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. Author manuscript; available in PMC: 2018 Oct 1.
Published in final edited form as: J Clin Neurosci. 2017 Jul 12;44:101–106. doi: 10.1016/j.jocn.2017.06.070

Clinical Outcomes in Recurrent Glioblastoma with Bevacizumab therapy: An Analysis of the Literature

Matthew Tipping 1, Jens Eickhoff 2,3, H Ian Robins 3,4
PMCID: PMC5581989  NIHMSID: NIHMS888343  PMID: 28711289

Abstract

Bevacizumab (BEV) is a common treatment for recurrent glioblastoma (GBM). After progression on BEV, there is no consensus on subsequent therapy, as multiple chemotherapy trials have failed to demonstrate discernible activity for salvage. A previous review (995 patients) estimated a progression free survival (PFS) on BEV of 4.2 months (SD±2.1) with an overall survival (OS) after progression on BEV at 3.8 months (SD +/− 1). We endeavored to establish a more rigorous historical control, both as a benchmark for efficacy, and a prognostic tool for clinical practice. A comprehensive literature review was performed utilizing PubMed and societal presentation abstracts. A total 2388 patients from 53 arms of 42 studies were analyzed in three groups: 1) thirty-two studies in which survival post-BEV was determined by subtracting PFS from OS (2045 patients): PFS on BEV =4.38 months (95% CI 4.09–4.68); OS post-BEV =3.36 months (95% CI 3.12–3.66); 2) two studies (94 patients) in which OS post-BEV is reported: OS= 3.26 (95% CI 2.39–4.42); 3) eight studies of salvage therapy after progression on BEV (249 patients): of OS post-BEV =4.46 months (95% CI 3.68–5.54). These estimates provide a firm historical control for PFS on BEV, as well as OS after disease progression on BEV therapy.

Keywords: bevacizumab, recurrent glioblastoma, overall survival

Introduction

Among primary brain cancers, glioblastoma (GBM) is both the most common and the most aggressive. Average survival from diagnosis is dismal at approximately 15 months [1]. Standard treatment consists of maximal surgical resection followed by concurrent radiotherapy with temozolomide and subsequent maintenance temozolomide. Unfortunately, glioblastomata uniformly recurs and effective salvage therapies at the time of recurrence are frustratingly limited.

One of the most frequently used salvage treatments is BEV, a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF). BEV received conditional accelerated American Food and Drug Administration (FDA) approval for treatment of recurrent GBM in 2009 based on promising non-controlled phase 2 trials. [2, 3]. (Two large phase 3 trials of BEV in the newly diagnosed setting failed to demonstrate improvement in overall survival over standard radiotherapy/temozolomide treatment [4, 5]). Even so, BEV remains a common choice for GBM therapy in the recurrent setting. Unfortunately, despite multiple trials of various salvage chemotherapy regimens, no chemotherapeutic agent has been demonstrated to significantly alter survival after tumor progression on BEV [612].

To date, we are aware of only one previous review exploring survival after progression on BEV. To establish a historical control for a phase 2 study of retreatment radiation, Magnuson et al performed a review of the literature including 922 patients, reporting a median overall survival (OS) after progression on BEV of 3.8 months (SD +/− 1.0 months) and a progression free survival (PFS) on BEV of 4.2 months (SD±2.1) [13]. This analysis, however, did not statistically incorporate confidence intervals of the included trials.

The study reported below was initiated in order to update this work and attempt a more rigorous statistical analysis of trials reporting outcomes in recurrent GBM therapy with BEV. The goal of this review is to provide a strong historical control/database, which can serve as a prognostic guide clinically for physicians, as well a target for success in future Phase II clinical trials of salvage therapies after progression on BEV.

Methods

Sources of data

We performed a comprehensive literature search via PubMed (updated through July 1, 2016) using the search words “bevacizumab”, “avastin” and “glioblastoma.” No language or date limitations were imposed. Abstracts and virtual meeting presentations from the American Society of Clinical Oncology conferences held between January 2010 and August 2015 and Society for Neuro-Oncology between November 2013 and November 2014 were also searched to identify relevant information. The reference lists of identified articles were examined for additional publications.

Study selection

The following selection criteria were applied: (i) the study population included only patients with histologically proven GBM (World Health Organization grade IV), all of whom had experienced tumor progression measurable on MRI and who received BEV as salvage chemotherapy; (ii) the study reported information on the diagnosis of recurrent GBM, treatment protocol, and reported data for the estimation of overall survival after progression on BEV (either directly, or as median PFS and OS after receiving BEV); and (iii) if there had been duplicate publication of the same patient cohort, the most recent or complete report was used for further analyses. Two authors (HIR, MDT) extracted the data.

Extraction of data

We extracted details regarding the number of patients and treatment information for all studies. For studies of BEV as therapy for recurrence median overall survival after BEV failure was used if available. If this value was not reported, median PFS was subtracted from median OS to estimate median overall survival post-progression on BEV. For studies of salvage therapies attempted after BEV failure median overall survival was extracted. Data reported in days were converted to months using 28 days per 1 month.

Statistical analyses

The analysis was conducted using a fixed effects parametric survival analysis model, assuming that survival (PFS and OS) follows an exponential distribution. The reported median and 95% confidence intervals (if reported) were used to estimate the parameters of the survival distribution for each study, utilizing the methods of moments estimator. The parametric bootstrap technique was utilized to estimate the survival parameters of the combined studies, which was then used to construct the pooled median survival times and corresponding 95% confidence intervals.

Results

A total of 2388 patients from 53 arms of 42 studies meeting the above selection criteria were identified (see Table 1 & 2). These data were analyzed in three separate groups:

  • Group 1: Thirty-two studies reported data for 2045 BEV naïve patients undergoing therapy with BEV for recurrent GBM without directly reporting median overall survival post-progression on BEV. For these studies, the median overall survival post-progression on BEV was estimated from the difference between the reported median PFS and median OS. Nine of the 32 studies did not report confidence intervals for these data. Pooled median estimate of OS post-BEV failure for these patients was 3.36 months (95% CI 3.12 – 3.66); PFS was determined as 4.38 months (95% CI 4.09–4.68). Figures 1 & 2 represent Forest plots of PFS on BEV and OS post-BEV respectively in Group 1.

  • Group 2: Two additional studies reported data for 94 BEV-naïve patients undergoing therapy for recurrent GBM, but directly reported median OS after progression on BEV. Neither study reported confidence intervals for these values. Pooled median estimate of OS for these patients was 3.26 months (95% CI 2.39 – 4.42).

  • Group 3: Eight studies comprising 249 patients investigated salvage regimens for patients that had progressed on BEV. Five of these studies did not provide confidence intervals for the extracted data. Pooled median estimate of OS for these patients was 4.46 months (95% CI 3.68–5.54). Figure 3 represents a Forest plot of OS post-BEV in Group 3.

Table 1.

Reviewed studies of BEV in recurrent glioblastoma

Study Year N Agents Median
PFS on
BEV
95% CI Median
OS
95% CI Post-BEV
Median OS
Group 1 BEV Studies
Vredenburgh [15] 2007 35 BEV + CPT-11 6 (4.5 – 9) 10.5 (8.75 – 15) 4.5
Ali [16] 2008 13 BEV + CPT-11 6 NR 6.75 NR 0.75
Kang [17] 2008 12 BEV + CPT-11 3.8 NR 7.1 NR 3.3
Friedman [2] 2009 85 BEV 4.2 (2.9 – 5.8) 9.2 (8.2 – 10.7) 5
Friedman [2] 2009 82 BEV + CPT-11 5.6 (4.4 – 6.2) 8.7 (7.8 – 10.9) 3.1
Gutin [18] 2009 20 BEV + RT 7.3 (4.4 – 8.9) 12.5 (6.9 – 22.8) 5.2
Kreisl [3] 2009 48 BEV 4 (3 – 6.5) 7.75 (5.25 – 13.5) 3.75
Poulsen [19] 2009 27 BEV + CPT-11 5.5 (4 – 7) 7 (3.25 – 10.75) 1.5
Reardon [20] 2009 27 BEV + VP-16 4.5 (3.25 – 10) 11.6 (6.25 – 17.5) 7.1
Zuniga [21] 2009 37 BEV + CPT-11 7.6 (4.8 – 10.5) 11.5 (8.3 – 15.6) 3.9
Chamberlain [22] 2010 50 BEV 1 NR 8.5 (3 – 174) 7.5
Francesconi [23] 2010 6 BEV + CBDCA + VP-16 4.75 NR 7.475 NR 2.725
Hasselbalch [24] 2010 43 BEV + cetuximab + CPT-11 4 (3.25 – 5) 7.5 (5.75 – 9.25) 3.5
Sathornsumetee [25] 2010 25 BEV + erlotnib 4.5 (3 – 5.975) 11.15 (7.1 – 17.175) 6.65
Desjardins [26] 2012 32 BEV + TMZ 3.95 NR 9.275 NR 5.325
Gil [27] 2012 92 BEV + CPT-11 5.1 (4.4 – 5.8) 8.8 (6.9 – 10.6) 3.7
Møller [28] 2012 32 BEV + CPT-11 5.2 (3.1 – 7.2) 7.9 (6.3 – 9.6) 2.7
Mrugala [29] 2012 14 BEV + CBDCA 4.75 (3.825 – 5.65) 10 (7.675 – 15.325) 5.25
Reardon [30] 2012 40 BEV + CBDCA + CPT-11 5.9 (4.4 – 8.3) 8.3 (5.9 – 10.7) 2.4
Arakawa [31] 2013 8 BEV + IFO, CBDCA, VP-16 3.7 (2.5 – 18.5) 6 (3.2 –19.7) 2.3
Cecchi [32] 2013 9 BEV 5.1 NR 6.8 NR 1.7
Cecchi [32] 2013 10 BEV + CPT-11 15.4 NR 11.1 NR NA
Demirci [33] 2013 93 BEV + CPT-11 6 (4.9 – 7.1) 8 (6.6 – 9.4) 2
Galanis [34] 2013 54 BEV + sorafenib 2.9 (2.3 – 3.6) 5.6 (4.7 – 8.2) 2.7
Piccioni [35] 2014 88 BEV 2nd recurrence 4.2 (3.2 – 5.3) 9.3 (7.2 – 10.7) 5.1
Piccioni [35] 2014 264 BEV 1st recurrence 4.1 (3.7 – 4.5) 8.4 (8 – 9.8) 4.3
Piccioni [35] 2014 36 BEV 3rd+ recurrence 3.4 (1.9 – 5) 6.4 (5.1 – 9.4) 3
Rahman [36] 2014 42 BEV + carmustine or CCNU 4.075 NR 4.675 NR 0.6
Soffietti [37] 2014 54 BEV + fotemustine 5.2 (3.8 – 6.6) 9.1 (7.3 – 10.3) 3.9
Taal [38] 2014 44 BEV + CCNU 90mg/m2 4 (3 – 8) 11 (8 – 12) 7
Taal [38] 2014 50 BEV 3 (3 – 4) 8 (6 – 9) 5
Taal [38] 2014 8 BEV + CCNU 110mg/m2 11 (1 – 27) 16 (2 – 34) 5
Chen [39] 2015 136 BEV vs BEV + various chemo 7 (6 – 9) 8.86 (7.06 – 10.44) 1.86
Field [40] 2015 62 BEV 3.5 (1.9 – 3.7) 7.5 NR 4
Field [40] 2015 60 BEV + CBDCA 3.5 (2.2 – 3.7) 6.9 NR 3.4
Lee [41] 2015 24 BEV + panobinostat 5 (3 – 9) 9 (6 – 19) 4
Liu [42] 2015 176 BEV + fotemustine 5 (2.4 – 7.5) 8 (6.7 – 9.2) 3
Sepúlveda [43] 2015 32 BEV + TMZ 4.2 (3.6 – 5.4) 7.3 (5.8 – 8.8) 3.1
Heiland [44] 2016 17 BEV 2.3 (1.87 – 4.39) 4.07 (3.02 – 12.98) 1.77
Heiland [44] 2016 18 BEV + CCNU 6.11 (3.41 – 12.98) 6.59 (5.51 – 16.3) 0.48
Odia [45] 2016 40 BEV + enzastaurin 2 NR 7.5 NR 5.5
Total N 2045
Group 2 Directly Reported BEV Studies
Nghiemphu [46] 2009 44 BEV + various chemo 4.32
Raizer [47] 2010 50 BEV 2.5
Total N 94
Group 3 Post-BEV Salvage Studies
Iwamoto [6] 2009 37 BEV + CPT-11 4.5 NR 4.5
Lu-Emerson [12] 2011 14 BEV + dasatinib 2.8 (1.5 – 4.9) 2.8
Reardon [7] 2011 25 BEV + CPT-11 or CBDCA 5.8 (4 – 7) 5.8
Reardon [8] 2011 13 BEV + VP-16 4.8 (2.8 – 6.4) 4.8
Reardon [8] 2011 10 BEV + TMZ 3.2 (1.2 – 5.8) 3.2
Lassen [48] 2013 13 BEV + temsirolimus 3.8 NR 3.8
Omuro [9] 2013 18 TMZ 4.3 NR 4.3
Kanner [10] 2014 23 Novo-TTF 100A 6 NR 6
Kanner [10] 2014 21 Various chemotherapies 3.3 NR 3.3
Robins [11] 2016 75 ABT888 + TMZ 4.7 NR 4.7
Total N 249

Abbreviations: NR = Not reported; BEV= bevacizumab; TMZ = temazolomide; CPT-11 = irinotecan; CBDCA = carboplatin; VP-16 = etoposide; IFO = ifosfamide; CCNU = lomustine; RT = radiotherapy

Table 2.

Pooled estimates across studies

Pooled Median
Estimate
Lower 95% CI Upper 95%
Group 1 OS post-BEV estimated from OS on BEV – PFS on BEV (n=2045) PFS on BEV 4.38 months 4.09 months 4.68 months
OS on BEV 8.18 months 7.67 months 8.70 months
OS post-BEV 3.36 months 3.12 months 3.66 months
Group 2 Directly reported OS after progression on BEV (n=94) OS post-BEV 3.26 months 2.39 months 4.42 months
Group 3 Studies of salvage after progression on BEV (n=249) OS post-BEV 4.46 months 3.68 months 5.44 months

Figure 1.

Figure 1

Forest plot of PFS on BEV in Group 1

Figure 2.

Figure 2

Forest plot of OS post-progression on BEV in Group 1

Figure 3.

Figure 3

Forest plot of OS post-progression on BEV in Group 3

Discussion

Our pooled median estimate of post-BEV OS in BEV studies confirm a short median survival of 3.36 months, while our pooled median estimate of OS in post-BEV salvage studies is slightly longer at 4.46 months. This is consistent with the findings of Magnuson et al (mean OS of 3.8 months (SD ± 1.0), an estimate that combined both BEV studies and post-BEV salvage studies [13]. Our data also include more than twice as many patients and a more sophisticated statistical model than this previous estimate. The similarity of results from the two directly reported studies of BEV salvage studies (3.23 months vs 3.36 months) also help confirm the validity of our method of estimating survival after BEV failure using PFS and OS data.

As previously noted, our estimate of median survival after progression on BEV is slightly longer amongst the post-BEV salvage studies. Relative to this, it should be noted, that any gap in time between identification of progression on BEV and initiation of a subsequent salvage regimen would potentially reduce estimated overall survival contingent on the definition of OS. Even so, many of these studies reported slightly longer median overall survival than was typical amongst the BEV salvage studies. One likely explanation is that patients selected for participation in trials of further salvage therapy were generally healthier than the overall population of patients experiencing progression on BEV. By way of illustration, in one retrospective study of 37 patients having progressed on BEV, nearly half of patients had a Karnofsky Performance Status (KPS) of < 70 at the time of progression [6]. This would have excluded these patients from most of post-BEV salvage studies included in this review. Another consideration is that, as a whole, the post-BEV salvage studies tended to have smaller numbers of patients than the BEV salvage studies. Additionally, publication bias may have been stronger among post-BEV salvage studies than BEV salvage studies, as criteria for success would not generally include post-BEV survival in BEV salvage studies.

Taking the results of this review collectively, it is apparent that, to date, drug therapy has demonstrated minimal potential for salvaging patients who have progressed on BEV. It is of interest to note there are limited data suggesting there are at least two non-pharmacological options for prolonging survival after failure on BEV, i.e., Radiotherapy [14] and Tumor Treating Fields Therapy [10].

In summary, it is obvious that a concerted preclinical and clinical research effort is required to address the dismal prognosis of BEV refractory patients. It was the goal of this review to foster that effort, and provide a historical benchmark for efficacy to be used in establishing a “signal” in the context of future phase 2 clinical trials, as well as providing a prognostic tool for clinical practice.

Highlights.

  • Bevacizumab (BEV) is a common treatment for recurrent glioblastoma (r-GBM).

  • Post BEV survival (OS) & progression free survival (PFS) are not well defined.

  • Post BEV-OS & BEV-PFS were analyzed in r-GBM from 53 arms of 42 clinical trials.

  • PFS =4.38 M (95% CI 4.09–4.68); post-BEV-OS =3.36 M (95% CI 3.12–3.66) [n=2045]

These estimates provide a historical control for BEV-PFS & post BEV-OS.

Acknowledgments

Funded by P30 CA014520 Core Grant, University of Wisconsin Carbone Cancer Center.

Footnotes

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Compliance with Ethical Standards

The authors have no conflicts of interests.

This article does not contain any studies with animals performed by any of the authors. This article does not contain any studies with human participants or animals performed by any of the authors.

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