|Year : 2016 | Volume
| Issue : 1 | Page : 267-270
Prognostic factors in patients with brain metastasis from non-small cell lung cancer treated with whole-brain radiotherapy
Hideyuki Harada1, Hirofumi Asakura1, Hirofumi Ogawa1, Keita Mori2, Toshiaki Takahashi3, Yoko Nakasu4, Tetsuo Nishimura1
1 Division of Radiation Oncology, Shizuoka Cancer Center, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan
2 Clinical Trial Coordinate Office, Shizuoka Cancer Center, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan
3 Division of Thoracic Oncology, Shizuoka Cancer Center, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan
4 Division of Neurosurgery, Shizuoka Cancer Center, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan
|Date of Web Publication||13-Apr-2016|
Shimonagakubo 1007, Nagaizumi-cho, Sunto-gun, Shizuoka
Source of Support: None, Conflict of Interest: None
Aims: The purpose of this study was to evaluate the prognostic factors associated with overall survival (OS) in nonsmall cell lung cancer (NSCLC) patients with brain metastasis who received whole-brain radiotherapy (WBRT).
Materials and Methods: This study included 264 consecutive NSCLC patients with brain metastasis who received WBRT. Patients with leptomeningeal metastasis and those who underwent craniotomy or stereotactic radiotherapy before WBRT were excluded. The evaluated prognostic factors for OS included gender, neurological deficit, histology, epidermal growth factor receptor (EGFR) mutation status, previous cytotoxic chemotherapy, previous EGFR-tyrosine kinase inhibitor treatment, recursive partitioning analysis (RPA) class, and diagnosis-specific graded prognostic assessment (DS-GPA) score. All factors with a P < 0.05 in univariate analysis were entered into multivariate analysis using Cox regression and a confidence interval of 99%.
Results: Two hundred thirty patients had died, 14 patients were alive, and 20 patients were lost to follow-up. The median follow-up time was 20.9 months. The median survival time was 5.5 months (95% confidence interval; 4.8–6.3). Univariate analysis showed that gender, neurological deficit, histology, EGFR mutation status, RPA class, and DS-GPA score were significant prognostic factors for OS. In multivariate analysis, RPA class and histology were found to be significant prognostic factors for OS, with P values of 0.0039 and 0.0014, respectively.
Conclusions: RPA Class I or II (Karnofsky Performance Status ≥70) and adenocarcinoma histology were associated with longer OS. These factors should be taken into account when considering indication for WBRT.
Keywords: Brain metastasis, nonsmall cell lung cancer, prognosis, radiotherapy
|How to cite this article:|
Harada H, Asakura H, Ogawa H, Mori K, Takahashi T, Nakasu Y, Nishimura T. Prognostic factors in patients with brain metastasis from non-small cell lung cancer treated with whole-brain radiotherapy. J Can Res Ther 2016;12:267-70
|How to cite this URL:|
Harada H, Asakura H, Ogawa H, Mori K, Takahashi T, Nakasu Y, Nishimura T. Prognostic factors in patients with brain metastasis from non-small cell lung cancer treated with whole-brain radiotherapy. J Can Res Ther [serial online] 2016 [cited 2019 Nov 12];12:267-70. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/267/167610
| > Introduction|| |
Whole-brain radiotherapy (WBRT) can improve neurologic dysfunction caused by brain metastasis. In 2007, an estimated 90,000 new patients were diagnosed with lung cancer in Japan. Brain metastasis is a common clinical cause of morbidity and mortality, which occurs in approximately 15–20% of lung cancer patients., In practice, the prognostic score might help in decision-making and treatment recommendations. Radiation Therapy Oncology Group recursive partitioning analysis (RPA) is a well-established scoring system that accounts for three prognostic factors (age, Karnofsky Performance Status [KPS] score, and disease status) and is based on databases of 1200 patients with brain metastases from a variety of primary tumors. The RPA system was re-evaluated and updated as the Graded Prognostic Assessment (GPA). The GPA uses four criteria (age, KPS score, number of brain metastases, and the presence of extracranial metastases) and was validated for nonsmall cell lung cancer (NSCLC) patients as a diagnosis-specific GPA (DS-GPA) score.
Recently, improved systemic therapies have become available and individualized according to histology or oncologic driver mutation status.,,,,, However, neither RPA nor DS-GPA includes these factors. In this study, we evaluated the prognostic factors on the overall survival (OS) of NSCLC patients with brain metastases who received WBRT.
| > Materials and Methods|| |
Two hundred and sixty-four NSCLC patients with brain metastasis who received WBRT in our institution between September 2002 and February 2011 were included in this study. Patients with leptomeningeal metastasis and those who had undergone craniotomy or stereotactic radiosurgery (SRS) before WBRT were excluded. The prognostic factors evaluated for OS were gender, neurological deficit, histology, the epidermal growth factor receptor (EGFR) mutation status, previous cytotoxic chemotherapy, previous EGFR tyrosine kinase inhibitor (TKI) treatment, RPA class, and DS-GPA score. RPA was used to classify patients into 1 of 3 categories: Class I included patients with a KPS score of <70, age <65 years, controlled primary tumor, and no extracranial metastases; Class III included patients with a KPS score of <70; and Class II included all other patients. The DS-GPA score calculated for each patient involved four criteria (age, KPS score, extracranial control, and number of lesions) scored with a value of 0, 0.5, or 1.0.
The Kaplan–Meier method was used to generate actual survival curves, and the log-rank test was used for statistical comparisons. All factors with a P < 0.05 in univariate analysis were evaluated by multivariate analysis using Cox regression with a confidence interval of 99%.
| > Results|| |
The patient characteristics are summarized in [Table 1]. At the time of analysis, 230 patients (87%) had died, 14 patients (5%) were alive, and 20 patients (8%) were lost to follow-up. The median follow-up time was 20.9 months for surviving patients. The median survival time (MST) was 5.5 months (95% confidence interval; 4.8–6.3), and the 1-year survival rate was 26.9%. MST according to gender, neurological deficit, histology, EGFR mutation status, previous chemotherapy, previous EGFR-TKI treatment, RPA class, and DS-GPA score are shown in [Table 2]. Gender, neurological deficit, histology, EGFR mutation, RPA class, and DS-GPA score were significant prognostic factors in univariate analysis and were entered into the multivariate analysis. In multivariate analysis, RPA class (Class I and II vs. III, KPS score ≥70 vs. <70) and histology (adenocarcinoma vs. nonadenocarcinoma) were found to be significant prognostic factors [Table 3]. Kaplan–Meier estimates of OS according to RPA class and histology are shown in [Figure 1].
|Figure 1: (a) Overall survival according to recursive partitioning analysis. (b) Overall survival according to histology (RPA: Recursive partitioning analysis, Ad: Adenocarcinoma)|
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| > Discussion|| |
In this study, the RPA class was the powerful prognostic factor for predicting OS in NSCLC patients with brain metastases. Only one patient was classified as Class I and 259 of 264 patients had extracranial metastases. This means that classification was dependent upon the difference between a high or low KPS score (≥70 vs. <70, Class II and III, respectively). On the other hand, DS-GPA did not demonstrate a strong correlation to OS in multivariate analysis. The RPA was established based on the database including 1200 patients from three consecutive WBRT trials conducted between 1979 and 1993. In brief, patients with KPS of <70 are RPA class III; KPS of <70, age <65 years, and no extracranial metastasis are RPA Class I; and others are in RPA Class II. RPA classes are corresponding to median survival. The RPA system was updated by adding new data including patients undergoing WBRT and SRS as the GPA  and the GPA was validated for NSCLC patients as the DS-GPA. KPS, age, and extracranial control were common prognostic factors in all three scoring systems, but number of brain metastases was a significant prognostic factor in the GPA and the DS-GPA. The DS-GPA score identifies the number of brain metastases, which are classified as 1, 2–3, and <3. However, of the 264 patients enrolled in this study, 237 (90%) had 4 or more brain metastases, and 95 (36%) had 11 or more brain metastases, because this study included patients receiving WBRT alone and excluded patients undergoing SRS as an initial treatment. Thus, the score decreased, and no patient scored 3 or 4 points. In light of these findings, the RPA class was considered to more accurately reflect the prognosis of patients who received WBRT than the DS-GPA score.
Adenocarcinoma histology was also a significant, good prognostic factor. Although it is still unclear if adenocarcinoma versus nonadenocarcinoma histology resulted in any differences in the nature of brain metastatic lesions, some differences were observed in survival prolongation after systemic treatment. In particular, the relationship with EGFR mutation status is notable. The systemic response to TKIs (60–80%) is dramatic in patients with NSCLC that harbors somatic EGFR mutations., In addition, the presence of EGFR mutation has been found to be an independent prognostic factor in patients with brain metastases and is associated with a longer OS. In this study, univariate analysis showed that that the prognosis of patients with EGFR-mutant NSCLC was excellent, although multivariate analysis did not demonstrate a strong correlation. As medical insurance in Japan did not cover testing for EGFR mutation status before 2007, most patients who entered this study from 2002 to 2007 did not undergo EGFR mutation analysis and their status is recorded in the database as “unknown.” However, treatment with EGFR-TKIs has been covered by medical insurance in Japan since 2002, and 69 of 202 adenocarcinoma patients (34%) were treated with an EGFR-TKI after WBRT. Patients with adenocarcinoma who are of East Asian ethnicity are likely to have EGFR mutation. This suggests that the better prognosis conferred by EGFR-TKI might be attributable to a greater number of adenocarcinoma patients with EGFR mutation in this study. Data on EGFR mutation status have been accumulated, and will clarify whether the presence of EGFR mutation is a prognostic factor for brain metastases after WBRT in the future.
This study has some limitations, including its single-center, retrospective nature. This study also excluded patients underwent craniotomy or SRS as an initial treatment. It would be beneficial for a future study to include these patients to investigate prognostic factors in them while comparing to those determined by this study. If a future study demonstrates that systemic treatment is more effective for brain metastasis, it would be more appropriate that WBRT is not recommended as a treatment strategy until symptoms or disease progression is observed. If so, prognostic factors of patients with brain metastases will change, and data should be periodically updated.
| > Conclusion|| |
RPA designation of Class I or II (KPS score ≥70) and adenocarcinoma histology were associated with longer OS after WBRT. These factors should be taken into account when considering indication for WBRT.
We wish to thank for Dr. Tsuyoshi Onoe, Dr. Hiroshi Fuji, Dr. Shigeyuki Murayama, Dr. Koichi Mitsuya, and Dr. Nakamasa Hayashi for their data analysis and Ms. Chiharu Naito for her data management.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Chao JH, Phillips R, Nickson JJ. Roentgen-ray therapy of cerebral metastases. Cancer 1954;7:682-9.
Matsuda A, Matsuda T, Shibata A, Katanoda K, Sobue T, Nishimoto H; Japan Cancer Surveillance Research Group. Cancer incidence and incidence rates in Japan in 2007: A study of 21 population-based cancer registries for the Monitoring of Cancer Incidence in Japan (MCIJ) project. Jpn J Clin Oncol 2013;43:328-36.
Langer CJ, Mehta MP. Current management of brain metastases, with a focus on systemic options. J Clin Oncol 2005;23:6207-19.
Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 2004;22:2865-72.
Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al.
Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997;37:745-51.
Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W. A new prognostic index and comparison to three other indices for patients with brain metastases: An analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 2008;70:510-4.
Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, et al.
Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: A multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys 2010;77:655-61.
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al.
Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26:3543-51.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al.
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8.
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al.
Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8.
Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al.
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-42.
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46.
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al.
Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50.
Paz-Ares L, Soulières D, Melezínek I, Moecks J, Keil L, Mok T, et al.
Clinical outcomes in non-small-cell lung cancer patients with EGFR mutations: Pooled analysis. J Cell Mol Med 2010;14:51-69.
Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al.
Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958-67.
Eichler AF, Kahle KT, Wang DL, Joshi VA, Willers H, Engelman JA, et al.
EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro Oncol 2010;12:1193-9.
Douillard JY, Shepherd FA, Hirsh V, Mok T, Socinski MA, Gervais R, et al.
Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: Data from the randomized phase III INTEREST trial. J Clin Oncol 2010;28:744-52.
Mok T, Yang JJ, Lam KC. Treating patients with EGFR-sensitizing mutations:First line or second line – is there a difference? J Clin Oncol 2013;31:1081-8.
[Table 1], [Table 2], [Table 3]