Abstract
The prognosis of patients affected by glioblastoma (GBM) is grim albeit the integrated therapeutic approaches now available. Standard surgery followed by chemoradiation median overall survival (OS) reaches 15 months in clinical trials. Despite primary treatment, recurrence is the rule in patients with GBM and for them OS ranges from 6 to 9 months. In recent years, the therapeutic scenario has been profoundly changed in view of the promising results obtained by bevacizumab (Avastin
*Avastin is a registered trade name of Bevacizumab, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
), the most promising anti-angiogenesis agent, in two clinical trials. The results of both trials were presented at the last ASCO meeting in Chicago. Progression free survival was significantly improved with an acceptable safety and tolerability profile but surprisingly quality of life was preserved only in the AVAGlio trial. However, both studies showed that overall survival was not improved adding bevacizumab to temozolomide and radiotherapy.The prognosis of patients affected by glioblastoma (GBM) is grim, despite the integrated therapeutic approaches now available. Standard surgery followed by chemoradiation has a median overall survival (OS) of 15 months in clinical trials and about 24 months in patients showing O-methyl-guanine-DNA-methyltrasferase (MGMT) gene methylation. Despite primary treatment, recurrence is the rule in patients with GBM. OS ranges from 6 to 9 months. Recurrent GBM is often managed by re-surgery in all patients considered fit, carefully considering the localization and the volume of the tumor.
Alternatives may be stereotaxic re-irradiation and/or chemotherapy. In the past, experiments have been made with several drugs in this setting: carmustine, lomustine, and temozolomide; irinotecan is accepted in both the United States and Europe; the new nitrosourea fotemustine is approved only in some European nations; others such as enzastaurin or cediranib failed in trials. All have shown no difference in activity, obtaining a modest response rate (RR) variable from 10 to 15%Citation1.
Chemotherapy failure derives in part from the incapacity of several anticancer agents used in the combination to cross the blood–brain barrier, although in the case of glioma a dramatic alteration of its integrity has been reportedCitation2.
Several expert opinions recommend a multidisciplinary approach aimed at performing an effective and well tolerated therapy based on patient and disease characteristics, such as performance status and neurological function.
Recently, the therapeutic scenario has been profoundly changed in view of the promising results obtained by bevacizumab (Avastin*), the most promising anti-angiogenesis agent, in some clinical trials. An open-label randomized phase II study evaluated bevacizumab with and without irinotecan in 167 recurrent GBM patients (BRAIN study). Friedman et al. obtained a response rate of 37.8% and 28.2% in the bevacizumab plus irinotecan (n = 82) and the bevacizumab alone (n = 85) groups, respectively. PFS-6m of 50.3% and 42.6%, respectively, was seen in this studyCitation3. These results were confirmed in another trial conducted by Kreisl et al., which showed the efficacy of single-agent bevacizumab in patients with recurrent glioblastomaCitation4.
On the basis of the good results obtained in a number of phase II trials, on 5 May 2009, the Food and Drug Administration (FDA) recently approved bevacizumab as a single agent for patients with recurrent glioblastoma after a first chemoradiotherapy line. On the other hand, the European Medicines Agency considered these results not sufficient to say that bevacizumab is warranted in recurrent glioblastoma. The FDA reviewed the data for responses and overall survival from an uncontrolled phase II study and compared these outcomes with historic controls, whereas in Europe EMA would rather see data from a true comparator.
Furthermore, in several European countries, such as Italy, the high impact on national health systems of the pharmaco-economic aspects of this regimen (both irinotecan and bevacizumab are extremely expensive agents) limits the use of this combination.
The most employed treatment option is nitrosourea based second-line chemotherapy – lomustine, carmustine or fotemustine, and temozolomide rechallenge are the most useful drugs. Recently, two randomized comparator trials using lomustine (CCNU) as the standard comparator to bevacizumab, either as a single agent or in combination with bevacizumab, have been initiated in patients with recurrent GBM, by a Dutch study (BELOB) and the European Organisation for Research and Treatment of Cancer (EORTC; EORTC 26101)Citation5.
The phase II three-arm Dutch study BELOB recently closed with 140 patients randomly allocated to either bevacizumab alone, lomustine alone, or a combination of these two agents using the RANO criteria for response assay. The primary endpoint, OS at 9 months, demonstrated better activity for bevacizumab/lomustine combination therapyCitation5.
Fotemustine is a third generation nitrosourea able to easily cross the blood–brain barrier that has demonstrated a marked anti-neoplastic activity in high grade glioma. Fotemustine has been employed in uncontrolled phase II clinical trials in recurrent GBM showing an interesting efficacy, being able to reach an ORR ranging from 20 to 40%, and a 6 month progression free survival (PFS-6) of about 25%Citation6. In a phase II study, the combination of bevacizumab and fotemustine in recurrent malignant gliomas showed promising activity with a safe profileCitation7.
In the first-line setting of therapy, two different randomized phase III trials were performed. RTOG 0825 is a large phase III trial targeting 720 patients, developed in the United States, and the other trial is the Effectiveness of Avastin in GBM (AVAglio) study targeting over 900 patients, the majority enrolled in a European country and sponsored by Hoffman-LaRoche (Basel, Switzerland)Citation8,Citation9. In this last case, it was surprising and confusing that the same community that rejected the drug for use in recurrent disease had enough confidence to try it in a front-line setting.
The results of both trials were presented at the last ASCO meeting in Chicago. Progression free survival was significantly improved with an acceptable safety and tolerability profile but, surprisingly, quality of life was preserved only in the AVAGlio trial. However, both studies showed that overall survival was not improved by adding bevacizumab to temozolomide and radiotherapy.
These results confirm that the Stupp schedule as a central treatment does not support the routine use of bevacizumab in the upfront treatment setting. This does not exclude the possibility that molecular analyses will reveal a beneficial effect of bevacizumab in subgroups of patients with glioblastoma. Therefore, a cost–benefit analysis may become a necessary endeavor in the future drug development process.
The dosing (5 mg/kg or 10 mg/kg) and scheduling of administration (every 2 weeks or 3 weeks) are clearly established. If the dosing could be lowered to 5 mg/kg, this could reduce bevacizumab use, leading to substantial savings. It is still unclear which dosing schedule is the most optimal for bevacizumab monotherapy in recurrent glioblastoma. A meta-analysis involving 548 patients treated with bevacizumab for recurrent glioblastoma showed that there was no difference in bevacizumab dose–response benefit between 5 mg/kg and 10 to 15 mg/kgCitation10.
For glioblastoma patients, treatment strategies that prolong survival remain lacking; however, for this population, symptom relief, time to neurologic progression, neurologic function, and quality of life continue to represent relevant endpoints because of the mediocre impact on overall survival of the available therapeutic options.
Quality of life is especially important for patients suffering from brain tumors, whose life expectancy may be very short. The non-homogeneous results regarding quality of life derived from these two trials complicate the ruling on the efficacy of bevacizumab in these patients. The VEGF pathway represents a promising road to walk in adding a new target drug to current treatment paradigms for glioblastoma. However, it remains to be determined whether clinical trials with such dual or multiple inhibitors will effectively impact GBM recurrence and invasion. It is necessary to know more about the tumor vascular biology and mechanisms of tumor growth, invasion, and metastasis to identify additional targeted drugs that act synergistically with angiogenesis inhibitors. On the other hand, controversial results of these new trials do not exclude the possibility that a specific setting of patients with glioblastoma, revealed via molecular analyses, may see beneficial effects of bevacizumab. The research into new predictive biomarkers to identify the patients who will benefit from such approaches is also important. Identifying the correct dosage and timing of bevacizumab therapy, the availability of clinical data from a true comparator, and definite information about the association with chemotherapeutic agents will help to revaluate the use of this drug in European nations.
Finally, further development and investigation on the nanotechnological delivery of anticancer agents (including target-based agents) in GMB may help to treat this cancer in the futureCitation11. Recent encouraging results obtained in the field of nanotechnology-based drug delivery (passive and active cancer targeting modalities) suggest the possibility of the development of new nanocarriers of old drugs to the brain, or new therapeutic weapons such as bevacizumab.
Transparency
Declaration of funding
This editorial was not sponsored.
Declaration of financial/other relationships
A.R., P.F., P.C., and D.V.S.G. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.
CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Notes
*Avastin is a registered trade name of Bevacizumab, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
References
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- Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009;27:740-5
- Taal W, Oosterkamp HM, Walenkamp AME, et al. A randomized phase II study of bevacizumab versus bevacizumab plus lomustine versus lomustine single agent in recurrent glioblastoma: the Dutch BELOB study. American Society for Clinical Oncology (ASCO), Chicago, IL, USA, 1 June 2013, Abstract #2001
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