Introduction
Brain metastases are present in 20% of the patients at
initial diagnosis of small cell lung cancer patients and in
autopsy series, 80% of the patients have been detected
with brain metastases.[] New treatment approaches are under evolution for the treatment of brain metastases
in small cell lung cancer. Prophylactic cranial irradiation
in limited-stage small cell cancer decreases
by 25% the development of cranial metastases and provides
survival advantage.[] After EORTC (European
Organization for Research and Treatment of Cancer) prospective randomized study, prophylactic cranial
irradiation became the standard treatment in extensive-
stage small cell lung cancer patients responding to
chemotherapy, too.[] However, another randomized
study performed in Japan did not demonstrate survival
advantage as observed in the EORTC study when the
patients were followed regularly by cranial MRI.[]
In small cell lung cancer patients with brain metastases,
cranial radiotherapy is the standard treatment.
Although chemotherapy can cross the blood-brain
barrier and provides a certain response in the presence
of brain metastases, chemotherapy itself cannot replace
radiotherapy.[] In a phase III EORTC study, Teniposid
alone was insufficient to control brain metastases
in comparison to Teniposid administered together
with cranial irradiation.[] In patients with isolated
cranial metastases, cranial irradiation provided a 50%
response rate and 55% neurologic control with 5.4
months response duration. However, cranial recurrence
is inevitable despite radiotherapy.[] Today with
the integration of immunotherapy to chemotherapy,
which provides better systemic control and survival,
the probability of cranial recurrence risk may increase.
In case of intracranial recurrence after cranial radiotherapy,
treatment choices are restricted. Cranial
re-irradiation may be an option and secondary cranial
irradiations were reported in the literature for solid
tumors.[] However, due to the detrimental effects of
cranial irradiation on cognitive functions, [-] cranial
re-irradiation may be proposed only to symptomatic
patients and for palliative intent. Stereotactic
radiotherapy (SRT), on the other hand, maybe less
detrimental concerning cognitive functions and can
be a better option for cranial re-irradiation.[,]
However, due to extensive cranial involvement in small
cell lung cancer, SRT can be an alternative treatment
only in selected cases, and data about the subject are
restricted. SRT can be offered to cranial metastases
when they are detected with a limited number and volume.
These kinds of metastases can be found when the
patients are followed regularly with cranial MRI after
prophylactic cranial radiotherapy or after treatment of
cranial metastatic disease.[]
In this study, we tried to investigate the role of
stereotactic re-irradiation in small cell lung cancer patients
who had relapsed after cranial radiotherapy.
Methods
Thirty-six small cell lung cancer patients who had
intracranial recurrence after total cranial irradiation and who were treated with salvage SRT in our clinic
between June 2010 and January 2019 were evaluated
retrospectively.
The patients were treated with a frameless robotic
radiosurgery system (Cyberknife -Accuracy Incorporated,
Sunnyvale, CA, USA). The gross tumor volumes
were determined from T1 weighted MRI images with
contrast. Planning target volume (PTV) was obtained
by adding a 1-2 mm margin to the gross tumor volume
(GTV). Median 20 Gy (10-24 Gy) was administered
in 1 to 4 fractions depending on the volume and relation
of the tumor with critical structures. Treatment
responses were evaluated according to the RECIST criteria.
Overall survival was calculated from the time of
primary diagnoses to death or last follow-up, and SRT
survival was calculated from the time of SRT treatment
to death or last follow-up. The time interval between
whole-brain irradiation and stereotactic radiotherapy
was calculated from the first day of whole brain radiation
therapy (WBRT) and SRT. All the patients were
included in the survival analysis. Patients who died
within three months after SRT were considered as early
deaths even in the absence of radiologic evaluation. These
patients were considered as neurologic deaths. Recursive
partitioning analysis (RPA), treatment volume,
chemotherapy administration after SRT, the interval
between WBRT and SRT, systemic disease status at the
time of SRT, the reason for initial cranial radiotherapy;
prophylactic or treatment of cranial metastases, and
initial stage of disease were all evaluated.
Statistical analysis was performed using SPSS version
17.00. A p-value of less than 0.05 was considered
significant. Kaplan-Meier method was used for survival
analysis and Cox, Log-rank analysis was performed.
Results
In this study, 29 out of 36 patients were male (80.6%),
and 7 were female (19.4%). Karnofsky performance
status of all the patients was between 80 to 100. Mean
age of the patients was 58.9 (min: 30, max: 81). Patients
were divided into two groups according to their age,
the patients between 30-59 years (16 patients), and the
ones above 60 years of age (20 patients). At the time
of initial diagnoses, 26 patients (72.3%) were staged
as limited-stage disease and 10 patients (27.7%) as
an extensive-stage disease. Whole brain radiotherapy
was performed for cranial prophylaxis in 16 patients
(44.5%) and for the treatment of brain metastases in 20
patients (55.5%). SRT was administered for intracranial recurrence after whole brain irradiation with two
fractions (range 1-3), and 20 Gy (range 10-24 Gy).
While thirteen patients (36%) were in the RPA1 group,
23 patients (64%) were in the RPA2 group. SRT was
performed for single metastases in 22 patients (61.2%),
for two to three metastases in 12 patients (33.3%) and
for more than four metastases in two patients (5.5%).
Mean SRT volume was 8 cc (min; 0.5, max; 57.6). Neurologic
symptoms like headache, ataxia, and epilepsy
were present before SRT in 24 patients. While no cranial
recurrence was observed in 11 out of 36 patients
(30%) during the follow-up, 12 patients (33.3%) had
recurrence outside the SRT volume, and one patient
(2.7%) had a recurrence in the SRT volume. Twelve
patients (33.3%) died within three months after SRT
without radiological evaluation.
Median follow-up time after SRT was 5.5 months.
Median time interval between WBRT and SRT was
11 months. Median survival was 30.2 months from
the time of initial diagnoses. One, two and three years
survivals were 91.7%, 63.9%, 36.1%, respectively. Median
one and two years survival after SRT were 33%
and 6.6%, and median survival was 4,1 months (Fig. 1).
Four patients were still alive at the last follow up date
(June-2019).
Fig 1: Post SRT life expectancy.
When we look at the prognostic factors like gender,
age, disease stage at initial diagnoses, the aim of WBRT,
RPA, the number of metastases, volume of metastases,
we did not observe any effects of these prognostic factors
on survival. While the median survival of patients who
were treated with salvage SRT after 11 months from the
initial WBRT was 13.5 months, it was only 3.3 months
when this interval was below 11 months (p<0.05). In
patients with controlled systemic disease, while the survival
was 14.4 months, it was 9.2 months for patients with stable disease, and only 2.9 months in patients with
uncontrolled systemic disease (p<0.05). In multivariate
analysis, the only time interval between WBRT and
SRT was found to be significant for survival after SRT
p=0.014 (HR: 2.66 95% CI:1.21-5.82) (Table 1).
Table 1: Post SRT life expectancy
Two-year local control rate was 86%. One patient
was operated for local recurrence 15 months after SRT.
This patient is still alive with intracranial control at the
last follow-up date. Median cranial control (Infield-
+outfield disease control) time was 12.8 months. One
year cranial control rate was 57%, and a two-year cranial
control rate was 15%.
When the factors that had an effect on cranial control
(Table 2), one- and two-years neurologic progression-
free survivals were 47.3% and 12.6%, respectively.
Median neurologic progression-free survival was 10.3
months.
Table 2: Post SRT cranial control
When 13 patients who died within three months after
SRT were evaluated, we realized that these patients
had a shorter interval between WBRT and SRT, and
they had neurologic symptoms more than the others
(Chi-square p=0.05).
Discussion
Cranial involvement is one of the most important
causes of death in small cell lung cancer patients.
[] In extensive-stage disease, an EORTC phase II
study demonstrated that brain control was the most
important prognostic factor for survival.[] After
several randomized studies, comparing whole brain
radiotherapy with stereotactic radiotherapy in the
treatment of cranial metastases of solid tumors rather
than small cell lung cancer, stereotactic cranial radiotherapy became the standard treatment due to better
quality of life, and better preservation of cognitive
functions.[] However, whole brain irradiation is
still the standard treatment in small cell lung cancer
due to extensive intracranial involvement. There are
studies investigating the role of SRT in small cell lung
cancer.[] Robin et al. reported better survival (10.8
months versus 7.1 months) with SRT in their observational
study comprising 5752 whole brain irradiation
and 200 stereotactic irradiation.[] Multivariate
analysis with SRT, including comorbidity, age, gender,
ethnicity, disease stage and SRT, demonstrated survival
advantage with SRT. Studies are needed to better
investigate the role of SRT in the treatment of cranial
metastases from small cell lung cancer.
Local treatments in solid tumor cranial metastases
play an important role. Inclusion of whole brain radiotherapy
after surgical resection of cranial metastases
or the addition of SRS (stereotactic radiosurgery) to
whole brain radiotherapy in single brain metastases
provides survival advantage.[,] Whole brain radiotherapy
is the preferred treatment in small-cell lung
cancer due to the disseminated involvement of brain.
[] On the other hand, Bernhardt, in a retrospective
analysis, demonstrated better prognosis with surgery
in treatment of single brain metastases of small cell
lung cancer.[] Local approaches have not been tested
sufficiently in the treatment of small cell lung cancer
patients. There is not much treatment alternative after
cranial recurrence in patients who underwent whole
brain radiotherapy either for cranial prophylaxis or for
cranial metastases. SRS may be investigated in these patients,
especially with a limited number of metastases.
Cranial recurrence is inevitable despite cranial radiotherapy
and carries a worse prognosis in small cell
lung cancer. In our study, median overall survival after
SRT was not sufficient and only found as 4.1 months.
Several retrospective series demonstrated survivals
ranging from 4.5 months to 16.9 months with salvage
SRT in small cell lung cancer patients after cranial
relapse.[-] In the study reported by Harris, they
found 57% local control rate, and they expressed the
insufficiency of SRT with a dose of 18 Gy in local control
of the cranial metastases.[] In addition to radiation,
dose is important in local control, they also found
that chemotherapy administration played an important
role in cranial disease control. In a series where
SRT dose was above 20 Gy, the local control rates were
found between 85-90%.[-] In our study, only one
patient had local recurrence with 85% local control
rate.
Harris et al., in their study, reported cranial recurrence
rate as 58% in 1-year and 75% in two years after
salvage SRT.[] Distant brain failure was observed
within three months. The most important factor for
distant brain recurrence was the presence of multiple
cranial metastases.[] Nakazaki et al. reported a 50%
recurrence risk within six months, especially with a
higher incidence in patients with multiple brain metastases
and meningeal involvement.[] In our study, the
median brain control time was 12.8 months with a control
rate of 57% in one year.
Recursive partitioning analysis (RPA) [] and
graded prognostic assessment (GPA) were the two
validated scoring systems to investigate the survival
in patients with brain metastases.[] While RPA
considers the age, extracranial disease and performance
status of the patients, GPA considers the histologic
diagnosis, as well. In recurrent cranial metastases
while these scoring systems can be utilized,
new scoring system proposals are also present.[]
In recurrent metastases and re-irradiated patients,
low-performance scores, the presence of extracranial
disease and small cell histology were associated with
poor prognosis.[] We did not find RPA as a prognostic
factor in our patients.
Yamamoto et al. have shown that SRT has the same
efficacy even in patients with more than four intracranial
metastases in solid tumors.[] Other than tumor
volume, the number of intracranial metastases does
not preclude treatment with SRT. There are retrospective
studies demonstrating no detrimental effect
of the number of intracranial metastases treated with
SRT in patients with small-cell lung cancer.[,]
Nakazaki et al. reported the prognostic significance of
the number of intracranial metastases.[] While in series
where no difference was observed concerning the
number of metastases, SRT was performed only for one
to four metastases. Nakazaki et al. treated more than
four cranial metastases with SRT besides one to three
metastases, too. In their study, 39% of the patients received
SRT for more than 10 metastases (median 5).
The prognosis was worse for patients with more than
10 metastases in this study.[] A significant number
of patients in our study received SRT for one to four
metastases and no correlation was observed between
the number of metastases and survival.
Age, small target volume, the interval between
WBRT and salvage SRT, systemic control of the primary
disease, KPS, number of metastases, and histology
were found to be prognostic in patients treated
with salvage SRT arising from different primary tumors, including small cell lung cancer.[] Nakazaki
et al. found that the number of metastases, meningeal
involvement, tumor size, and KPS as prognostic factors
for patients undergoing salvage SRT.[] Sheehan, on
the other hand, found KPS, tumor volume, the interval
between initial diagnoses and cranial recurrence as
prognostic for salvage SRS.[]
Hariss et al. defined systemic disease control and
concomitant chemotherapy as prognostic for salvage
SRT.[] We found the time interval between WBRT
and salvage SRT as a prognostic factor for our patients.
Bernhardt et al. found chemotherapy resistance as
the most important prognostic factor in multivariate
analysis in small cell lung cancer patients with single
brain metastases.[] Systemic disease control outside
the brain has an effect on the results. We think that intracranial
disease control becomes important in small
cell lung cancer if systemic disease can be controlled.
Brain tissue is different from other tissues by its different
microenvironment and its special immune system
and blood brain barrier. Although chemotherapy
provides a response, no survival benefit was seen with
chemotherapy.[] In phase III randomized RTOG
study in non-small cell lung cancer, brain metastases,
the addition of erlotinib or temozolomide to the radiotherapy
increased the toxicity and decreased survival.
[] The role of targeted treatments and immunotherapies
are being investigated actively in NSCLC brain
metastases. There are few data demonstrating the efficacy
of chemotherapy in small cell lung cancer patients
with brain metastases. Harris et al. reported better survival
when chemotherapy continued after salvage SRT.
[] The better result with chemotherapy may be due
to the extracranial disease control.[,] In our study,
patients with extracranial disease control had better
survival as well. Systemic disease control determines
the prognosis after salvage SRT. In patients under systemic
disease control or patients who have effective
treatment for the systemic disease may have better results
after salvage SRT.
Conclusion
The most important limitation of our study is that
this study was performed retrospectively with a small
number of patients. At the same time, the radiologic
response could not be evaluated in all patients due to
early deaths. SRT should be considered as a treatment
alternative, especially in patients with long time intracranial
control after whole brain radiotherapy and
in patients with systemic disease control.
Peer-review: Externally peer-reviewed.
Conflict of Interest: None declared.
Ethics Committee Approval: This is a retrospective study.
Financial Support: None declared.
Authorship contributions: Concept - N.I., G.Y.; Design -
G.Y., C.G.; Supervision - C.G., Ö.A.; Funding - None; Materials
- N.I., Ö.A.; Data collection and/or processing - Ö.A.;
Data analysis and/or interpretation - N.I.; Literature search
- G.Y.; Writing ? C.G.; Critical review - N.I., G.Y.
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