients without metastases. Physical
examination, blood samples including blood count
and biochemical tests, chest X-ray or thorax CT were
followed up every 3 months for the first 2 years and then
every four to 6 months. In case of clinical necessity, PET
CT and brain MRI were performed. Response assessment
was performed according to the Response Evaluation
Criteria for Solids Tumors ver.1.1. Patients were followed
up regularly from the date of diagnosis to March
2022, or the date of death. The primary endpoints of the
study were overall survival (OS), progression-free survival
(PFS), and local regional recurrence-free survival
(LRRFS). Secondary endpoints were to identify all prognostic
factors such as stage, the timing of RT, and PCI. In
addition, to avoid potential bias, a subgroup of patients
who underwent PCI and did not undergo PCI due to patient
demand or non-referral by a physician was defined.
OS was defined as the interval from the date of diagnosis
to the date of death or last follow-up. PFS was
calculated as the interval from the date of diagnosis to
the date of disease progression or death or last follow-up.
LRRFS was calculated as the interval from the date of diagnosis
to the local recurrence, death, or last follow-up.
Statistical Analysis
SPSS version 25.0 (IBM Corp., Armonk, NY, USA)
software was used for statistical analysis. Categorical
variables were expressed as numbers and percentages,
continuous variables were displayed as medians. Kaplan-
Meier method was used to calculate OS, PFS, and
LRRFS, and differences were assessed using the Logrank
test. The Cox proportional hazard regression model
was performed to evaluate the potential prognostic
variables. P<0.05 was indicated statistical significance.
Results
At a median follow-up of 14 (3-83) months, 5 of the patients
were alive at the final follow-up. While primary
disease recurrence was observed in 31 patients, distant metastases were detected in 51 patients. Median OS
was 16 months (95% CI, 11.9-23.3), 1-y, 2-y, and 4-y OS
rates were 62.4%, 31.8%, and 10.9% (Fig. 1a). In univariate
analysis, gender (p=0.546), age (p=0.936), tumor
stage (p=0.678), tumor size (p=0.856), nodal stage
(p=0.740), RT dose (p=0.249), timing of RT (p=0.331),
hypoalbuminemia (p=0.081), anemia (p=0.723), LDH
(p=0.914), and CRP (p=0.517) were not found to be effective
on survival. In subgroup analysis, median OS
was 26 months (95% CI, 18.2-33.7). PCI was statistically
significant on OS, with 2-y OS rates of 62.5% and
27.5% (p=0.045; 31 months vs. 19 months) (Table 2 and
Fig. 2a). There was a trend on survival with PCI, but
not statistically significant in multivariate regression
analysis (p=0.055; HR 2.11 95% CI 0.98-4.53) (Table 3).
Fig 1: (a) Kaplan-Meier graphs of OS for patients. (b)
Kaplan-Meier graphs of PFS for patients. (c) Kaplan-
Meier graphs of LRRFS for patients.
OS: Overall survival; PFS: Progression-free survival; LRRFS:
Local regional recurrence-free survival.
Fig 2: (a) Kaplan-Meier graphs of OS; impact of PCI. (b)
Kaplan-Meier graphs of PFS; impact of PCI. (c)
Kaplan-Meier graphs of LRRFS; impact of PCI.
OS: Overall survival; PCI: Prophylactic cranial irradiation;
LRRFS: Local regional recurrence-free survival.
Median PFS was 11 months (95% CI, 9.1-12.8),
and 1-y, 2-y, and 4-y PFS rates were 38.5%, 20.5%,
and 8.5% (Fig. 1b). In univariate analysis, gender
(p=0.719), age (p=0.586), tumor stage (p=0.538), tumor size (p=0.225), nodal stage (p=0.966), RT dose
(p=0.203), timing of RT (p=0.251), anemia (p=0.714),
LDH (p=0.940), and CRP (p=0.886) were not found to
be effective on survival. Hypoalbuminemia was found
to be statistically significant on PFS (p=0.033) (Table
2 and Fig. 3a). In multivariate regression analysis, hypoalbuminemia
was independently prognostic on PFS
(p=0.022; HR 2.24 95% CI 1.12-4.48) (Table 3). In subgroup
analysis, median PFS was 19 months (95% CI,
13.3-24.6). The median PFS was 21 versus 14 months
in patients with and without PCI, but this difference
was not statistically significant in the univariate analysis
(p=0.271) (Fig. 2b).
Median LRRFS was 14 months (95% CI, 12.1-
15.8), and 1-y, 2-y, and 4-y LRRFS rates were 50.2%,
26.9%, and 8.7% (Fig. 1c). In univariate analysis, gender
(p=0.397), age (p=0.168), tumor stage (p=0.589),
tumor size (p=0.736), nodal stage (p=0.337), RT dose
(p=0.726), timing of RT (p=0.139), anemia (p=0.885), LDH (p=0.494), and CRP (p=0.579) were not found to
be effective on survival. Hypoalbuminemia (p=0.044)
was found to be statistically significant on LRRFS
(p=0.017; 14 months vs. 9 months) (Table 2 and Fig.
3b). In multivariate regression analysis, hypoalbuminemia
was shown to be independently prognostic
on LRRFS (p=0.032; 2.08 (1.06-4.08) (Table 3). In
subgroup analysis, the median LRRFS was 21 months
(95% CI, 12.3-29.7). There was no difference between
the groups in terms of LRRFS with the application of
PCI (p=0.196) (Fig. 2b).
Fig 3: (a) Kaplan-Meier graphs of PFS; impact of hypoalbuminemia. (b) Kaplan-Meier graphs of LRRFS; impact of hypoalbuminemia.
PFS: Progression-free survival; LRRFS: Local regional recurrence-free survival.
Table 2: Univariate analysis for overall survival, progression-
free survival, and local regional recurrence
free survival
Table 3: Multivariate cox regression analysis for overall survival, progression-free survival, and local regional recurrence
free survival
Discussion
In our single-center retrospective study, survival outcomes
in limited-stage SCLC treated with definitive
CRT were evaluated and its relationship with factors
affecting survival was examined. PCI was found to be prognostic on OS in univariate analysis, but failed to
show an association with OS in multivariate analysis.
Low albumin levels at the time of diagnosis were also
found to negatively affect PFS and LRRFS.
The strengths of this study are as follows. Extensive
stage patients and patients who were not given concomitant
chemotherapy were not included in the study
concept. In addition, patients with a performance status
of at most 1 were included in the study because low
survival rates are known to be associated with poor
performance. So a more homogeneous patient group
could be formed.
The fact of PCI in SCLC is based on the following
findings from historical studies.[,] The risk
of brain metastases is quite high in SCLC patients.
Chemotherapy agents used in the standard treatment
of SCLC cannot penetrate the blood-brain barrier. Although
SCLC patients respond well to chemotherapy,
a high rate of brain metastases is encountered due to the limited effectiveness of chemotherapy agents to the
central nervous system. A significant contribution of
OS has been demonstrated with PCI for this purpose.
In a meta-analysis published in 1999, it was reported
that the incidence of 3-y brain metastasis decreased
with PCI (58.6% vs. 33.3%), 3-y OS increased significantly
from 15.3% to 20.7%.[] Subsequently, a second
meta-analysis was published in 2001 showing the
contribution of PCI to survival by reducing the incidence
of brain metastases.[] In this context, PCI has
been an accepted treatment approach for many years
in the treatment of limited-stage SCLC, as it both increases
survival and reduces the development of brain
metastasis. In our study, it was determined that PCI
contributed positively to survival in univariate analysis,
but it did not show a relationship with OS in multivariate
analysis.
However, an important consideration is response
assessment prior to PCI implementation. PCI is recommended
in patients with a complete or partial response
to the primary disease. In the patients included
in our study, PCI was not performed due to the
detection of progression and/or brain metastasis in
38.5% of the patients during restaging. On the other
hand, PCI could not be performed in 15.6% of the patients
due to patient preference or not being referred
by the physician. While PCI contributes significantly
to survival, the decrease in neurocognitive functions
is an undeniable side effect and therefore may not be
accepted by patients. It has been shown that the radiation
dose given to the hippocampus is associated with neurocognitive toxicity, and in this context, hippocampus-
sparing treatment approaches were primarily
investigated in patients receiving whole-brain RT for
brain metastases.[] In a recently published phase 3
study, 150 SCLC patients were randomized to hippocampal
avoidance-PCI or standard PCI and showed
significantly better neurocognitive function in the
hippocampal avoidance-PCI arm (5.8% vs. 23.5%,
p=0.003).[] It was also stated that there was no difference
between the two arms in terms of local brain
failure and OS, which were the secondary endpoints
of the study. There are also drugs being investigated to
preserve neurocognitive functions. 518 patients with
brain metastases were randomized to hippocampal
avoidance plus memantine or whole-brain RT plus
memantine. This phase 3 study demonstrated improved
neurocognitive functions with hippocampal
avoidance plus memantine, with no difference between
groups in terms of PFS and OS. Since successful
results have been obtained with the use of memantine
to preserve neurocognitive functions, it is now recommended
for whole-brain RT.[,] The decrease
in neurocognitive functions due to PCI is beyond the
scope of our study, but it should be applied to all patients
knowing that this concern can be relieved with
alternative methods instead of avoiding PCI.
Another important prognostic factor in limitedstage
SCLC is the early timing of thoracic RT. A metaanalysis
of 2140 patients with limited-stage SCLC including
13 studies showed a 14% reduction in mortality
with combined treatment with thoracic RT compared to chemotherapy alone.[] After meta-analysis results
showing that survival was significantly improved with
the addition of RT, studies were published examining
the effect of optimal timing of RT and sequencing of
chemotherapy on survival.[-] In the meta-analysis published by De Ruysscher, it was reported that 5-y OS
improved with the initiation of thoracic RT within the
first 30 days after the start of chemotherapy (OR: 0.64,
95% CI 0.44-0.92, p=0.02).[] Thus, RT initiated with
the first or second cycle of chemotherapy is superior
to delayed RT. In our study, although RT was applied
in the first 2 cycles in most of the patients, the survival
benefit could not be shown statistically.
In the first studies, it is known that a total of 45 Gy
RT was delivered in twice-daily fractions over 3 weeks.
[] However, it is not practical to apply twice a day in
terms of clinical functionality. Therefore, when compared
with conventional fractionation, studies have
shown that doses of 60-70 Gy have similar efficacy to
the hyperfractionated schedule.[-]. Two phase 3
randomized studies evaluating the efficacy of high dose
once-daily thoracic RT showed no superiority over
twice-daily accelerated thoracic RT, but both studies
showed similar survival with dose escalation.[,]
Hypofractionated treatments that shorten the
treatment day are quite indispensable. In this context,
in a phase 2 randomized study comparing twice daily
thoracic RT and 42 Gy once-daily thoracic RT for 3
weeks in both arms, the median OS was better in the
twice-daily arm, although no statistically significant
survival difference was demonstrated (p=0.61; 25.1
vs. 18.8 months).[] In an another phase 2 randomized
study comparing twice-daily thoracic RT with
higher-dose hypofractionated thoracic RT, a significant
difference in PFS was obtained with 65 Gy oncedaily
thoracic RT (p=0.031; 13.4 vs. 17.2 months).
[] Finally, a phase 2 randomized study compared
60 Gy twice-daily fractions for 4 weeks and 45 Gy
twice-daily fractions for 3 weeks. At 2 years, in the 60
Gy arm, 74.2% of the patients were alive, while 48.1%
were alive in the 45 Gy arm. It has been suggested that
60 Gy twice-daily thoracic RT can be an alternative to the standard twice-daily schedule.[] RT fractionation
studies are still ongoing.[] Today, one of
these alternative schedules can be selected according
to clinical functionality, physician, or patient preference.
The conventional schedule with a median of 60
Gy was used in our clinic.
Tumor size and lymph node involvement are also
among clinical factors known to be prognostic. According
to the Veterans Affairs Lung Working Group
in 1957, it was divided into two stages as limited and
extensive-stage based on tumor volume involving a
single radiation portal. This classification was found
to be prognostic on survival. When analyzed by the
International Association for the Study of Lung Cancer
by restaging 8088 SCLC patients according to
the TNM system, the effect of the TNM system on
prognosis was demonstrated.[,] However, in our
study, there was no difference because the majority
of the patients were stage 3 according to the 8th edition
of AJCC.
Until today, laboratory parameters were also
checked for prognosis, and Hb, LDH, and CRP values
were found to be correlated with survival.[,,-]
It is known that increased LDH and CRP values are
associated with tumor burden, and low albumin level
is one of the indicators of tumor-related cachexia and
malnutrition.[] In studies evaluating the prognostic
effect of albumin, it is often combined with other inflammatory
and nutritional parameters.[-] Zhou
et al.[] reported that the albumin/globulin ratio was
a predictive factor for OS, Yang et al.[] reported that
Hb, albumin, lymphocyte, and platelet score was an independent
prognostic factor for OS, and Hu et al.[]
showed that advanced lung cancer inflammation index
affects survival. In our study, no relationship was found
between anemia, LDH, and CRP and survival, but it
was shown that hypoalbuminemia negatively affects
PFS and LRRFS.
Limitations of the Study
Despite the long duration of the study, the small number
of patients who met the study criteria and the fact
that it was a single-center study can be said to be the
limitations of the study. Another is that the majority
of patients in the study were at an advanced stage according
to AJCC, which may have resulted in shorter
expected survival times than in other studies. The inability
to show a relationship between survival and factors
known to be prognostic may be due to the small
number of patients included in the study and the high
number of patients with advanced stages.
Conclusion
In our study, the addition of PCI improved survival
in patients with limited-stage SCLC who responded
to primary therapy in univariate analysis. There was a
trend on survival with PCI, but failed to show an association
with OS in multivariate analysis. The decrease
in neurocognitive functions due to PCI is beyond the
scope of our study, but it should be applied to all patients
knowing that this concern can be relieved with
alternative methods instead of avoiding PCI. In addition,
the decrease in albumin levels may also be important
in terms of prognosis.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by
the University of Health Sciences, Samsun Training and Research
Hospital Non-Interventional Clinical Research Ethics
Committee (no: 2021/20/15, date: 15/12/2021).
Financial Support: None declared.
Authorship contributions: Concept - E.D.S., E.O.; Design
- E.D.S., E.O., A.B.; Supervision - E.D.S., E.Ş., Z.E., E.A.A.;
Funding ? None; Materials - E.D.S., E.O., A.B., E.A.A.; Data
collection and/or processing - E.D.S., E.Ş., Z.E., E.A.A.; Data
analysis and/or interpretation - E.D.S., Z.E., A.B., A.A.; Literature
search - E.D.S., E.Ş.; Writing - E.D.S., E.O., A.A.;
Critical review - E.D.S., A.A.
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