|Year : 2014 | Volume
| Issue : 4 | Page : 915-921
Management of brain metastases from non-small cell lung cancer
Meltem Baykara1, Gokhan Kurt2, Suleyman Buyukberber3, Umut Demirci4, Necdet Ceviker2, Efnan Algin3, Ugur Coskun3, Sukru Aykol2, Hakan Emmez2, Ahmet Ozet3, Mustafa Benekli3
1 Department of Medical Oncology, Sakarya University Training and Research Hospital, Sakarya, Turkey
2 Department of Neurosurgery, Gazi University Medical Faculty, Ankara, Turkey
3 Department of Medical Oncology, Gazi University Medical Faculty, Ankara, Turkey
4 Department of Medical Oncology, Ankara Ataturk Training and Research Hospital, Ankara, Turkey
|Date of Web Publication||9-Jan-2015|
Department of Medical Oncology, Sakarya University Training and Research Hospital, Korucuk, Sakarya
Source of Support: None, Conflict of Interest: None
Purpose: The purpose of the following study is to evaluate the treatment modalities, clinical status and prognostic factors affecting survival rates in patients with newly diagnosed brain metastasis from non-small cell lung cancer (NSCLC).
Patients and Methods: NSCLC patients with a new diagnosis of one to four brain metastasis evaluated retrospectively for the effects of treatment regimens on local failure-relapse-free survival (LRFS) and overall survival (OS). The relationship between age, gender, performance status, recursive partitioning analysis (RPA) classification, the primary tumor under control, number of metastatic tumors in the brain and total volume of brain metastasis and prognosis is analyzed.
Results: Out of a total of 138 (121 male and 17 female) patients, nearly 44.2% received only gamma-knife (GK); 24.6% were received both GK and whole brain radiotherapy (WBRT), 2.9% had GK and surgery, 3.6% received GK, surgery and WBRT, 10.9% had surgery and WBRT and 12.3% received only WBRT for treatment. Median LRFS of surgery plus WBRT group was significantly higher when compared with WBRT group (P < 0.0001). The OS was significantly longer for surgery plus WBRT group than the other treatment groups (P = 0.037). When median survival of WBRT-only group compared with surgery plus WBRT, it was significantly higher (29.6 months vs. 16.7 months, P = 0.006). Median OS of surgery plus WBRT group was significantly higher than GK plus WBRT group (29.6 months vs. 9.3 months, P = 0.007).
Conclusion: WBRT is still the most effective treatment method following surgery in selected patients according to their age, performance status and spread of the primary disease with NSCLC had limited number brain metastasis. Adding WBRT treatment after surgery significantly improved OS and LRFS.
结果：总共138（121名男性和17名女性）患者，近44.2%只接受伽玛刀（GK）；24.6%接受伽玛刀和全脑放疗（WBRT），2.9%有伽玛刀和手术，3.6%行伽玛刀，外科手术和放疗，10.9%手术和伽玛刀，12.3%只接受伽玛刀治疗。中值LRFS的手术加全脑放疗组明显高于放疗组（P＜0.0001）。总生存时间，手术加全脑放疗组较其他治疗组明显延长（P = 0.037）。全脑放疗组的中位生存时间与手术加全脑放疗组相比，明显延长（29.6个月vs 16.7个月，P = 0.006）。中位OS手术加全脑放疗组显著高于伽玛刀加全脑放疗组（29.6个月 vs 9.3个月，P = 0.007）。
Keywords: Brain metastasis, non-small cell lung cancer, recursive partitioning analysis, stereotactic radiosurgery, whole brain radiotherapy
|How to cite this article:|
Baykara M, Kurt G, Buyukberber S, Demirci U, Ceviker N, Algin E, Coskun U, Aykol S, Emmez H, Ozet A, Benekli M. Management of brain metastases from non-small cell lung cancer. J Can Res Ther 2014;10:915-21
|How to cite this URL:|
Baykara M, Kurt G, Buyukberber S, Demirci U, Ceviker N, Algin E, Coskun U, Aykol S, Emmez H, Ozet A, Benekli M. Management of brain metastases from non-small cell lung cancer. J Can Res Ther [serial online] 2014 [cited 2019 Nov 22];10:915-21. Available from: http://www.cancerjournal.net/text.asp?2014/10/4/915/137939
| > Introduction|| |
Non-small cell lung cancer (NSCLC) constitutes 80% of the primary lung cancers and is the leading cause of cancer-related deaths. , Brain metastasis develops in 20% of NSCLC patients and the prognosis is significantly worse, with a median survival is about 6 months despite active treatment.  For many years, the standard treatment has been whole brain radiotherapy (WBRT) alone or combined with surgery. Patients with brain metastasis have a survival rate about 3-6 months when treated with WBRT.  After 1980's a new treatment approach, stereotactic radiosurgery (SRS), was developed for patients with brain metastasis. The difference between WBRT and SRS is that with SRS, the normal surrounding brain tissue is exposed to minimal radiation and high-dose radiotherapy can be applied to a target lesion. Moreover, the duration between two approaches is different, as SRS is generally a 1-day treatment. Another advantage is most of the adverse effects that are caused by WBRT are not seen with SRS treatment.  However, it is not yet clear, how the treatment of brain metastasis should be optimized. In patients with a single brain metastasis and have a good performance status (Eastern Cooperative Oncology Group PS 0-1), WBRT can be added after surgical resection, which significantly increases the survival rate compared to surgery only. ,, However, post-surgery WBRT is very destructive for patients with multiple brain metastases and thus, has a very low feasibility in this patient group. ,, Median survival may be increased to 7-14 months with SRS treatment. ,,
In specific patient groups with diagnosis of brain metastasis, type of treatment is chosen according to the parameters such as age and performance status of patients, whether the primary cancer is under control or not, the number, location and diameter of brain metastasis and presence of extra-cranial disease. With regard to these parameters, WBRT, SRS and surgical resection alone or combined are the treatment options. ,, In this study, we evaluated the treatment modalities, clinical status and prognostic factors affecting survival rates in 138 patients diagnosed with NSCLC and had one to four brain metastasis. This evaluation was performed on patients who applied to Gazi University Medical School Medical Oncology and Neurosurgery clinics between 2005 and 2011.
| > Patients and methods|| |
NSCLC patients with a new diagnosis of brain metastasis between May 2005 and June 2011 were selected and medical records of the patients were evaluated retrospectively for clinical characteristics and treatment methods that were used. Patients with more than four brain metastases were excluded from the evaluation. Age, gender, performance status, recursive partitioning analysis (RPA) classification, whether the primary tumor under control or not, number of metastatic tumors in brain, total volume of brain metastasis and treatment methods were recorded.
According to the dose-fractionation scheme for WBRT a median dose of 30 Gy (range: 5-54 Gy) was applied in 10 fractions. Patients who were treated with SRS received a median dose of 20 Gy (range: 14-22 Gy) radiotherapy with a 50% isodose line by using Leksell 60 Co gamma knife (GK) model C.
Survival analyses were performed using Kaplan-Meier method. Local relapse-failure-free survival (LRFS) was defined as the time from diagnosis to brain metastasis progression or new metastasis in brain. Similarly, overall survival (OS) was calculated as the time elapsed from the date of brain metastasis diagnosis to the date of death or the last visit. Cox proportional hazard was used in multivariate analysis. Statistical analyses were carried out using SPSS 15.0 program.
| > Results|| |
A total of 138 NSCLC patients (121 male and 17 female) with 1-4 brain metastases were retrospectively evaluated. Median follow-up was 13.4 months (range: 0.33-85.5 months) and 79% (n = 109) of patients died during this period. Median age was 61 years (range: 42-85). Palliative chemotherapy was administered to 71% (n = 98) of patients. Patients with a single brain metastasis comprised 62.3% (n = 86) of the study cohort, while patients with two, three or four metastases made up 19.6% (n = 27), 13% (n = 18) and 5.1% (n = 7), respectively. Of these patients, 44.2% (n = 61) received only GK radiosurgery, 24.6% (n = 34) received both GK radiosurgery and WBRT, 2.9% (n = 4) had GK radiosurgery and surgery, 3.6% (n = 5) received GK radiosurgery, surgery and WBRT, 10.9% (n = 15) had surgery and WBRT and 12.3% (n = 17) received only WBRT for treatment. Since the number of patients in groups "GK + surgery," "GK + surgery + WBRT" and "surgery alone" were ≤5, they were excluded from the analysis. Only four groups were included in statistical analysis: "GK alone," "GK + WBRT," "surgery + WBRT" and "WBRT alone;" (N = 127). Patient characteristics are summarized in [Table 1].
Prognostic factors and survival analysis
Univariate analyses of prognostic factors affecting survival are summarized in [Table 2]. Median OS for the GK-only group was 16 months (95% confidence interval [CI], 10.54-21.5), the GK + WBRT group was 9.3 months (95% CI, 7.9-10.6), the surgery + WBRT group was 29.6 months (95% CI, 17.7-41.5) and the WBRT-only group was 16.7 months (95% CI, 14.1-19.2). OS was significantly longer for the surgery + WBRT group compared to other treatment groups (P = 0.037) [Figure 1]. When the GK-only group was compared to the GK + WBRT group, there was no statistically significant difference in median OS (16 months vs. 9.3 months, P = 0.55). At 1-year OS was 56% in the GK-only group, 41% in the GK + WBRT group (P = 0.49). Comparison of median OS of the WBRT-only group and the surgery + WBRT group revealed that OS was significantly higher in the surgery + WBRT group (29.6 months vs. 16.7 months, P = 0.006). One-year OS was 80% for the surgery + WBRT group, 76% for the WBRT group (0.62), whereas 2-year OS was 53% for the surgery + WBRT and 11% for the WBRT group (0.031). Median OS for the surgery + WBRT group was significantly higher compared to the GK + WBRT group (9.3 months vs. 29.6 months, P = 0.007). One-year OS was 41% and 86% for the GK + WBRT and surgery + WBRT groups (P = 0.036), respectively. Two-year OS was 24% for the GK + WBRT group and 53% for the surgery + WBRT group. When the GK + WBRT group was compared to the WBRT-only group, no significant difference was found between median OS (9.28 months vs. 16.6 months, P = 0.76). One-year OS was 41% for the GK + WBRT group and 76% for the WBRT group, while 2-year OS was 24% and 11% for the GK + WBRT and WBRT groups, respectively.
When clinical parameters affecting OS were evaluated, we found that survival was substantially shorter for patients ≥65 years of age with Karnofsky performance status <70. Furthermore, RPA class III, extracranial metastases and lack of salvage treatment after local recurrence or progression were poor prognostic indicators. Sex, control of primary disease, tumor volume and palliative chemotherapy had no effect on OS. Survival was superior in patients with 1-3 brain metastases compared to patients with four brain metastases; however, the difference was not statistically significant (P = 0.077) [Figure 2]. Multivariate analysis confirmed that age ≥ 65 years (hazard ratio [HR] = 2.90, 95% CI, 1.59-5.30, P = 0.001) and RPA class III (HR = 2.96, 95% CI, 1.44-6.04, P = 0.003) [Figure 3] maintained statistical significance after multivariate analysis [Table 3]. Moreover, multivariate analysis showed that treatment modality; number of metastatic tumors in the brain and salvage treatment had no significant effect on OS.
Median LRFS was 8.31 months (95% CI, 3.95-12.66) for the GK-only group, 9.1 months (95% CI, 7.98-10.21) for the GK + WBRT group, 15.5 months (95% CI, 11.27-19.73) for the surgery + WBRT group and 8.8 months (95% CI, 6.64-10.96) for the WBRT-only group (P = 0.159). When median LRFS was compared among four treatment groups, no significant differences were observed between groups regarding local recurrence and development of new metastatic lesions in the brain (P = 0.159) [Figure 4]. However median LRFS for the surgery + WBRT group was significantly higher compared to the WBRT group (P < 0.0001). One-year LRFS was 60% for the surgery + WBRT group and 17% for the WBRT group (P = 0.027). Furthermore, median LRFS was significantly shorter for patients with Karnofsky PS < 70 (P < 0.0001) and RPA class III (P < 0.0001). Age (P = 0.054), sex (P = 0.71), number of metastatic tumors in the brain (P = 0.127), tumor volume (P = 0.69), presence of extracranial metastases (P = 0.61), control of primary disease (P = 0.087) and palliative chemotherapy (P = 0.59) had no significant effect on LRFS.
| > Discussion|| |
Lung cancer is the leading cause of cancer-related deaths worldwide. At the time of diagnosis, 10% of NSCLC patients have brain metastasis. Only 6-9% of NSCLC patients had recurrent metastasis in the brain after radical treatment. However, brain metastases occur in 25-40% of the patients during the follow-up period. Prognosis is poor in patients with brain metastasis. Untreated patients with brain metastases have a median survival of 1 month. The OS is about 5 months with WBRT treatment and only 5% of the patients can live up to 1 year.  Other than supportive care with corticosteroids, WBRT, surgery, SRS and chemotherapy either alone or in various combinations, are the treatment options for patients with brain metastasis. 
Definitive treatment can improve neurological functions, quality of life and survival. Number of metastasis is important for the selection of treatment modality. Surgery is the primary choice for patients with a single metastasis with a size over 4 cm that causes mass effect. In patients with 2-4 metastases, surgery and adjuvant WBRT and/or SRS produce better results. Patients' age, Karnofsky performance status, neurological status, number, localization and diameter of tumors and the extend of the primary disease are the factors affecting the choice of optimal treatment modality.  Advancements in neuro-oncology techniques also increased the surgical indications: surgical resection is currently applicable not only to single metastasis but to multiple metastases as well. Retrospective studies suggested that median survival increases to 10.9-16.4 months with surgery in a single brain metastasis. ,, A study done by Iwadate et al. showed that median OS prolonged to 12.4 months with surgery in patients that have multiple metastases. 
About 70% of patients with multiple brain metastases at the time of diagnosis and cannot be treated with surgery or SRS effectively. Currently, WBRT is the most commonly used treatment modality in patients with brain metastasis. Moreover, WBRT has a significant importance for control of the tumor bed or distant microscopic metastases, improving symptoms in patients with residual disease after surgery. , Median survival of patients who were treated with WBRT after surgical resection increases up to 1-2 years. ,
SRS is a non-invasive treatment technique, which enables single-fraction high-dose of ionizing radiation delivery within the target while minimizing damage to the surrounding normal tissues.  SRS has survival rates similar to surgery.  Morbidity rates are lower with SRS and it causes less impairment in neurocognitive functions in the long term. 
There are many studies comparing WBRT to more aggressive combined therapies in the treatment of oligometastatic brain tumors. In the study performed by Patchel et al., 95 patients with solitary brain metastasis evaluated and surgery alone was compared with surgery + WBRT. Post-operative WBRT decreased brain recurrence and the risk of distant brain metastasis significantly, however, no significant difference was found regarding survival rates. 
Aoyama et al. compared SRS alone with SRS + WBRT in 132 patients with oligometastatic brain tumors (number of metastases in the brain is 1-4) and stated that adding WBRT to SRS significantly decreased local recurrence and distant relapse risk with no significant effect on OS. One-year survival is 28.4% in SRS group and 22.8% in SRS + WBRT group. 
Chang et al. compared SRS and SRS + WBRT treatments in 58 patients with 1-3 brain metastases. This study shows that adding WBRT to SRS significantly decreased occurrence of distant brain metastasis and improved local tumor control. However, survival rates of patients treated with SRS alone was longer than SRS + WBRT treatment group (P = 0.003). The difference in OS rates may be attributed to the difference in prognostic factors and salvage treatments and using more aggressive treatments for patients in SRS alone group in case of recurrence.  In our study, SRS and SRS + WBRT groups showed no difference regarding median OS and median LRFS. We were not able to show the contribution of adding WBRT to SRS with these parameters.
In the EORTC 22952-26001 study, results of adding WBRT to local treatment (surgery or SRS) were evaluated in 359 patients with 1-3 brain metastases. Adjuvant WBRT following surgery decreased local relapse (27% vs. 59% P < 0.001) and development of new brain metastases (23% vs. 42%, P = 0.008) significantly. Similarly, adjuvant WBRT following SRS also significantly decreased local recurrence 19% vs. 31%, P = 0.04) and development of new brain metastases (33% vs. 48%, P = 0.02). , Unfortunately, as the number of patients in surgery alone group was not sufficient, we did not compare the surgery alone with surgery + WBRT group in our study.
Studies comparing WBRT alone with surgery + WBRT in patients with solitary brain metastasis show a significant increase in survival, decrease in local recurrence and increase in LRFS of patients who had adjuvant surgery. ,, Similarly, significant increase in both OS and LRFS was found in this study when WBRT alone group compared with surgery + WBRT. However, the study performed by Mintz et al. showed no difference between WBRT and surgery + WBRT regarding survival of patients. 
WBRT alone was compared with WBRT + SRS when given to patients with 1-3 brain metastases in the RTOG 9508 study. Addition of SRS to WBRT increased local control. Adjuvant SRS increases survival rates in patients with solitary brain metastasis (4.9 months vs. 6.5 months, P = 0.04). On the other hand, with the increase in number of brain metastasis (2-3 metastasis) this beneficial effect is lost.  In our study, we also compared the results of WBRT alone with SRS + WBRT treatment groups we were not found significant differences regarding OS and LRFS. However, 1-year LRFS was higher in SRS + WBRT than WBRT alone group and better local control was obtained (38% vs. 17%, P = 0.086).
In the study performed by Roos et al. two combined treatments (surgery + WBRT vs. SRS + WBRT) was compared in 21 patients with solitary brain metastasis. Unfortunately, this study was terminated as the enrollment was slow due to lack of suitable patients. Although the number of subjects was not sufficient to make clear statistical evaluation, no difference between groups was obtained regarding OS and LRFS when the available patients were compared.  When we compared SRS + WBRT combination with surgery + WBRT, we found that median OS was significantly higher in the surgery group (9.3 months vs. 29.6 months, P = 0.007). Similarly, LRFS was also longer in surgery + WBRT group than SRS + WBRT (9.1 months vs. 15.5 months, P = 0.43), however no statistical significance was found.
| > Conclusion|| |
The best OS and LRFS were obtained by surgery + WBRT in this retrospective study. Contrary to the results of previous studies, we could not show a beneficial effect of adding WBRT to SRS treatment in this study. However, adding WBRT treatment after surgery significantly improved OS and LRFS. SRS is a method that has lower adverse effects, noninvasive, easy-to-apply and preferred for treatment of solitary/oligometastatic brain tumors. Moreover, in some studies, results obtained with SRS were similar to surgery. However, WBRT is still the most effective treatment method following surgery in selected patients according to their age, performance status and spread of the disease.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]