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. 2014 Feb 4;16(6):829–840. doi: 10.1093/neuonc/not330

Historical benchmarks for medical therapy trials in surgery- and radiation-refractory meningioma: a RANO review

Thomas Kaley 1, Igor Barani 1, Marc Chamberlain 1, Michael McDermott 1, Katherine Panageas 1, Jeffrey Raizer 1, Leland Rogers 1, David Schiff 1, Michael Vogelbaum 1, Damien Weber 1, Patrick Wen 1
PMCID: PMC4022224  PMID: 24500419

Abstract

Background

The outcomes of patients with surgery- and radiation-refractory meningiomas treated with medical therapies are poorly defined. Published reports are limited by small patient numbers, selection bias, inclusion of mixed histologic grades and stages of illness, and World Health Organization (WHO) criteria changes. This analysis seeks to define outcome benchmarks for future clinical trial design.

Methods

A PubMed literature search was performed for all English language publications on medical therapy for meningioma. Reports were tabulated and analyzed for number of patients, histologic grade, prior therapy, overall survival, progression-free survival (PFS), and radiographic response.

Results

Forty-seven publications were identified and divided by histology and prior therapies, including only those that treated patients who were surgery and radiation refractory for further analysis. This included a variety of agents (hydroxyurea, temozolomide, irinotecan, interferon-α, mifepristone, octreotide analogues, megestrol acetate, bevacizumab, imatinib, erlotinib, and gefitinib) from retrospective, pilot, and phase II studies, exploratory arms of other studies, and a single phase III study. The only outcome extractable from all studies was the PFS 6-month rate, and a weighted average was calculated separately for WHO grade I meningioma and combined WHO grade II/III meningioma. For WHO I meningioma, the weighted average PFS-6 was 29% (95% confidence interval [CI]: 20.3%–37.7%). For WHO II/III meningioma, the weighted average PFS-6 was 26% (95% CI: 19.3%–32.7%).

Conclusions

This comprehensive review confirms the poor outcomes of medical therapy for surgery- and radiation-refractory meningioma. We recommend the above PFS-6 benchmarks for future trial design.

Keywords: anaplastic meningioma, atypical meningioma, chemotherapy meningioma, malignant meningioma, meningioma

The clinical course of meningiomas treated with systemic medical therapies is poorly defined. Reports of medical therapy for meningiomas suffer from many limitations, including small patient numbers, selection bias, and inclusion of a mixture of histologic grades and patients at various stages of illness from new diagnosis to multiple recurrences after surgery and/or various forms of radiation therapy (RT).1 In addition, a variety of agents with different mechanisms of action have been examined. Importantly, there are no uniform response criteria or well-documented benchmarks regarding overall survival (OS), progression-free survival (PFS), or 6-month PFS (PFS-6) for recurrent meningioma. Additionally, the histology at the time of treatment may be unconfirmed (radiographic diagnosis only), and some tumors classified as World Health Organization (WHO) grade I on initial pathology may have transformed to a higher-grade tumor at the time of medical therapy initiation. Finally, with recently updated WHO criteria there are likely fewer grade I and more grade II meningiomas (due to stage migration), potentially altering interpretation of previous trials.

This analysis of currently available published studies of systemic therapy for recurrent meningioma is part of an effort to define common parameters and benchmarks to use for future clinical trial design. The goal is not to critique published studies or draw conclusions about efficacy of specific agents, but rather to describe the historical outcomes with systemic medical therapies. The objective of this review is to provide endpoint benchmarks for effectiveness for trials in recurrent meningioma that will improve and standardize new clinical trials of medical therapies in this disease.

Materials and Methods

A PubMed literature search was performed for all English language publications reporting on the use of chemotherapy or systemic therapy for the treatment of recurrent meningioma. All reports identified were initially tabulated with the number of patients, histologic grade, prior therapy, and outcome measures, including OS, PFS, PFS-6, and radiographic response. However, these survival outcomes were not uniformly available in all of the studies, and the only survival outcome measure that was available for all, either as reported or extracted from tables, was PFS-6. Studies were divided by histology, and only studies that treated patients who had failed prior radiation and surgery were selected. The only outcome measure that was reproducible across studies was PFS-6. In order to obtain a single historical benchmark, a weighted average was calculated across studies where the PFS-6 value from each study was weighted for the individual sample size of the study compared with the overall sample size.

The analysis characterizes the outcome of meningiomas that fail radiation and surgery and establishes a historical baseline from relatively homogeneous groups of patients for future studies. For medical treatment outcomes, we excluded studies that reported only radiographic response data.

Results

The results of all identified studies of medical therapies for recurrent surgery- and radiation-refractory meningioma are summarized in Table 1.2–47 It is immediately apparent that there is marked heterogeneity in study design and patient inclusion, leading to challenges interpreting the literature and difficulty comparing treatments.

Table 1.

Overall systemic therapies for meningioma

Agent/Regimen Mechanism of Action Author Year n WHO Grade
 Median PFS PFS-6 Best Radiographic Response
n/a I II III SD MR PR CR PD
Hydroxyurea Ribonucleotide reductase inhibitor Schrell 199742 4 – 3 – 1 – – 1 1 2 0 0
Hydroxyurea Ribonucleotide reductase inhibitor Newton 200032 17 – 16 1 – 80 wk – 14 0 0 0 2
Hydroxyurea Ribonucleotide reductase inhibitor Mason 200229 20 – 16 3 1 – – 16 1 0 0 3
Hydroxyurea Ribonucleotide reductase inhibitor Rosenthal 200239 15 – 10 5 – – – 11 0 0 0 2
Hydroxyurea Ribonucleotide reductase inhibitor Paus 200335 1 – 1 – – 22 mo+ – 1 0 0 0 0
Hydroxyurea Ribonucleotide reductase inhibitor Loven 200427 12 – 8 4 – 13 mo – 9 1 0 0 0
Hydroxyurea (with RT) Ribonucleotide reductase inhibitor Hahn 200519 21 4 13 2 2 – – 19 2 0 0 0
Hydroxyurea Ribonucleotide reductase inhibitor Weston 200646 6 1 5 – – – – 3 0 0 0 1
Hydroxyurea Ribonucleotide reductase inhibitor Swinnen 200925 28 – 28 – – 27 mo – 20 0 0 0 6
Hydroxyurea Ribonucleotide reductase inhibitor Chamberlain 20117 60 – 60 – – 4 mo 10% 21 0 0 0 39
Hydroxyurea Ribonucleotide reductase inhibitor Chamberlain 20124 35 – – 22 13 2 mo 3% 15 0 0 0 20
Temozolomide Alkylator Chamberlain 20048 16 – 16 – – 5 mo 0% 13 0 0 0 3
Irinotecan Topoisomerase 1 inhibitor Chamberlain 20069 16 – 16 – – 4.5 mo 6% 12 0 1 0 3
Cyclophos + Adriamycin + vincristine (adjuvant CAV) Combination cytotoxic chemotherapy Chamberlain 19963 14 – – – 14 4.6 y 12 0 2 0 0
Interferon-α Immunomodulation Kaba 199723 6 – 2 1 3 – – 6 0 0 0 0
Interferon-α Immunomodulation Muhr 200130 12 2 6 1 3 – – – – – – –
Interferon-α Immunomodulation Chamberlain 20085 35 – 35 – – 7 mo 54% 26 0 0 0 9
Mifepristone (RU486) Anti-progesterone Grunberg 199118 14 2 7 3 2 – – 8 4 0 0 1
Mifepristone (RU486) Anti-progesterone Steven 200144 80 – 80 – – 10 mo (placebo was 12 mo) – – – – – –
Mifepristone (RU486) Anti-progesterone Grunberg 200617 28 4 22 – 2 – – 8 – – – –
Megestrol acetate Progesterone receptor agonist Grunberg 199016 9 – 8 – 1 – – 6 0 0 0 3
Medroxy-progesterone acetate Synthetic progesterone Jaaskelainen 198620 5 – 4 – 1 – – 4 0 0 0 1
Tamoxifen Anti-estrogen Markwalder 198528 6 – – – – – – 5 0 1 0 0
Tamoxifen Anti-estrogen Goodwin 199312 21 – – – – 15.1 mo – – – – – –
Octreotide Somatostatin analogue Runzi 198940 1 1 – – – – – 1 0 0 0 0
Octreotide Somatostatin analogue Garcia-Luna 199311 3 – 2 – 1 – – 3 0 0 0 0
Octreotide Somatostatin analogue Jaffrain-Rea 199821 1 – – – – – – 1 0 0 0 0
Octreotide Somatostatin analogue Johnson 201122 11 – 3 3 5 17 wk – 8 0 0 0 3
Sandostatin LAR Somatostatin analogue Chamberlain 20076 16 – 8 3 5 5 mo 44% 5 0 5 0 6
Pasireotide LAR (SOM230C) Somatostatin analogue Norden 20112 26 – 9 17 20 wk 29% 16 0 0 0 6
Imatinib PDGFR TKI Wen 200644 1 – – – – – – – – – – –
Imatinib PDGFR TKI Wen 200945 23 – 12 5 5 2 mo 29.4% 9 0 0 0 10
Erlotinib EGFR TKI Raizer 201037 1 – – 1 – – – 1 0 0 0 0
Erlotinib or gefitinib EGFR TKI Norden 201034 25 – 8 9 8 10 wk 28% 8 0 0 0 17
Imatinib + hydroxyurea PDGFR TKI + ribonucleotide reductase inhibitor Reardon 201229 21 – 8 9 4 7 mo 61.9% – – – – –
Vatalanib (PTL-787) VEGFR + PDGFR TKI Raizer 201037 21 – – 14 7 – 37.5% 12 0 1 0 5
Sunitinib VEGFR + PDGFR TKI Kaley 201024 36 – – 30 6 5.2 mo 42% 25 0 1 1 8
Bevacizumab Anti-VEGF antibody Puchner 201036 1 – – – 1 – – 0 0 1 0 0
Bevacizumab Anti-VEGF antibody Goutagny 201113 1 1 – – – – – 0 1 0 0 0
Bevacizumab + paclitaxel Anti-VEGF antibody Wilson 201247 1 – 1 – – 15 mo + – 0 1 0 0 0
Bevacizumab Anti-VEGF antibody Lou 201226 14 1 5 5 3 17.9 mo 85.7% 11 0 1 0 2
Bevacizumab Anti-VEGF antibody Nayak 201231 15 – – 6 9 26 wk 43.8% 13 2 0 0 0
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Abbreviations: PDGFR, platelet-derived growth factor receptor; TKI, tyrosine kinase inhibitor; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; SD, stable disease; MR, minor response; PR, partial response; CR, complete response; PD, progressive disease. *Some numbers may not add up due to differences in number accrued vs number reported on or evaluable.

One major problem with interpreting the literature on medical therapies for recurrent meningioma is the inclusion of differing histologies in the reports. Therefore, studies were divided into 2 groups, one including patients with WHO grade I meningiomas only and one including WHO grades II and III meningiomas. WHO grades II and III meningiomas were grouped together, as these grades of meningioma were almost universally reported together, and consequently no further separation could be made between these tumor grades.

Another major problem with interpreting the literature is the inclusion of patients at various stages of their illness, ranging from newly diagnosed tumors to tumors that have recurred despite multiple surgeries and radiation treatments and, in some cases, multiple chemotherapy regimens. Therefore, only studies that included a majority of patients who failed both surgery and radiation were included in the analysis.

The heterogeneity of response criteria further adds to the difficulty of comparison across studies. Standard Macdonald criteria, which were defined for high-grade gliomas, define disease progression as a 25% increase in tumor burden; however, many studies did not define criteria as to what constituted progression prior to study entry.48–50 Most studies report survival outcomes but not in uniform fashion, with some studies reporting median OS and others reporting median PFS or PFS-6. Progression-free survival at 6 months was the most uniform response metric, either reported specifically or extractable from tabulated patient outcomes. In addition, PFS-6 rate was the only method that could then be summed across studies allowing for a combined single historical value.

Radiographic response rate was recorded when available but not selected as the primary outcome measure, as this provided little insight into treatment outcome and additionally is hindered by the variety of measures of response assessment. In addition, when response was reported, the vast majority of patients manifested stable disease as the best response.

WHO Grade I Meningioma

The WHO grade I meningioma group (Table 2) is unique in having the only phase III study of chemotherapy reported to date. Mifepristone (RU486, an anti-progesterone agent) was investigated in a phase III double-blind randomized placebo-controlled trial.44 However, this trial was reported in only abstract form, so the full details regarding patient characteristics, outcomes, and statistical analyses are not available, and the study has not yet been published after formal peer review. The trial included only patients with a pathologic diagnosis (surgery) who had failed RT (unless medically unsafe or patient refusal, a number not stated in the abstract). The only outcome reported was median PFS, which did not differ among the 80 treated patients (10 mo) and the 80 placebo patients (12 mo) (P = .44).

Table 2.

WHO grade I meningioma

Agent/Regimen Author Year WHO Grade
 Prior Therapy Median PFS (TTP) PFS-6 Median OS Best Radiographic Response of Evaluable patients
n/a I SD MR PR CR PD
Hydroxyurea Schrell 199742 – 3 3 prior surgery – 2/3 – 0 1 2 0 0
2 prior RT
Hydroxyurea Newton 200032 4 13 13 prior surgery 80 wk – – 14 0 0 0 2
7 prior RT
9 with POD pre-tx
1 atypical due to brain invasion
Hydroxyurea Mason 200229 – 16 16 prior surgery NR – – 15 1 0 0 0
4 prior RT
Hydroxyurea Paus 200335 – 1 None 22 mo+ – 22 mo+ 1 0 0 0 0
Hydroxyurea Loven 200427 – 8 All prior surgery – – – 6 1 0 0 0
6 prior RT
Hydroxyurea (with RT) Hahn 200519 – 13 All surgery – – – 11 2 0 0 0
None prior RT
Hydroxyurea Weston 200646 1 5 Not documented – – – 3 0 0 0 1
Hydroxyurea Swinnen 200925 – 28 Not documented 27 mo – NR 20 0 0 0 6
Hydroxyurea Chamberlain 20117 – 60 All prior surgery (29 >1 op) 4 mo 10% – 21 0 0 0 39
All prior RT
Temozolomide Chamberlain 20048 – 16 All prior surgery 5 mo 0% 7 mo 13 0 0 0 3
All prior RT
Irinotecan Chamberlain 20069 – 16 All prior surgery 4.5 mo 6% 7 mo 12 0 1 0 3
All prior RT
Interferon-α Kaba 199723 – 2 All prior surgery – – – 2 0 0 0 0
1 had RT
Interferon-α Chamberlain 20085 – 35 All prior surgery 7 mo 54% 8 mo 26 0 0 0 9
All prior RT
34 prior chemotherapy
Mifepristone (RU486) Steven 200144 – 80 Not described, but prior surgery and RT for eligibility 10 mo – – – – 2 – –
Megestrol acetate Grunberg 199016 – 8 All biopsy – 5/8 – 6 0 0 0 2
None had RT 62.50%
Medroxy-progesterone acetate Jaaskelainen 198620 – 4 All prior surgery – – – 4 0 0 0 0
Octreotide Garcia-Luna 199311 – 2 All surgery – – – 2 0 0 0 0
Octreotide Johnson 201122 – 3 All surgery – – – 3 0 0 0 0
9/11 overall had RT
Sandostatin LAR Chamberlain 20076 – 8 Overall: – 3/7 – 2 0 3 0 3
14/16 prior surgery
13/16 prior RT
12/16 prior chemo
Pasireotide LAR (SOM230C) Norden 20112 – 9 Overall: 27 wk 50% – – – – – –
All prior surgery
22/26 prior RT
Imatinib Wen 200945 – 13 Overall: 3 mo 45% – – – – – –
1–8 surgery
0–5 RT
Erlotinib or gefitinib Norden 201034 – 8 Overall: 9 wk 25% 13 mo – – – – –
All prior surgery
21/25 prior RT
8/25 prior chemotherapy
Imatinib + hydroxyurea Reardon 201229 – 8 Overall 7/21 > 3 recurrences 13.9 mo 87.50% 66 mo – – – – –
Bevacizumab Loe 2012 5 3–7 prior treatments 12.2 mo 80% – – – – – –
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Abbreviations: POD, progression of disease; tx, therapy; TTP, time to progression; SD, stable disease; MR, minor response; PR, partial response; CR, complete response; PD, progressive disease.

The remaining manuscripts are heterogeneous and summarized in Table 3 by survival outcomes. These studies generally reported patients who had failed prior surgery and RT. A variety of agents were used (hydroxyurea, temozolomide, irinotecan, interferon-α, octreotide analogues, and tyrosine kinase inhibitors, including imatinib, erlotinib, and gefitinib in addition to mifepristone), and included were retrospective studies, a pilot study, a phase II study, an exploratory arm of 2 phase II studies, and a phase III study. None of these studies reported clinically significant activity as defined by radiographic response and PFS. The majority lacked a statistical plan for comparison, did not have a historical control for comparison, or appeared unlikely to meet their predetermined endpoint or accrual and stopped early. For the purposes of this paper, these therapies were considered ineffective.

Table 3.

Survival of WHO grade I meningiomas that failed surgery and RT

Agent/Regimen Author (study type) Registration Number Year WHO Grade
 Prior Therapy Response Criteria Median PFS (TTP) PFS-6 Median OS
n / a I
Hydroxyurea Schrell (retrospective) – 199742 – 3 3 prior surgery Defined percent change – 2/3 –
2 prior RT 67%
Hydroxyurea Chamberlain (retrospective) – 20117 – 60 All prior surgery (29 >1 op) Macdonald 4 mo 10% –
All prior RT
Temozolomide Chamberlain (phase II) – 20048 – 16 All prior surgery Macdonald 5 mo 0% 7 mo
All prior RT
Irinotecan Chamberlain (phase II) – 20069 – 16 All prior surgery Macdonald 4.5 mo 6% 7 mo
All prior RT
Interferon-α Chamberlain (phase II) – 20085 – 35 All prior surgery Macdonald 7 mo 54% 8 mo
All prior RT
34 prior chemotherapy
Mifepristone (RU486) Steven (phase III) – 200144 – 80 Prior surgery and RT for eligibility Not defined 10 mo – –
Sandostatin LAR Chamberlain (pilot) – 20076 – 8 Overall: Macdonald – 3/7 –
14/16 prior surgery 43%
13/16 prior RT
12/16 prior chemo
Pasireotide LAR (SOM230C) Norden (phase II) NCT00859040 20112 – 9 Overall: Macdonald 27 wk 50% –
All prior surgery
22/26 prior RT
Imatinib Wen (phase II) NCT00045734 200945 – 13 Overall: Macdonald 3 mo 45% –
1–8 surgery
0–5 RT
Erlotinib or gefitinib Norden (exploratory arm of phase II) NCT00045110 201034 – 8 Overall: Macdonald 9 wk 25% 13 mo
NCT00025675 All prior surgery
21/25 prior RT
8/25 prior chemotherapy
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Abbreviation: TTP, time to progression.

The primary outcome common to all but the phase III mifepristone study was PFS-6. Including only the prospective studies of temozolomide, irinotecan, interferon-α, Sandostatin long-acting release (LAR), pasireotide LAR, imatinib, erlotinib, and gefitinib in patients who had failed surgery and RT, the weighted average PFS-6 rate was 29% (range 0%–54%; 95% confidence interval [CI]: 20.3%–37.7%).2,5,6,8,9,34,45 If the 2 retrospective studies reporting on hydroxyurea were included, the weighted average PFS-6 dropped to 23% (range 0%–67%; 95% CI: 16.6%–29.4%).7,42

Median PFS and median OS are less frequently reported. For 8 papers with data available, patients receiving some form of medical therapy after failure of surgery and radiation had a median PFS ranging from 9 to 30.4 weeks.2,5,7–9,34,43,45 In the 4 manuscripts with data available, median OS ranged from 7 to 13 months.5,8,9,34 The single phase III trial reported a median PFS of 10 months.43 Notably, the longest OS reported is derived from the combined erlotinib/gefitinib paper, a study that recruited very few patients, stopped early, and demonstrated no difference in outcome in patients with WHO grade I meningioma compared with WHO combined grade II/III meningioma.

In summary, these data suggest that patients with WHO grade I meningioma who fail surgery and RT and receive medical or systemic therapy have poor survival outcomes. Progression-free survival at 6 months is the most uniform outcome reported, with various studies reporting PFS-6 rates ranging from 0% to 67%. Combining all of these patients from retrospective and prospective studies, the weighted average PFS-6 rate is 23%; combining only the prospective studies, the weighted average PFS-6 rate is 29%. The only phase III data suggest a median PFS of 10 months, but this study was performed years ago and is reported only in abstract, rendering generalization of these data challenging. In conclusion, the current analysis suggests use of a PFS-6 benchmark of 29%, ignoring the prospective phase III mifepristone data for the reasons noted above. This analysis confirms the aggressive nature of surgery- and radiation-refractory recurrent WHO grade I meningioma.

WHO Grade II/III Meningioma

The natural history of WHO grades II and III meningiomas that have failed surgery and RT is also challenging to interpret in the available literature (Table 4). No phase II or phase III study restricted to this patient population has been completed and published aside from abstracts. The recent phase II studies of sunitinib, pasireotide LAR, and vatalanib are completed, and publication is expected in the near future.2,24,51

Table 4.

WHO grade II/III meningioma

Agent/Regimen Author Year WHO Grade
 Prior Therapy Group Median PFS PFS-6 Med OS Best Radiographic Response of Evaluable Patients
II III SD MR PR CR PD
Hydroxyurea Schrell 199742 – 1 Failed surgery and RT WHO III – 1/1 – 1 0 0 0 0
Hydroxyurea Newton 200032 1 – ? ? ? ? ? ? ? ? ?
Hydroxyurea Mason 200229 3 1 All >1 surgery WHO II 19 wk 1/3 – 2 0 0 0 1
All prior RT WHO III 4 wk 0/1 – 0 0 0 0 1
Hydroxyurea Loven 200427 4 – All surgery WHO II – – – 3 0 0 0 0
0 had prior RT
Hydroxyurea (with RT) Hahn 200519 2 2 All surgery II/III 13 mo – – 4 0 0 0 0
None prior RT
Hydroxyurea Chamberlain 20124 22 13 All prior surgery Overall 2 mo 3% II–8 mo 15 0 0 0 20
All prior RT III–6 mo
Cyclophos + Adriamycin + vincristine (adjuvant CAV) Chamberlain 19963 – 14 Adjuvant tx after surgery and RT WHO III 4.6 y – 5.3 y 8 0 2 0 0
4 GTR, 10 STR
Interferon-α Kaba 199723 1 3 All prior surgery II/III – – – 4 0 0 0 0
All prior RT
Megestrol acetate Grunberg 199016 – 1 Prior surgery, RT, and chemotherapy III 2 mo 0/1 – 0 0 0 0 1
Medroxy-progesterone acetate Jaaskelainen 198620 – 1 Prior surgery III – – – 0 0 0 0 1
Octreotide Garcia-Luna 199311 – 1 biopsy III 6 wk – – 1 0 0 0 0
Octreotide Johnson 201122 3 5 All surgery II – – – 3 0 0 0 0
9/11 overall had RT III – – – 2 0 0 0 3
Sandostatin LAR Chamberlain 20076 3 5 Overall: II – 0/2 – 1 0 1 0 1
14/16 prior surgery
13/16 prior RT III – 2/5 – 1 0 1 0 3
12/16 prior chemo
Pasireotide LAR (SOM230C) Norden 20112 17 Overall: II/III 26 wk 20% – – – – – –
All prior surgery
22/26 prior RT
Imatinib Wen 200945 5 5 Overall: II/III 2 mo 0% – – – – – –
1–8 surgery
0–5 RT
Erlotinib Raizer 201037 1 – Not discussed II – – – 1 0 0 0 0
Erlotinib or gefitinib Norden 201034 9 8 Overall: II/III 16 wk 29% 33 mo – – – – –
All prior surgery
21/25 prior RT
8/25 prior chemotherapy
Imatinib + hydroxyurea Reardon 201229 9 4 Overall 7/21 > 3 recurrences II/III 5.3 mo 46.20% 20.9 mo – – – – –
Vatalanib (PTL-787) Raizer 201051 14 7 All prior surgery All – 37.50% – 12 0 1 0 5
All prior RT II 3.7 mo – 22.9 mo – – – – –
III 3.6 mo – 19.6 mo – – – – –
Sunitinib Kaley 201024 30 6 All prior surgery II/III 5.2 mo 42% 24.6 mo 25 – 1 1 8
All prior RT
Bevacizumab Puchner 201036 – 1 Prior surgery + RT III – – – 0 0 1 0 0
Bevacizumab Loe 2012 5 3 1–7 prior treatments II/III 15.8 mo 87.50% – – – – – –
Bevacizumab Nayak 201231 6 9 All prior surgery II/III 26 wk 43.80% 15 mo 13 2 0 0 0
All prior RT
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Abbreviations: Cyclophos, cyclophosphamide; GTR, gross total resection; STR, subtotal resection; SD, stable disease; MR, minor response; PR, partial response; CR, complete response; PD, progressive disease; tx, therapy.

Only those studies of patients who have failed surgery and RT are summarized in Table 5. These studies represent a heterogeneous group of treatments and trial designs, including phase II studies, exploratory arms of other studies, retrospective reports, and case studies. These trials used a variety of agents, including hydroxyurea, megestrol acetate, octreotide analogues, bevacizumab, and tyrosine kinase inhibitors. Importantly, there is no completed phase III study in this patient population. Combining these studies including prospective and retrospective studies and possibly active agents, patients treated with some form of systemic therapy at the time of radiation failure have a PFS-6 ranging from 0% to 64% with a weighted average PFS-6 of 26% (95% CI: 19.3%–32.7%).

Table 5.

Survival of WHO grade II and III meningioma that failed surgery and RT

Agent/Regimen Author (study type) Registration Number Year WHO Grade
 Response Criteria Prior Therapy Group Median PFS PFS-6 Median OS
II III
Hydroxyurea Schrell (retrospective) – 199742 – 1 Defined percent change Failed surgery and RT WHO III – 1/1 –
Hydroxyurea Mason (retrospective) – 200229 3 1 Macdonald All >1 surgery WHO II 19 wk 1/3 –
All prior RT WHO III 4 wk 0/1 -
Hydroxyurea Chamberlain (retrospective) – 20124 22 13 Macdonald All prior surgery Overall 2 mo 3% II–8 mo
All prior RT III-6 mo
Megestrol acetate Grunberg (retrospective) – 199016 – 1 Not defined Prior surgery, RT, and chemotherapy III 2 mo 0/1 –
Sandostatin LAR Chamberlain (pilot) – 20076 3 5 Macdonald Overall: II – 0/2 –
14/16 prior surgery III – 2/5 –
13/16 prior RT
12/16 prior chemo
Pasireotide LAR (SOM230C) Norden (phase II) NCT00859040 20112 17 Macdonald Overall: II/III 26 wk 20% –
All prior surgery
22/26 prior RT
Imatinib Wen (phase II) NCT00045734 200945 5 5 Macdonald Overall: II/III 2 mo 0% –
1–8 surgery
0–5 RT
Erlotinib or gefitinib Norden (exploratory arm of phase II) NCT00045110 201034 9 8 Macdonald Overall: II/III 16 wk 29% 33 mo
NCT00025675 All prior surgery
21/25 prior RT
8/25 prior chemo
Vatalanib (PTL-787) Raizer (phase II) NCT00348790 201151 14 7 Macdonald All prior surgery II 7.6 mo 64.30% 26 mo
All prior RT III 3.6 mo 37.50% 23 mo
Sunitinib Kaley (phase II) NCT00589784 201024 30 6 Macdonald All prior surgery II/III 5.2 mo 42% 24.6 mo
All prior RT
Bevacizumab Nayak (retrospective) – 201231 6 9 RANO All prior surgery II/III 26 wk 43.80% 15 mo
All prior RT
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A North American Brain Tumor Consortium (NABTC) phase II study of the platelet-derived growth factor receptor tyrosine kinase inhibitor imatinib, terminated prematurely due to slow accrual and lack of response, was arguably the best designed prospective trial.45 Therefore, although its statistical criteria were not met, it suggested that imatinib is an ineffective drug, with a median PFS of 2 months and PFS-6 of 0% (it is important to note that this included only 10 patients). This may reflect the natural history of essentially untreated radiation- and surgery-refractory recurrent grade II/III meningiomas. Other prospective studies include the somatostatin analogues (both the Sandostatin LAR pilot study and the pasireotide LAR phase II study) and the NABTC phase II studies of erlotinib and gefitinib in malignant glioma that enrolled patients with recurrent meningioma to an exploratory arm. These studies report PFS-6 rates of 20%–29% in surgery- and RT-refractory high-grade meningioma.

The activity of these drugs is uncertain. For the patients enrolled in most of these trials, such treatments were deemed ineffective. Therefore, if we exclude from our analysis the sunitinib, vatalanib, and bevacizumab trials in which treatment appears to have some activity, the PFS-6 rate for patients treated with hydroxyurea, megestrol acetate, Sandostatin LAR, pasireotide LAR, imatinib, erlotinib, and gefitinib is 14% (95% CI: 6.9%–21.1%).2,4,6,16,29,34,42,45 These results are summarized in Table 6.

Table 6.

PFS-6 analysis of WHO grade II and III meningioma that failed surgery and RT

Drug Design n PFS-6
Including all agents (hydroxyurea, megestrol acetate, Sandostatin LAR, pasireotide LAR, imatinib, erlotinib, gefitinib, vatalanib, sunitinib, and bevacizumab) Retrospective reports, pilot study, phase II trials 164 26%
Including all agents except the case reports Retrospective reports, pilot study, phase II trials 158 25%
Including all agents except the potentially active drugs (ie, excluding bevacizumab, sunitinib, and vatalanib) Retrospective reports, pilot study, phase II trials 92 14%
Including only negative phase II studies (imatinib and SOM230C) Phase II 27 11%
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Other survival outcomes are more difficult to ascertain from these studies. For publications with data available, patients receiving some form of medical therapy after failure of surgery and radiation had a median PFS ranging from 4 weeks to 26 weeks.2,4,6,16,29,34,35,45 This patient population had a median OS ranging from 6 months to 33 months.4,34

One additional challenge to interpreting these data is that this report includes outcomes of the combined group including both WHO grades II and III tumors. It is quite possible, and arguably likely, that the outcomes differ according to WHO grade. Where available, stratification by grade II versus III is presented in Table 5. However, the overall numbers are very low.

In summary, currently available data suggest that patients with WHO grades II and III meningioma who fail surgery and RT and receive medical therapy have very poor survival outcomes. PFS-6 is the most uniform outcome to report, with various studies reporting PFS-6 rates ranging from 0% to 64%. The most conservative approach to the natural history of these tumors is a PFS-6 rate of 0% based upon the prospective phase II imatinib trial. Combining all studies and patients together, including inactive therapies, active agents, retrospective and prospective studies, and both histologies, the overall PFS-6 rate is 26% (95% CI: 19.3%–32.7%), similar to the summed value seen with surgery- and radiation-refractory recurrent grade I meningioma.

Discussion

Our comprehensive review of the available literature confirms the poor clinical outcome of recurrent meningiomas that have failed surgery and RT and have been subsequently treated with chemotherapy or other systemic agents. PFS-6 is the most consistently recorded endpoint in these various studies. The considerable heterogeneity in these studies, in addition to the patient selection bias, limits our conclusions, notwithstanding our attempt to homogenize the published literature as best as possible (Table 7).

Table 7.

Survival outcome estimates for medical treatment after surgery and radiation failure

Median PFS PFS-6 Median OS
WHO grade I meningioma
 Phase III data 10 mo – –
 All prospective trials 9–30.4 wk 29% 7–13 mo
 All reports (prospective + retrospective) 9–30.4 wk 23% 7–13 mo
WHO grade II and III meningioma
 Imatinib 2 mo 0% –
 All negative reports (prospective + retrospective) 1–6 mo 14% 6–33 mo
 All reports (prospective + retrospective + possibly active agents) 1–6 mo 26% 6–33 mo
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Upon analysis of the literature, multiple limitations pervade a meaningful comparison across studies, in addition to the heterogeneity discussed above. First, no studies have any criteria on the growth rate of the tumors prior to treatment, which is compounded by the lack of uniform time points of imaging for detection of tumor progression. Most variability occurs between using a 2-month imaging interval and a 3-month imaging interval, which is unlikely to alter the 6-month statistics; however, the growth rate may cause discrepancies. The growth rate may also account for the similarity in results of the grade I and grade II/III groups, and authors should include this parameter to help us better interpret future study results. A second issue that may affect these results is the lack of uniform criteria for documenting true tumor progression after multiple radiation treatments in order to exclude patients who actually have radiation necrosis. This may affect not only the “negative” studies in which drugs were deemed ineffective, but also the anti-angiogenic therapy studies in which the therapy may have an effect on necrosis itself. Third, the reporting of survival outcomes such OS and PFS was rather poor. Therefore, we are unable to correlate PFS with OS to determine whether PFS is truly a surrogate for OS and an ideal endpoint. Finally, our study is limited by publication bias, as we included only peer-reviewed literature from PubMed. Therefore, we may have missed negative studies that were never published in full or those published in only meeting abstracts.

Using the collated tables included herein, there are several different benchmarks that can be used at the discretion of the investigators, goals of the study, and tumor histology. However, to limit overstating the benefit of ineffective therapies, the Revised Assessment in Neuro-Oncology (RANO) working group recommends the following suggestions (Table 8) for single arm or phase II studies. For WHO grade I meningioma, consider powering future trials against a PFS-6 rate of 29%, with PFS-6 <40% probably not of interest. For WHO grade II/III meningiomas, future trials should be powered against a PFS-6 of 26%, with PFS-6 <30% probably not of interest. Of course, how high or low to set the bar is at the discretion of each investigator and study, but this should be reported in each study to allow broader interpretation of positive and negative results. These may also change as more information is learned, particularly about pretreatment growth rates, which may provide better subgroups than WHO grade. Radiographic responses are very uncommon, although currently it is unclear whether this is an effect of tumor biology or ineffective therapy. Additionally, the growth rate of meningiomas is quite variable and may need consideration as well. For comparative trials and specifically phase III trials, investigators may prefer other endpoints—such as survival—that may be more feasible in that setting.

Table 8.

PFS-6 benchmarks for future studies

PFS Rate WHO Grade I WHO Grade II and Grade III
Benchmark 29% 26%
Rate not of interest <40% <30%
Rate probably of interest >50% >35%
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What is very clear from these data is that as a field we need to improve and standardize not only the historical comparisons but the data that are reported, which should include PFS and OS, prior therapies, and probably pretreatment growth rate. A future RANO manuscript in preparation will specifically address meningioma response criteria and attempt to address some of these issues.

Funding

None declared.

Conflict of interest statement. Drs Kaley, Chamberlain, McDermott, Panageas, and Weber have no conflict of interest. Dr Barani has a BrainLab Inc research grant. Dr Raizer is on advisory boards for Novartis and Roche/Genentech and on a speakers bureau for Roche/Genentech. Dr Rogers has received an NCI ACTNOW (Accelerating Clinical Trials and Novel Oncologic Pathways Initiative) grant to study meningioma. This was applied to RTOG 0539 and used solely to increase reimbursement for enrolling institutions. Dr Schiff is on an advisory board for Genentech. Dr Vogelbaum has received honoraria from Merck. Dr Wen received research support from Pfizer, Novartis, and Genentech and is on an advisory board for Novartis and Genentech.

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