Background
Lung cancer has become the leading cause of cancer related deaths in worldwide [
1]. Brain metastasis (BM) is one of the most common complications in non-small-cell lung cancer (NSCLC) patients with more than 10% patients presented with BM at their first hospital visit [
2,
3] and 30–40% patients developed it during the course of disease [
4]. Whole brain radiotherapy (WBRT) is the standard treatment strategy for BM. However, the prognosis of patients with BM remains poor after WBRT with a median overall survival (OS) of 4–6 months. The effect of systemic chemotherapy is limited due to the impenetrability of brain blood barrier [
5,
6], as reported that several chemotherapy drugs in combination with WBRT failed to improve the survival [
7].
For the past few decades researchers have found that some drugs may have a positive effect on the NSCLC with BM [
8‐
10]. Temozolomide (TMZ) is a new oral alkylating agent, which is able to cross the brain blood barrier with demonstrated survival benefit in the treatment of high-grade gliomas when administered concurrently with adjuvant radiotherapy [
11]. Studies demonstrated that TMZ could be used against a broad range of cancers in vitro including NSCLC [
12‐
14]. Adding TMZ to WBRT may improve the response rate of NSCLC patients with BM [
15‐
17]. However, the potential neurocognitive risks and the influence on the patients’ living quality of combing TMZ with WBRT were less studied. The purpose of this study is to investigate the survival benefits, neurocognitive function (NCF) and quality of life (QOL) influence of WBRT with or without TMZ in the treatment of NSCLC patients with BM.
Methods
Patients
We retrospectively reviewed NSCLC patients with BM treated at the First Affiliated Hospital of Wenzhou Medical University from January 2008 to December 2015. The eligibility criteria for this study were as follows: patients were historically diagnosed with NSCLC and had confirmed BM by magnetic resonance imaging (MRI); had at least one measurable BM with diameter larger than 10 mm; patients had no history of TKI administration; had adequate function of major organs (including cardiac, hepatic, and renal function) and hematologic function (absolute neutrophil ≥ 1.5 × 109/L or platelet count ≥100 × 109/L); had no uncontrolled morbidities (e.g., myocardial infarction in the last 12 months); with Eastern Cooperative Oncology Group performance status ≤3; Treated by WBRT with a prescription of 3 Gy/fraction × 10 fractions.
The exclusion criteria were as follows: patients had small cell or mixed small cell histology; patients had EGFR mutations; without at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; lost to follow-up or died within 1 month after starting the treatment; received prior radiotherapy to the brain or TMZ or targeted drugs. This study was carried out according to ethical standards, national and international guidelines. It was approved by the Institutional Review Board and performed at the 1st Affiliated Hospital of Wenzhou Medical University (IRB#:2015041). Written informed consent was obtained from each patient before treatment.
Treatment schemes
Patients were divided into WBRT + TMZ (RCT) arm and WBRT (RT) arm, respectively. WBRT was planned with two lateral parallel-opposite conformal beams at a prescription of 30 Gy for 10 fractions with a 6-MV photon beam on an Elekta Synergy® linac (Elekta Ltd, Crawley, UK). WBRT plans were delivered through a record and verify system (MosaiQ® v. 1.60Q3, IMPAC Medical Systems, Inc., Sunnyvale, CA). In the RCT arm, TMZ 75 mg/m2/day was administered daily during radiation treatment. After the completion of WBRT, TMZ 100 mg/m2 was continued for 14 days and repeated every 28 days until unacceptable toxicity or disease progression for up to six cycles.
Neurocognitive function and quality of life assessment
NCF was assessed by using revised Hopkins Verbal Learning Test (HVLT-R), Controlled Oral Word Association (COWA) test and Trail-making Test (TMT). The HVLT-R is a learning and memory test, in which the patient was asked to learn and recall a list of 12 words over three trials [
18]. The TMT is a measure of graphomotor speed and set-shifting to measure the executive function [
19]. The COWA Test provides a relatively quick test of verbal fluency and it is believed to place high demands on executive control processes [
20].
QOL was assessed by the Functional Assessment of Cancer Treatment-Lung (FACT-L) Chinese version 4.0 questionnaire, which has 34 items with a 5-point Likert scale [
21]. The FACT-L had been shown to be reliable and valid instruments to measure the QOL of Chinese lung cancer patients [
22].
Treatment evaluation and follow-up
The response and progression were evaluated weekly during WBRT. Evaluation included a complete history, neurologic examination, QOL assessment, blood counts, and biochemistry profile. After RT, the evaluation was done monthly for the first 6 month, then every 3 months after. Evaluation included physical examination, neurologic examination, QOL assessment, a complete blood count measurement, liver function test, and chest computed tomography (CT) scan. Brain CT with and without contrast, abdominal CT, or bone scan, as well as MRI if necessary, were performed when there were relevant symptoms in patients.
Definitions and statistical analyses
Pearson chi-square or Fisher’s exact tests (when there were fewer than 5 expected counts in the contingency table) were used to compare the baseline characteristics between RCT and RT arms. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors 1.1. OS was defined as the interval from the date of initiation WBRT to the date of death resulted from NSCLC. Intracranial progression-free survival (PFS) was defined as local disease progression, the appearance of new intracranial lesions or both. Intracranial PFS was calculated from the initiation WBRT and the date of confirming progression or death from intracranial progression (if death occurred within 60 days of the last central nervous system assessment date). If the complete survival time of a patient was impossible to obtain or the disease did not progress, patient’ status was assumed as the last known survival and/or contact date. The baseline neurocognitive status was recorded at the first neurocognitive assessment before the start of BM treatment. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v3.0.
Intracranial PFS and OS were estimated by Kaplan-Meier method. Differences between groups were compared by the log-rank test. In order to identify risk factors associated with intracranial progression, multivariate analyses were conducted with Cox proportional hazard model. Reliable Change Index was used to categorize the change or improvement on NCF and QOL scores [
23]. The Reliable Change Index was derived from the standard error of measurement (SEM) of each test, which is calculated from the test-retest reliability (r) and the standard deviation (SD) of test scores: SEM = SD (1-r)
1⁄2. The standard error (SE) of difference was then calculated as: SE
diff = [2 (SEM
2)]
1⁄2. All Reliable Change Index thresholds were rounded to the nearest whole number. Scores in any tests decreased from baseline status and met the Reliable Change Index threshold were categorized as deterioration at a specific time period (e.g. 3 months, 5 months and 7 months). The predictive accuracy of various Cox regression models was quantified by Harrell’s concordance index (C-index), which ranges from 0.5 (no predictive power) to 1 (perfect prediction). Statistical analyses were computed using SPSS (version 17.0, SPSS Inc., Chicago, IL) and the R stats package (R Foundation for Statistical Computing, Vienna, Austria). Tests were two sided and
p < 0.05 was considered statistically significant.
Discussion
The effects and influence on Neurocognitive function and QOL of adding TMZ to WBRT in the treatment of NSCLC with BM were investigated in a total of 238 patients. Our study suggested that TMZ combined with WBRT could significantly enhance the intracranial ORR and DCR, as well as median PFS compared with WBRT alone in the treatment of NSCLC patients with BM, but no remarkable difference on median OS was found. NCF and QOL were also prevented from worsening by adding TMZ.
In this study, the intracranial ORR and DCR of NSCLC patients with BM treated by WBRT + TMZ were 34.9 and 98.4%, respectively, which were significantly higher than 20.2 and 92.7% in the RT arm (both
p < 0.05). These were consistent with results reported in previous studies that TMZ + WBRT may enhance the overall ORR of NSCLC patients with BM compared with WBRT alone [
23,
24]. A multi-institutional trial showed a higher overall ORR (48% vs. 27%,
p = 0.03) in 103 lung cancer patients with BM treated with TMZ 75 mg/m
2 per day plus WBRT compared with WBRT alone [
24]. Through a meta-analysis, Liao Kai et al. also reported that WBRT + TMZ could significantly improve ORR (risk ratio = 1.55,
p = 0.003) in the treatment of BM from NSCLC compared with WBRT alone [
23]. However, a phase II trial reported that adding TMZ to WBRT did not improve the ORR compared with WBRT alone for 12 chemotherapy-native NSCLC patients with BM [
25]. In another phase II trial, for 30 pre-treated recurrent NSCLC patients with BM treated by concurrent WBRT and TMZ (150–200 mg/m
2/d), only 3 (10) and 6 (20%) patients achieved an objective response and disease control [
26]. We inferred that pretreatment influenced the efficacy of TMZ in these phase II patients.
The median OS for all NSCLC patients with BM observed in this study was 7.3 months, which is close to the reported median OS of 8.0 months in the study of Wang Q et al., in which NSCLC patients with BM were treated by WBRT followed by intensity-modulated boost combined with concomitant TMZ [
16]. In this study, the median OS and PFS in the WBRT + TMZ group and in the WBRT alone group were 8.5 vs. 5.9 months and 5.9 vs. 4.9 months, respectively. Daniel Chua et al. also demonstrated that WBRT + TMZ had a higher median OS (5.7 vs. 4.4 months) and PFS (3.8 vs. 3.1 months) compared with WBRT alone in the treatment of NSCLC patients with BM [
27]. However, their reported median OS and PFS were inferior than ours. We speculated that the difference may resulted from different TMZ doses were administered in two studies. In the study of Daniel Chua, patients received TMZ daily for 21 days, while in our study, TMZ 75 mg/m
2/day was administered daily during radiation treatment and TMZ 100 mg/m
2/day was continued for 14 days and repeated every 28 days until unacceptable toxicity or disease progression for up to six cycles.
Previous studies reported that TMZ combing with RT could improve QOL in high grade glioma [
28,
29]. A single-institution phase I clinical trial on patients with multiple brain lesions from breast carcinoma treated by capecitabine and TMZ demonstrated that significant improvements in attention span (
p = 0.047) and emotional function (
p = 0.016) were observed indicating that adding TMZ was not neurotoxic and may have a beneficial effect [
30]. Addeo R et al. also reported that a statistically significant improvement on QOL was found at 3,6 and 9 months for 59 patients treated by 30 Gy WBRT with concomitant TMZ [
31]. Similarly, our result implied that adding TMZ in the treatment of NSCLC patients with BM could prevent the NCF and QOL from worsening at 5 months. These studies implied that TMZ as a maintenance therapy may improve patients’ NCF and QOL. This may due to a better intracranial ORR and DCR in RCT group. TMZ may has a certain function of preventing tumor recurrence in brain.
Nausea and fatigue were the most frequent side effects observed for both RCT and RT arms, followed by anemia, vomiting, neutropenia, anorexia and thrombocytopenia, etc. Addition TMZ in the RCT arm showed a trend of increasing the rate of side effects compared with RT alone, as reported in previous studies [
27,
32]. However, the difference of the adverse events occurrence between RCT and RT arms was not statistically significant.
One limitation of current study is that it is a retrospective methodology from a single institution experience. The impact of various treatments related outcomes could not be fully evaluated. The number of patients enrolled may not be sufficient enough and the follow-up duration of the study may not be long enough. External validation using other large database for further evaluating the prognostic effect of adding TMZ in the treatment of NSCLC patients with BM would be of great value in clinical practice.