|Year : 2016 | Volume
| 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
Xiu-Jun Chen1, Jian-Ping Xiao2, Xiang-Pan Li2, Xue-Song Jiang2, Ye Zhang2
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 Publication||13-Apr-2016|
Radiation Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021
Source of Support: None, Conflict of Interest: None
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 2020 May 31];12:215-20. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/215/160925
| > Introduction|| |
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. 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.,,,,,,,,,,,,,, Karnofsky performance scale (KPS) is one of the most important factors for prognosis in patients with BMs both in recursive partitioning analysis (RPA) and graded prognostic assessment (GPA) 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, 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. The recommended treatment for these patients by ASTRO is the best supporting care with or without WBRT. 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.,,,, 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|| |
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.
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.
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.
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.
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|| |
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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| > Discussion|| |
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. 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.,,,, Though the recommended treatments by ASTRO for these patients were WBRT or palliative care without WBRT, it is controversial whether these patients were suitable for more aggressive local treatment.
Sanghavi et al. 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. 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,,,,,,,, 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,,,,,,,,,, and therefore, it was included in the majority of existing prognostic schemes.,,, Once BMs have been controlled by WBRT and focal treatments, death will be caused in the majority of patients (>%) by progressive extracranial malignant disease.,, 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. 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  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.
| > References|| |
Posner JB. Management of brain metastases. Rev Neurol (Paris) 1992;148:477-87.
Mehta MP, Rozental JM, Levin AB, Mackie TR, Kubsad SS, Gehring MA, et al.
Defining the role of radiosurgery in the management of brain metastases. Int J Radiat Oncol Biol Phys 1992;24:619-25.
Alexander E 3rd
, Moriarty TM, Davis RB, Wen PY, Fine HA, Black PM, et al.
Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 1995;87:34-40.
Auchter RM, Lamond JP, Alexander E, Buatti JM, Chappell R, Friedman WA, et al.
A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys 1996;35:27-35.
Cho KH, Hall WA, Gerbi BJ, Higgins PD, Bohen M, Clark HB. Patient selection criteria for the treatment of brain metastases with stereotactic radiosurgery. J Neurooncol 1998;40:73-86.
Chidel MA, Suh JH, Reddy CA, Chao ST, Lundbeck MF, Barnett GH. Application of recursive partitioning analysis and evaluation of the use of whole brain radiation among patients treated with stereotactic radiosurgery for newly diagnosed brain metastases. Int J Radiat Oncol Biol Phys 2000;47:993-9.
Kim DG, Chung HT, Gwak HS, Paek SH, Jung HW, Han DH. Gamma knife radiosurgery for brain metastases: Prognostic factors for survival and local control. J Neurosurg 2000;93 Suppl 3:23-9.
Weltman E, Salvajoli JV, Brandt RA, de Morais Hanriot R, Prisco FE, Cruz JC, et al.
Radiosurgery for brain metastases: A score index for predicting prognosis. Int J Radiat Oncol Biol Phys 2000;46:1155-61.
Noël G, Proudhom MA, Valery CA, Cornu P, Boisserie G, Hasboun D, et al.
Radiosurgery for re-irradiation of brain metastasis: Results in 54 patients. Radiother Oncol 2001;60:61-7.
Sanghavi SN, Miranpuri SS, Chappell R, Buatti JM, Sneed PK, Suh JH, et al.
Radiosurgery for patients with brain metastases: A multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method. Int J Radiat Oncol Biol Phys 2001;51:426-34.
Weltman E, Salvajoli JV, Brandt RA, de Morais Hanriot R, Prisco FE, Cruz JC, et al.
Radiosurgery for brain metastases: Who may not benefit? Int J Radiat Oncol Biol Phys 2001;51:1320-7.
Ford J, Lam HW, Selch M, Salles DA, Solberg T, Wallance R et al
. Prognostic factors for patients with cerebral metastases treated with stereotactic radiosurgery: Comparison with the RTOG recursive partitioning analysis of patients treated with whole brain irradiation. In: Kondziolka D, editor. Radiosurgery. Vol. 4. Basel: Karger; 2002. p. 143-51.
Chang EL, Hassenbusch SJ 3rd
, Shiu AS, Lang FF, Allen PK, Sawaya R, et al.
The role of tumor size in the radiosurgical management of patients with ambiguous brain metastases. Neurosurgery 2003;53:272-80.
Lutterbach J, Cyron D, Henne K, Ostertag CB. Radiosurgery followed by planned observation in patients with one to three brain metastases. Neurosurgery 2003;52:1066-73.
Sheehan J, Niranjan A, Flickinger JC, Kondziolka D, Lunsford LD. The expanding role of neurosurgeons in the management of brain metastases. Surg Neurol 2004;62:32-40.
Chang EL, Selek U, Hassenbusch SJ 3rd
, Maor MH, Allen PK, Mahajan A, et al.
Outcome variation among “radioresistant” brain metastases treated with stereotactic radiosurgery. Neurosurgery 2005;56:936-45.
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.
Nieder C, Nestle U, Motaref B, Walter K, Niewald M, Schnabel K. Prognostic factors in brain metastases: Should patients be selected for aggressive treatment according to recursive partitioning analysis (RPA) classes? Int J Radiat Oncol Biol Phys 2000;46:297-302.
Tsao MN, Rades D, Wirth A, Lo SS, Danielson BL, Gaspar LE, et al.
Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol 2012;2:210-25.
Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al.
Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: A randomized controlled trial. JAMA 2006;295:2483-91.
Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, et al.
Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled trial. Lancet Oncol 2009;10:1037-44.
Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG, et al.
Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: Results of the EORTC 22952-26001 study. J Clin Oncol 2011;29:134-41.
Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999;45:427-34.
Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, et al.
Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: Phase III results of the RTOG 9508 randomised trial. Lancet 2004;363:1665-72.
Lutterbach J, Bartelt S, Stancu E, Guttenberger R. Patients with brain metastases: Hope for recursive partitioning analysis (RPA) class 3. Radiother Oncol 2002;63:339-45.
Lagerwaard FJ, Levendag PC, Nowak PJ, Eijkenboom WM, Hanssens PE, Schmitz PI. Identification of prognostic factors in patients with brain metastases: A review of 1292 patients. Int J Radiat Oncol Biol Phys 1999;43:795-803.
Jeremic B, Becker G, Plasswilm L, Bamberg M. Activity of extracranial metastases as a prognostic factor influencing survival after radiosurgery of brain metastases. J Cancer Res Clin Oncol 2000;126:475-80.
Mintz AH, Kestle J, Rathbone MP, Gaspar L, Hugenholtz H, Fisher B, et al.
A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 1996;78:1470-6.
O'Neill BP, Iturria NJ, Link MJ, Pollock BE, Ballman KV, O'Fallon JR. A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases. Int J Radiat Oncol Biol Phys 2003;55:1169-76.
McDermott MW, Sneed PK. Radiosurgery in metastatic brain cancer. Neurosurgery 2005;57:S45-53.
Coia LR. The role of radiation therapy in the treatment of brain metastases. Int J Radiat Oncol Biol Phys 1992;23:229-38.
Noordijk EM, Vecht CJ, Haaxma-Reiche H, Padberg GW, Voormolen JH, Hoekstra FH, et al.
The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 1994;29:711-7.
Chernov MF, Nakaya K, Izawa M, Hayashi M, Usuba Y, Kato K, et al.
Outcome after radiosurgery for brain metastases in patients with low Karnofsky performance scale (KPS) scores. Int J Radiat Oncol Biol Phys 2007;67:1492-8.
Caissie A, Culleton S, Nguyen J, Zhang L, Zeng L, Holden L, et al.
EORTC QLQ-C15-PAL quality of life scores in patients with advanced cancer referred for palliative radiotherapy. Support Care Cancer 2012;20:841-8.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]