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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 215-220

Prognostic effect of symptomatic extracranial lesions on survival of recursive partitioning analysis Class III brain metastatic patients treated with stereotactic radiotherapy


1 Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan 250012, China
2 Department of Radiation Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China

Date of Web Publication13-Apr-2016

Correspondence Address:
Jian-Ping Xiao
Radiation Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.160925

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 > Abstract 


Objective: To explore the outcome and prognostic factors of recursive partitioning analysis (RPA) Class III brain metastatic patients treated with stereotactic radiotherapy (SRT).
Materials and Methods: Fifty-six consecutive patients with metastatic brain tumors and Karnofsky performance scale (KPS) scores <70 treated with SRT from January 2008 to October 2013 were involved in the analysis. Twenty-five patients (44.6%) were with symptomatic extracranial lesions (SELs), and the other 31 patients (55.4%) were without SELs. The detailed follow-up data of KPS scores were available in 44 patients. The KPS score drop time (KDT) was calculated as the time between SRT and 10 points drop of KPS scores compared to the baseline. Kaplan–Meier and Cox proportional hazards regression analyses were performed for univariate and multivariate analyses.
Results: The median overall survival time was 5.0 months (95% confidence interval [CI] 3.42–6.59) for the whole group. In multivariate analysis, the presence of SELs (P = 0.007, relative risk = 4.44, 95% CI 1.036–20.818) was the independent prognosis factor for survival. Median survival time was 3 months for the patients with SELs, 8 months for the patients without SELs. The median KDT of the 44 patients was 3.0 months (95% CI, 1.927–4.073 months). Again only the presence of SELs (P = 0.001, OR = 6.622, 95% CI, 2.108–20.801) was significantly related to KDT in multivariate analysis. The median KDT of the patients with SELs was 1.5 months, which was 5 months for the patients without SELs.
Conclusion: The presence of SELs was a negative prognosis factor for the survival of RPA Class III brain metastatic patients. If RPA Class III brain metastatic patients were without SELs, SRT may be a reasonable treatment option, but if they had SELs, SRT may not be a reasonable treatment due to the short overall survival time and KDT.

Keywords: Brain metastases, prognosis, recursive partitioning analysis Class III, stereotactic radiotherapy, symptomatic extracranial lesions


How to cite this article:
Chen XJ, Xiao JP, Li XP, Jiang XS, Zhang Y. Prognostic effect of symptomatic extracranial lesions on survival of recursive partitioning analysis Class III brain metastatic patients treated with stereotactic radiotherapy. J Can Res Ther 2016;12:215-20

How to cite this URL:
Chen XJ, Xiao JP, Li XP, Jiang XS, Zhang Y. Prognostic effect of symptomatic extracranial lesions on survival of recursive partitioning analysis Class III brain metastatic patients treated with stereotactic radiotherapy. J Can Res Ther [serial online] 2016 [cited 2019 Nov 13];12:215-20. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/215/160925




 > Introduction Top


Tumor patients have achieved longer survival with the improvement of anti-tumor therapy, but there has been an increase in the incidence of brain metastases (BMs). Now, BMs occur in approximately 15% of cancer patients, making BMs a very common clinical problem with incidence and mortality rates greater than any other individual malignancy.[1] Stereotactic radiotherapy (SRT) with or without whole-brain radiation therapy (WBRT) is an effective management for both single and multiple BMs. It provides 69–91% actuarial 1-year local tumor control rate, and median survival after treatment varies in different series from 7 to 15 months.[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16] Karnofsky performance scale (KPS) is one of the most important factors for prognosis in patients with BMs both in recursive partitioning analysis (RPA)[17] and graded prognostic assessment (GPA)[18] schemes. The cases with KPS < 70 were an important group in the patients having BMs, and they occupied about 40% of all the cases in a retrospective non case-control study,[19] which is more higher than that in case-control studies. These patients were assumed to have a worse prognosis, and the median survival time was reported to be about 2 months.[17] The recommended treatment for these patients by ASTRO is the best supporting care with or without WBRT.[20] Few randomized clinical trials explored the survival outcome of this group of patients, and these patients were excluded from all the prospective clinical trials on SRT of patients with BMs because of their poor prognosis.[21],[22],[23],[24],[25] Then, the question is “Whether all the brain metastatic patients with poor performance status will not benefit from more aggressive local treatment?” The objective of this study was an evaluation of SRT in RPA Class III brain metastatic patients and to explore the prognostic factors of this group of patients.


 > Materials and Methods Top


Patient population

This study included 56 RPA Class III brain metastatic patients who were treated with SRT ± WBRT for primary treatment at our center between January 2008 and October 2013. Cancer and cerebral metastases were confirmed on the basis of histologic analysis of the specimens obtained from extracranial sites, and findings of magnetic resonance imaging (MRI) of the brain, respectively. The demographic and clinical characteristics of the patients are shown in [Table 1], and all clinical and SRT data were extracted from prospectively maintained database.
Table 1: Patient characteristics

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Stereotactic radiotherapy and whole brain radiation therapy

The BrainLab 5.31 system was used for SRT in the patients. The treatment plan was formulated by a radiation oncologist and a radiation physicist. Delineation of gross tumor volume (GTV) was identified using computed tomography and MRI fusional images. To determine the planning target volume (PTV), we used a margin of 2 mm in all directions around the GTV, and 80–90% isodose enclosed the PTV. Dose fractionation schemes were 20–24 Gy/1 f/1 day and 24–40 Gy/5–12 Gy/2–8f. Fractionated radiation therapy was performed daily or on alternate days. The radiation dose was contingent on tumor volume and location in the brain, and the SRT fractionation scheme is listed in [Table 2]. Dose fractionation scheme of WBRT was 30Gy/3Gy/10f, daily.
Table 2: SRT fractionation scheme

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Further treatment

Twelve patients (21.4%) underwent additional treatment for BMs during further follow-up, which included WBRT (four cases), SRT (five cases), and a combination of these (three case). The decision to taper or continue glucocorticoids after SRT was done by the referring physician, and no information in this regard was available. The data considering efficacy of treatment of the progressive extracranial lesions were not available at the time of this analysis.

Follow-up

The first follow-up occurred at 1–2 months after stereotactic radiation therapy, and further follow-up was conducted at 2 to 3 months intervals thereafter. At each visit, a recent brain contrast-enhanced MRI study was reviewed and compared with previous report. The median follow-up time was 5 months; the final follow-up was on April 15, 2014. No patients were alive at the time of the last follow-up.

Statistical analysis

The overall survival time was calculated as the time between SRT and death from any cause. The KPS score drop time (KDT) was calculated as the time between SRT and 10 points drop of KPS scores compared to the baseline. Kaplan–Meier and Cox proportional hazards regression analyses were used for univariate and multivariate analyses, respectively, for all possible prognostic factors. A two-sided P ≤ 0.05 was considered as statistically significance.


 > Results Top


The MST of the whole group was 5 months (95% confidence interval [CI], 3.4–6.6 months). The presence of symptomatic extracranial lesions (SELs) [P < 0.001, χ2 = 12.256, [Figure 1], GPA class (P = 0.028, χ2 = 4.822), the status of extracranial metastases (P = 0.017, χ2 = 5.730) were the significant prognostic factors in univariate analysis, but the age, sex, number of metastases, KPS score, total target volume, histologic characteristics, treatment regimen were not independent prognostic factors in univariate analysis [Table 3]. Only the presence of SELs (P = 0.001, OR = 5.777, 95% CI, 2.127–15.695) was significantly related to the overall survival time in multivariate analysis [Table 4]. The median survival time of the patients with SELs was 3 months (95% CI, 0.9–5.1 months), which was 8 months (95% CI, 5.3–10.7 months) for the patients without SELs.
Figure 1: Kaplan-Meier curves after SRT for brain metastases in RPA class III patients: those with symptomatic extracranial lesions (n = 25), those without symptomatic extracranial lesions (n = 31). Median survival was 3.0 (95% confidence interval [CI], 0.9-5.1), 8.0 (95% CI, 5.3-10.7) months for the two groups, respectively

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Table 3: Univariate analysis results of overall survival for fifty-six patients

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Table 4: Multivariate analysis results of overall survival for fifty-six patients

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Detailed KPS scores of 44 patients both at the baseline and in the follow-up duration were available and included in the analysis of KDT. The data of the other 12 patients were not complete for the limitation of a retrospective analysis. The median KDT of the 44 patients was 3 months (95% CI, 1.927–4.073 months). The presence of SELs [P < 0.001, χ2 = 19.748, [Figure 2], GPA class (P = 0.029, χ2 = 4.784), the status of extracranial metastases (P = 0.011, χ2 = 6.474) were the significant prognostic factors in univariate analysis, the age, sex, number of metastases, KPS score, total target volume, histologic characteristics, treatment regimen were not independent prognostic factors in univariate analysis [Table 5]. Again only the presence of SELs (P = 0.001, OR = 6.622, 95% CI, 2.108–20.801) was significantly related to KDT in multivariate analysis [Table 6]. The median KDT of the patients with SELs was 1.5 months (95% CI, 0.5–2.5 months), which was 5 months (95% CI, 3.9–6.1 months) for the patients without SELs.
Figure 2: Kaplan-Meier curves after SRT for brain metastases in RPA class III patients: those with symptomatic extracranial lesions (n = 23), those without symptomatic extracranial lesions (n = 21). Median KPS drop time (KDT) was 2.0 (95% confidence interval [CI], 0.5-3.2), 5.0 (95% CI, 3.9-6.1) months for the two groups, respectively

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Table 5: Univariate analysis results of KDT for forty-four patients

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Table 6: Multivariate analysis results of KDT for forty-four patients

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 > Discussion Top


Earlier studies showed that the prognosis of the patients with KPS < 70 was very poor, and the median survival time after WBRT was about 2 months.[17] It is difficult to follow up these patients for the poor prognosis, so RPA Class III brain metastatic patients were excluded from all the randomized clinical trials on brain metastasis treated with SRT.[21],[22],[23],[24],[25] Though the recommended treatments by ASTRO for these patients were WBRT or palliative care without WBRT,[20] it is controversial whether these patients were suitable for more aggressive local treatment.

Sanghavi et al.[10] reported their retrospective cohort study in 2001. Five hundred and two patients with BMs who received WBRT + SRS were compared against the RTOG database and stratified by RPA classification, and the evidence supports a qualified level 3 recommendation regarding a survival advantage for SRS + WBRT over WBRT alone for patients with a KPS < 70 (8.7 months vs. 2.3 months). The study of Lutterbach et al.[26] also gave hope for the patients with RPA Class III. There were 408 brain metastatic patients with RPA Class III, among these patients 315 cases received WBRT, and 93 cases received resection of brain metastatic diseases and WBRT. They defined three prognostic subgroups: Class IIIa (n = 51): age <65 years, controlled primary tumor, single brain metastasis; Class IIIc (n = 44): Age ≥65 years, uncontrolled primary tumor, multiple BMs; Class IIIb (n = 313): All other patients. Median survival in Classes IIIa, IIIb, and IIIc was 3.2, 1.9, and 1.2 months, respectively (P < 0.0001). Intra-class comparisons showed that resection followed by WBRT yielded a significant better survival time compared with WBRT alone. The research showed that even Class III patients may benefit from more aggressive treatment strategies. Hence, we considered that KPS < 70 should not become an exclusion criteria for more aggressive local treatment, and there is need for further study in these patients.

Brain metastatic patients with RPA Class III treated with SRT had a 1.5–6.6 months survival time,[5],[7],[8],[9],[12],[13],[14],[16] which is consistent with our findings. Extracranial disease status, defined as uncontrolled primary cancer, presence of extracranial metastases, or both, consistently showed statistically significant associations with the outcome after radiosurgical or radiotherapeutic management of BMs,[4],[5],[6],[7],[19],[27],[28],[29],[30],[31] and therefore, it was included in the majority of existing prognostic schemes.[5],[8],[17],[18] Once BMs have been controlled by WBRT and focal treatments, death will be caused in the majority of patients (>%) by progressive extracranial malignant disease.[2],[32],[33] SELs not only affect the patient's performance status and organ function, but also more likely lead to recent death. The study reported by Chernov et al.[34] showed that if poor patient performance status was caused by extracranial tumor(s), the median survival time was about 1 month. In our study, SELs had the strongest association with the overall survival in both univariate and multivariate statistical analyses. It was shown that SRT might be effective for patients with poor performance status but without SELs. In such cases, despite relatively large-sized tumors, more number of brain metastasis, the median survival constituted 8 months. In contrast, if the patients with poor performance status had SELs, median survival was just 3 months. Therefore, SELs may be used as a selection criterion for SRT, which may be prognostically important in RPA Class III cohort.

In our study, detailed KPS scores of 44 patients both before and after treatment were available. The median KDT was 3 months for the whole group, the median KDT was 5 months for patients without SELs after SRT, multivariate analysis showed SELs was the only independent prognostic factor of KDT. The patients without SELs have a longer KDT after SRT, which means these patients have a longer duration with stabilized or improved KPS scores. Published Study [35] has shown that for patients with advanced cancers, higher KPS scores correlated significantly with better overall quality of life and higher physical and emotional functioning. Therefore, if RPA Class III brain metastatic patients were without SELs, SRT may likely to improve or stabilize the quality of life of them, of course, further research is needed.

As a retrospective analysis, our study certainly had some limitations. First of all, the results of this study are subjected to any of the biases inherent in a retrospective analysis. Second, there were only 56 patients in the study which may be one of the reasons that made GPA lose its significance in multivariate analysis. Furthermore, we had no data on systemic chemotherapy of the patients at the time of this analysis, and cannot evaluate its therapeutic benefits to the patients.

We are aware that the limitations of our study weaken the strength of our conclusions. However, on the basis of our findings, we conclude that our data support the use of SRT to RPA Class III brain metastatic patients if they were without SELs, but if they had SELs, SRT may not be a reasonable treatment due to the short overall survival time and KDT.

 
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