Prognosis of Patients with Brain
Metastasis from Non-Small Cell Lung Cancer According to Gefitinib
Administration
Eriko Ayabe,
Kyoichi Kaira, Hideyuki Harada, Haruyasu Murakami, Asuka Tsuya, Yukiko
Nakamura, Tateaki Naito, Masahiro Endo, Tetsuo Nishimura, Nobuyuki Yamamoto,
Toshiaki Takahashi
Eriko
Ayabe, Kyoichi Kaira, Haruyasu Murakami, Asuka Tsuya, Yukiko Nakamura, Tateaki
Naito, Nobuyuki Yamamoto, Toshiaki Takahashi,
Division of Thoracic
Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi-cho, Sunto-gun,
Shizuoka, 411-8777, Japan
Hideyuki
Harada, Tetsuo Nishimura, Division of Radiation Oncology, Shizuoka Cancer Center,
1007 Shimonagakubo Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
Masahiro
Endo, Division of Diagnostic Radiology, Shizuoka Cancer Center,
1007 Shimonagakubo Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
Correspondence
to: Kyoichi Kaira, MD, Division of Thoracic Oncology, Shizuoka
Cancer Center, 1007 Shimonagakubo Nagaizumi-cho Sunto-gun, Shizuoka, 411-8777,
Japan. kkaira1970@yahoo.co.jp
Tel: +081-55-989-5222
Fax: +081-55-989-5634,
Received: July 20, 2013
Revised: August 20, 2013
Accepted: August 22, 2013
Published
online: October 18, 2013
ABSTRACT
AIM: Brain metastases (BMs) are associated with poor outcomes in patients with
advanced non-small cell lung cancer (NSCLC). Recent reports demonstrated that
gefitinib, an epidermal growth factor tyrosine kinase inhibitor (EGFR TKI),
could be beneficial in a subset of NSCLC patients with BMs; however, its
ability to improve the outcome of NSCLC patients with BMs is unknown. The aim of this study was to investigate
the prognostic significance of gefitinib therapy in NSCLC patients with BMs.
MATERIALS AND METHODS: We retrospectively analyzed 107
NSCLC patients who had synchronous BMs and received chemotherapy before or
after whole brain radiotherapy.
RESULTS: Fifty-eight patients received gefitinib therapy [Gefitinib (+)], while 49
patients did not [Gefitinib (-) group]. The Gefitinib (+) group had a higher
proportion of female patients and patients with adenocarcinoma. The median
overall survival (OS) was significantly higher in the Gefitinib (+) group (657
days, range: 79-2163) than in the Gefitinib (-) group (287 days, range:
73-1859) (P=0.0071). In
multivariate analysis, good performance status (PS) and asymptomatic BMs were
significant, independent factors for predicting a favorable outcome in the
Gefitinib (+) group. In the Gefitinib (-) group, the maximum diameter of the
largest BM was a prognostic factor, with borderline significance.
CONCLUSIONS: Our results suggest that gefitinib therapy
prolongs OS in NSCLC patients with synchronous BMs and that good PS and
asymptomatic BMs are favorable prognostic factors in patients treated with
gefitinib.
© 2013 ACT. All rights reserved.
Key words: Brain metastasis; Gefitinib; Non-small cell lung cancer;
Prognosis; Radiotherapy; Chemotherapy
Ayabe E, Kaira K,
Harada H, Murakami H, Tsuya A, Nakamura Y, Naito T, Endo M, Nishimura T,
Yamamoto N, Takahashi T. Prognosis of Patients with Brain Metastasis from
Non-Small Cell Lung Cancer According to Gefitinib Administration. Journal of
tumor 2013; 1(5): 28-31 Available from: URL: http://www.ghrnet.org/index.php/JT/article/view/488
INTRODUCTION
Brain metastases
(BMs) represent an important cause of morbidity in patients with non-small cell
lung cancer (NSCLC). The frequency
of central nervous system involvement in NSCLC patients is reported to reach
40%[1], and 25% to 30% of NSCLC patients have synchronous BMs at the
time of diagnosis[2]. The presence of BMs in NSCLC cases is
associated with a poor outcome, with a median overall survival (OS) of
approximately 4 months[3]. More than 50% of patients with
synchronous BMs die of systemic disease progression, even when BMs are
controlled by radiotherapy[4]; therefore, the treatment of BMs
should focus on both local control of the cranial metastases and systemic
disease management for the prolongation of survival. Recently, increasing efforts have been
made to identify and use prognostic factors, such as performance status (PS),
neurological symptoms, the size of the BMs, the number of BMs, and the presence
of extracranial metastases, in the treatment of NSCLC patients with BMs[5,6].
Epidermal growth factor
receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are very effective in
NSCLC patients, particularly in women, patients who have never smoked, patients
with pulmonary adenocarcinomas, and patients of Asian descent[7,8].
Gefitinib is a small-molecule EGFR-TKI.
Among NSCLC patients who receive gefitinib, those with EGFR mutations
have a significantly longer survival than those with wild-type EGFR[9,10].
Although reports suggest that gefitinib is a possible option for the treatment
of BMs secondary to NSCLC, it is unknown if gefitinib therapy can prolong the
survival of NSCLC patients with synchronous BMs at initial diagnosis[11,12].
Furthermore, there are no data on the prognostic factors for NSCLC patients
with synchronous BMs who receive gefitinib therapy. Recent reports have
discussed the prognostic factors in populations with NSCLC with synchronous BMs
who received gefitinib and those that did not. It is unclear if there are
differences in the OS of NSCLC patients with BMs at initial diagnosis according
to gefitinib treatment, and the prognostic significance of these patients
should be examined. If these patients have received treatment with chemotherapy
and whole brain radiotherapy (WBRT), their prognostic factors may be biased by
treatment. In this study, we retrospectively analyzed prognostic factors in
advanced NSCLC patients with synchronous BMs, treated by both systemic
chemotherapy and WBRT, according to the receipt of gefitinib therapy.
MATERIALS AND METHODS
We retrospectively
reviewed the medical records of 258 patients with histopathologically proven
NSCLC with synchronous BMs who received both WBRT and chemotherapy between
September 2002 and December 2008. Synchronous BMs were defined as those
diagnosed by magnetic resonance imaging (MRI) at the time of initial
evaluation. Pretreatment work-up
included taking of clinical history, Eastern Cooperative Oncology Group PS
determination, physical examination, blood tests, chest radiography, computed
tomography (CT) of the thorax and upper abdomen, bone scintigraphy or positron
emission tomography (PET), and brain MRI.
Staging was performed according to the TNM classification of the Union
for International Cancer Control (UICC)[13]. Histological analysis
of the tumor was based on the World Health Organization classification for cell
types[14], and the Response Evaluation Criteria in Solid Tumors were
used to assess the response to chemotherapy[15]. The overall
response was defined as the best response recorded from the start of treatment
until disease progression or recurrence, confirmed by repeated assessments
performed no less than 4 weeks after the criteria for response were first met.
Of the 258 analyzed
patients, 162 had BMs at the time of initial staging workup. Among those patients with synchronous
BMs, 55 were excluded from the analysis because they did not receive systemic
chemotherapy. In all, 107 NSCLC patients who had synchronous BMs and received
chemotherapy before or after WBRT were registered in this study. Seventy-one
patients received chemotherapy followed by WBRT, while 36 patients received
WBRT followed by chemotherapy.
Precursory WBRT was determined by the patient’s physician or
neurosurgeon on the basis of neurological symptoms or the number, size, and
location of the cranial metastatic lesions.
We categorized the 107 patients
included in this study into 2 groups according to the receipt of gefitinib:
Gefitinib (+) and Gefitinib (-).
The neurosurgery techniques were surgical resection of the brain tumors
and Gamma knife and stereotactic radiosurgery (SRS). The radiation dose for
WBRT was 30 gray (Gy) in 10 fractions (98 patients), 40 Gy in 20 fractions (7
patients), and 39 Gy in 13 fractions (2 patients).
Survival was recorded from
the first day of treatment to the date of death or last follow-up, and survival
curves were calculated using to the Kaplan-Meier method. A P value of
<0.05 was considered to be statistically significant. Fisher’s exact test was used to examine
the association of categorical variables, and survival difference was analyzed
using the log-rank test.
Multivariate analyses were performed using stepwise Cox proportional
hazards model to identify independent prognostic factors. Statistical analysis was performed using
JMP 8 (SAS, Institute Inc., Cary, NC, USA) for Windows.
RESULTS
Patient characteristics
The patient
demographic characteristics are summarized in Table 1. Fifty-eight patients received gefitinib
therapy [Gefitinib (+) group], while 49 patients did not undergo gefitinib
treatment [Gefitinib (-) group]. There were no statistically significant
differences in age, PS, symptoms, the number of BMs, the size of the largest
BM, and the chemotherapy regimen, but gender distribution, histological type,
and presence of extracranial, extrathoracic metastases differed significantly
between the 2 groups.
Treatment and response
Forty-three patients
(74.1%) in the Gefitinib (+) group and 28 patients (57.1%) in the Gefitinib (-)
group received chemotherapy followed by WBRT. Of the 107 patients, 94 (87.8%) received
platinum-based regimens, with no significant difference in OS between the
Gefitinib (+) and Gefitinib (-) groups.
Five patients in the Gefitinib (+) group were treated with gefitinib as
first-line therapy. Eleven (18.9%)
and 12 (24.5%) patients in the Gefitinib (+) and Gefitinib (-) groups,
respectively, underwent neurosurgery (P=0.637).
The overall response to
first-line chemotherapy was assessed, with no cases of complete remission
observed in this series. The
objective response rates for first-line chemotherapy were 29.3% and 25.0% in
the Gefitinib (+) and Gefitinib (-) groups, respectively (P = 0.666).
Survival
The median OS was
657 days (range: 79-2163) in the Gefitinib (+) group and 287 days (range:
73-1859) in the Gefitinib (-) group (Figure 1). Thus, OS was significantly
longer in the Gefitinib (+) group than in the Gefitinib (-) group (P=0.0071).
Prognostic factors
Univariate analysis
of OS (Table 2) showed that PS, symptoms, and the chemotherapy regimen were
statistically significant prognostic factors in the Gefitinib (+) group and
that the maximum diameter of the largest BM was the only significant factor in
the Gefitinib (-) group.
Multivariate analysis showed that a good PS and asymptomatic BMs were
significant, independent factors for predicting a favorable outcome in the
Gefitinib (+) group (Table 2), while the maximum diameter of the largest BM was
a prognostic factor in the Gefitinib (-) group, with borderline significance
(Table 3).
DISCUSSION
The recent, widespread
use of MRI has led to the increased identification of asymptomatic BMs. NSCLC
patients with BMs often receive various forms of treatment, including surgery,
radiosurgery, WBRT, and chemotherapy, depending on the clinical status and
clinical practice. Surgery and radiosurgery such as SRS and Gamma knife may be
important therapeutic approaches for patients with a limited number of cerebral
lesions. In patients with multiple intracranial metastases, WBRT followed by
chemotherapy or best supportive care is a common approach. Although the use of systemic
chemotherapy for BMs has been limited because of a presumed lack of
effectiveness due to the blood-brain barrier (BBB), the BBB is reported to be
partially disrupted at metastatic sites[16]. In fact, some trials of
platinum-based chemotherapy showed comparable response rates between patients
with intra-cranial and extra-cranial disease, suggesting that chemotherapy
should be considered for patients with multiple, asymptomatic BMs[17].
Additionally, a few reports indicated a potential role of EGFR-TKIs such as
gefitinib in the treatment of NSCLC patients with metastatic brain disease[11,12].
As the survival difference
between NSCLC patients having synchronous BMs treated with and without
gefitinib was unknown, we compared 2 groups: patients that did [Gefitinib (+)])
and did not [Gefitinib (-)] receive gefitinib. The aims of the study were to evaluate
the effect of gefitinib treatment on survival time in NSCLC patients with BMs
and to identify significant prognostic factors in each group. In our series, the median OS was
significantly longer in the Gefitinib (+) group [657 days (range, 79–2163
days)] than in the Gefitinib (-) group [287days (range, 73–1859 days)];
however, such a strict comparison may be unreasonable because of the
differences between the subjects in the Gefitinib (+) and Gefitinib (-)
groups. In the survival analysis of
NSCLC patients with BMs, the OS in the Gefitinib (+) group in our study was
longer than that reported previously.
Although EGFR mutation status was not investigated in our study, the
Gefitinib (+) group had a higher proportion of female patients and patients
with adenocarcinoma, suggesting that this group was more likely to have
patients with EGFR mutations. Our results indicated that NSCLC patients with
BMs who had good PS and asymptomatic BMs may benefit from gefitinib
therapy. As this is a retrospective
study, a prospective study is warranted to confirm the efficacy of gefitinib in
NSCLC patients with BMs.
Some studies have reported
that EGFR-TKIs are also effective in patients with leptomeningeal metastasis
(LM)[18,19]. Currently, there is no efficient therapeutic option for
LM from NSCLC other than palliative measures, including whole brain and/or
spinal axis irradiation. Therefore, EGFR-TKIs may also have the potential to
contribute to the management of NSCLC patients with LM. Currently, systemic chemotherapy
provides an improved prognosis in patients with NSCLC, and we now have more
treatment options for patients with brain diseases. Recent studies indicated that
chemotherapy, including with EGFR-TKIs, should be considered for the management
of BMs as an essential part of multimodality treatment[20,21]. Our
results suggested that the efficacy of gefitinib for cerebral lesions
associated with NSCLC and prognostic factors such as PS and symptoms should be
considered when choosing gefitinib as a strategy for the management of NSCLC
patients with BMs.
The limitations of this
study include its retrospective nature and small sample size. We did not consider the mutation status
of EGFR in this study, and thus, it is unclear if EGFR mutation status is a
prognostic factor for predicting outcomes in patients with NSCLC with BMs.
In conclusion, our observations
suggest that gefitinib therapy prolongs OS and that good PS and asymptomatic
BMs are favorable prognostic factors in NSCLC patients with synchronous BMs
treated with gefitinib.
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Peer reviewers:
Alessandro
Landi MD, PhD, Neurosurgeon and Spine surgeon, Dpartment of Neurology and
Phsychiatry, Division of Neurosurgery, University of Rome Sapienza, Italy;David
H. Garfield, M.D., Associate Medical Director, ProMed Cancer Centers-Shanghai,
#170 Danshui Rd., Shanghai 200020, P.R , China.
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