Grade II Pleomorphic Xanthoastrocytoma; a meta-analysis of data from previously reported 167 cases

Journal of Clinical Neuroscience xxx (2018) xxx–xxx

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Clinical study

Grade II Pleomorphic Xanthoastrocytoma; a meta-analysis of data from previously reported 167 cases Supriya Mallick, Rony Benson ⇑, Wineeta Melgandi, Prashanth Giridhar, G.K. Rath Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India

a r t i c l e

i n f o

Article history: Received 9 October 2017 Accepted 17 May 2018 Available online xxxx Keywords: Pleomorphic Xanthoastrocytoma Adjuvant Chemotherapy Radiotherapy Surgery

a b s t r a c t Pleomorphic Xanthoastrocytoma [PXA] is a rare low grade glial tumor commonly affecting young adults. We did this systematic review and meta-analysis to identify prognostic factors and optimal treatment in these patients. A thorough search of the PubMed, Google scholar was made to find all possible publications related to grade II PXA. A total of 167 patients from 89 articles were included in the analysis. Median age of the entire cohort was 20 years. Headache was the most common presentation in 49.1% of the patients followed by seizure in 27.9%. Temporal lobe was the most common location of the tumor. 63% patents underwent a gross total resection [GTR] and 26.7% underwent a sub total excision [STR]. Adjuvant radiation was given to 17.6% of patients. Median follow-up for the entire cohort was 33 months. Estimated median overall survival [OS] for the entire cohort was 209.0 months [96% CI: 149.7–268.3]. Estimated median progression free survival [PFS] was 48 months [95% CI: 31.9–64.0]. In univariate and multivariate analysis younger patients and patients who underwent a GTR had a significantly better survival outcome. Use of adjuvant therapy was not found to be a significant factor affecting PFS or OS. Radiotherapy was used in salvage treatment in 76.1% of the patients. Younger patients and patients who undergo a GTR, have better survival outcomes. There is inadequate evidence to recommend routine adjuvant radiation or chemotherapy in all patients with grade II PXA. Ó 2018 Elsevier Ltd. All rights reserved.

1. Introduction

2. Materials and methods

Pleomorphic Xanthoastrocytoma [PXA] is a low grade glial tumor and commonly affects young adults. Kepes et al in 1979 identified this as a distinct entity [1], later WHO recognized these tumors as grade II and III tumors. These tumors are usually present as localized disease, but isolated reports of early leptomeningeal dissemination have been reported [2]. Surgical resection is considered the cornerstone of therapy and remains so. However, there is debate regarding the extent of resection with few reports suggesting a prolonged survival in patients treated with a gross total resection [GTR] alone. The role of adjuvant treatment in grade II Pleomorphic Xanthoastrocytoma has been not been agreed upon and practice varies widely. The greatest limitation is the sporadic reporting of PXA in the literature owing to its rarity. Hence, in the absence of a robust data, we did this systematic review and individual patient’s data analysis to identify prognostic factors and optimal treatment in these patients.

2.1. Search methodology

⇑ Corresponding author.

A thorough search of the PubMed, Google scholar was made with the MesH terms: ‘‘Xanthoastrocytoma; Pleomorphic Xanthoastrocytoma, Xanthoastrocytoma AND treatment; and Xanthoastrocytoma AND survival” to find all possible publications related to grade II Pleomorphic Xanthoastrocytoma. We retrieved full length articles of those remaining to complete articles for data extraction. In addition, we searched the references in articles to fetch any missing article in our search strategy. After duplicates were removed, the remaining articles were looked into detail. We extracted individual patient data in excel chart with the headings of ‘‘age, gender, presenting complaint, surgery, type of surgery, radiation, chemotherapy, recurrence, duration of progression free interval, overall survival and salvage treatment. Articles which described only the pathological, molecular and other factors unrelated to treatment and outcome were excluded from the data extraction. Once the data extraction was completed it was rechecked by the authors independently to rule out any error and duplication. A total of 89 articles were retrieved on grade II

E-mail address: [email protected] (R. Benson). https://doi.org/10.1016/j.jocn.2018.05.003 0967-5868/Ó 2018 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Mallick S et al. Grade II Pleomorphic Xanthoastrocytoma; a meta-analysis of data from previously reported 167 cases. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.05.003

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S. Mallick et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx

Fig. 1. The PRISMA flow chart showing summary of the search methodology.

PXA with 167 patients [2–89]. The PRISMA flow chart [Fig. 1] explains the data synthesis from the eligible studies. 2.2. Statistical analysis The data was analyzed, categorical variables were summarized as frequency and percentage and quantitative variables as the median and range. Progression free survival [PFS] and overall survival [OS] were calculated from the date of diagnosis to the date of documented progression or death. Kaplan-Meier method was used to for survival analysis. Univariate analysis was performed using log-rank test to find the impact of age, gender, type of surgery, use of radiation, use of chemotherapy on survival outcome. Multivariate analysis was performed using Cox regression test to further evaluate factors significant on univariate analysis. A p value of <0.05 was taken as significant. SPSS v16 [SPSS for Windows, Version 16.0 Chicago, SPSS Inc.] was used for all statistical analysis.

lobe was the most common location of the tumor seen in 42.6% of the patients. 7.7% of the patients had a tumor location in the infratentorial part with 3.9% having it in the spinal cord. Two patients had leptomeningeal dissemination at diagnosis. Median MIB-1 labeling index was found to be 2 [Range: 1–10]. BRAF mutational analyses were performed for 14 cases, and mutations were identified in 10/14 (71.4%.) 3.2. Treatment Surgical details were available for 157 cases. Of these 99 [63%] patients underwent a gross total resection [GTR] and 42 [26.7%] patients underwent a subtotal excision [STR]. Adjuvant radiation details were available in 142 patients of whom only 17.6% received adjuvant radiation. One patient received radiation therapy with palliative intent. In the available reports, all patients received local radiation alone. Adjuvant chemotherapy was used in 8 patients. Chemotherapy regimen varied widely within this cohort. Patient characteristics and treatment details are summarized in Table 1.

3. Results 3.3. Survival outcome 3.1. Demography We retrieved data of 167 individual patients from a total of 89 publications pertaining to grade II PXA. Of these only 3 had a sample size more than 10. The median age of the entire cohort was 20 years [Range 1–84 years]. Interestingly, 30% patients were diagnosed in second decade of life making it the most common age group affected [Fig. 2]. PXA was equally distributed among males and females. Symptom at presentation was available in 71% of the patients of whom headache was the most common presentation in 49.1% followed by seizure in 27.9% of the patients. Temporal

Median follow-up for the entire cohort was 33 months. Estimated median OS for the entire cohort was 209.0 months [96% CI: 149.7–268.3]. In univariate analysis younger patients [30 years] found to have better OS compared to elder patients [>30 years] [Hazard ratio 4.4, p-0.001]. Patients that underwent a GTR had a significantly better OS than those treated with a STR only [Hazard ratio 3.7, p-0.006] [Fig. 3]. Locations of the tumor, use of adjuvant radiation or chemotherapy were not found to be significant factors affecting OS. Multivariate analysis confirmed that age and extent of surgery were significant factors affecting

Please cite this article in press as: Mallick S et al. Grade II Pleomorphic Xanthoastrocytoma; a meta-analysis of data from previously reported 167 cases. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.05.003

S. Mallick et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx

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Fig. 2. Decade wide age distribution in patients with grade II pleomorphic Xanthoastrocytoma.

survival with Hazard ratio of 4.5[p-0.002] and 3.6[p-0.008] respectively [Table 2]. Estimated median PFS was 48 months [95% CI: 31.9–64.0]. In univariate analysis younger patients [30 years] were found to have better PFS compared to elder patients [>30 years] [Hazard ratio 2.2, p-0.007] and patients underwent a GTR had a significantly better PFS than those treated with a STR only [Hazard ratio 2.5, p-0.002]. Multivariate analysis showed that both age and extent of surgery were significant for progression free survival with Hazard ratio of 2.4[p-0.005] and 2.6[p-0.001] respectively. Use of adjuvant therapy was not found to be a significant factor affecting PFS [Fig. 4] [Table 2]. 3.4. Pattern of recurrence and salvage treatment At a median follow-up of 33 months, 63 patients experienced disease progression. The most common pattern of recurrence was local although one patient had leptomeningeal dissemination. Two [3.1%] patients had a different histology at relapse, one each anaplastic astrocytoma and one Glioblastoma. Details of salvage therapy were available in 46 [73%] patients. 10 [21.7%] patients underwent a repeat surgery alone and 10 [21.7%] patients received radiation alone as salvage treatment. 11 [23.9%] patients underwent surgery followed radiation therapy, while 10 [21.7%] patients underwent a repeat surgery followed by chemoradiation. Salvage chemoradiotherapy was used in 5 patients. Radiotherapy was used in salvage treatment plan in 35 [76.1%] patients. Chemotherapy was used as salvage treatment in 15 [32.6%] patients. Chemotherapy regimen varied widely from Temozolomide, Bevacizumab, Carmustine, and Lapatinib. Temozolomide was the most commonly used agent in salvage setting, and was used 9 [60%] of the patients. 4. Discussion Since 1979 when Kepes et al. identified PXA as a distinct tumor entity a limited number of cases have been reported leading to a

dilemma regarding the clinical behavior and optimum treatment of these patients [1]. The present study was formulated with the aim to find the optimum treatment and look into the various prognostic factors in patients with grade II PXA. The rarity of the disease precludes conducting a trial and hence deriving a level I evidence is not realistic. However, an individual patient data analysis is one of the best possible solutions to come up with a better level of evidence than case report or case series only. For the purpose of the analysis, we retrieved 89 publications and derived individual patient data of 167 odd patients. Median age of the entire cohort was 20 years which reflects that PXA is predominantly a disease of the young adults. A Surveillance, Epidemiology, and End Results [SEER] dataset analysis also revealed the median age of 20 years in an analysis of 214 patients [90]. But that analysis included grade II and grade III tumors. Surgery has long been considered the standard of care. The present analysis also showed that extent of surgery and age were significant factors affecting both OS and PFS. An earlier SEER dataset analysis highlighted the importance of achieving a GTR which conferred an OS advantage than those with a STR or no surgery [90]. Surgical standards have improved over last few years with modern techniques like intra-operative MRI, and awake craniotomy. This finding clearly highlights the importance of achieving a GTR. It also appears important to refer such patients to a center with expertise for better management. The aim of study was to identify prognostic factors and optimal treatment in patients with grade II PXA. In the present analysis only 17.6% received adjuvant radiation and this makes it difficult to assess the role of adjuvant radiation in this rare tumor. Radiation in salvage setting was used in 71% of the patients and most commonly in combination with surgery or chemotherapy. The use of multimodality approach has made a significant impact on longterm survival in these patients. The present analysis revealed an impressive median OS of 209.0 months, but with a modest PFS of 48 months. In the recent years, great enthusiasm has been witnessed in exploring the

Please cite this article in press as: Mallick S et al. Grade II Pleomorphic Xanthoastrocytoma; a meta-analysis of data from previously reported 167 cases. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.05.003

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S. Mallick et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx

Table 1 Demographic features and patterns of care in patients with PXA. Age (n = 166)

Median: 20 years (Range 1–84)

1–13 14–20 21–30 31–40 41–50 51–60 >60

50 34 33 23 11 10 5

Table 2 Summary of univariate and multivariate analysis. Factor 30.1 20.5 19.8 13.8 6.6 6 3

Gender (n = 166) Male 83 Female 83

50 50

Symptom at presentation (n = 118) Headache 58 Seizure 33 Others 27

49.1 27.9 23

Location (n = 151) Temporal lobe 64 Parietal lobe 18 Frontal lobe 14 Infratentorial 12 region Spinal cord 6 others 37 BRAF mutation status (n = 14) Positive 10 Negative 4 Surgery (n = 157) Gross total 99 resection Subtotal 42 resection Debulking or 16 biopsy Radiation (n = 142) Adjuvant 24 radiotherapy Palliative 1 radiotherapy No radiotherapy 117 Chemotherapy (n = 129) Adjuvant 8 Salvage 15 (Temozolomide n = 9; Carmustine/Lapatinib or Bevacizumab; n = 6)

42.6 11.6 9.3 7.7 3.9 24.9 71.4 28.6 63.1 26.8 10.1

17.6 0.7

Overall survival Age [30 years vs >30 years] Extent of Surgery (Gross total vs. Subtotal Resection) Progression free survival Age [30 years vs >30 years] Extent of Surgery (Gross total vs. Subtotal Resection)

Univariate analysis

Multivariate analysis

Hazard Ratio

p value

Hazard Ratio

p value

4.4

0.001

4.5

0.002

3.7

0.006

3.6

0.008

2.2

0.007

2.4

0.005

2.5

0.002

2.6

0.001

activates RAS/RAF/MEK/ERK signaling pathway [6]. Different BRAF inhibitors like Vemurafenib and Dabrafenib has shown promising results in the management of recurrent PXA especially in grade III tumors [92,93]. The present analysis revealed 71% BRAF mutation rate which makes PXA an interesting candidate for targeted therapy. This analysis has all few limitations as well. As in individual patient data analyses have been extracted from publications over a long period a temporal bias is of paramount importance. In this time frame, diagnostic criteria, surgical skill, treatment approach has changed which may have a definite impact on the quality of report. In addition, the publications included in the analysis are retrospective which also adds to different types of bias. Because of inhomogeneity in reporting the cases all relevant data of each case was not retrieved. But in rare diseases like PXAs it is difficult to get better quality data than this and a randomized controlled trial is unrealistic. The use of individual patient characteristics for analysis may be considered as one of the merits of this work.

81.7 6.3 11.6

molecular pattern of PXA [91]. V600E BRAF mutation has been reported in around 70% patients with PXA, which constitutively

5. Conclusion Grade II PXA is a disease of young adults with favorable prognosis. Median PFS and OS of these patients are 48 and 209 months. Younger patients and patients who undergo a GTR, have a better outcome. There is inadequate evidence at present to recommend either adjuvant chemotherapy or adjuvant radiation routinely in all patients with Pleomorphic Xanthoastrocytoma.

Fig. 3. Kaplan Meier curves showing overall survival in patients with grade II pleomorphic Xanthoastrocytoma for entire cohort, and Nature of surgery.

Please cite this article in press as: Mallick S et al. Grade II Pleomorphic Xanthoastrocytoma; a meta-analysis of data from previously reported 167 cases. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.05.003

S. Mallick et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx

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Fig. 4. Kaplan Meier curves showing progression free survival in patients with grade II pleomorphic Xanthoastrocytoma for entire cohort, and Nature of surgery.

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Please cite this article in press as: Mallick S et al. Grade II Pleomorphic Xanthoastrocytoma; a meta-analysis of data from previously reported 167 cases. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.05.003