Effective long-term treatment with bevacizumab for relapsed glioblastoma: case report and review of the literature
© Schweneker et al.; licensee BioMed Central. 2014
Received: 12 November 2014
Accepted: 12 December 2014
Published: 17 December 2014
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Despite the use of optimized first-line therapy, GBM is still associated with a poor prognosis and an effective second-line therapy remains an important challenge in this patient population. In 2009, the US Food and Drug Administration (FDA) approved the monoclonal anti-VEGF-antibody bevacizumab for the treatment of relapsed GBM after two phase-II studies showed its efficacy and safety, alone or in combination with irinotecan, in relapsed GBM. In contrast, the European Medicines Agency (EMA) concluded from the same published data that a clear benefit in terms of overall survival was not shown and subsequently did not grant approval for bevacizumab in this setting. Here, we report on a 53-year old patient with relapsed GBM who was treated with bevacizumab as single agent. After three months, the tumor volume was reduced and the Karnofsky performance status was substantially improved compared to the baseline at the time of relapse. After continued long-term treatment for 26 months, the patient remains in an excellent general condition. Moreover, the measurement of the tumor volume using multiple imaging modalities shows a sustained treatment response. In conclusion, this case supports the notion that individual patients respond exceptionally well to treatment with anti-VEGF therapy and suggests that future trials are needed to better identify the patient population that responds to bevacizumab.
KeywordsRelapsed glioblastoma Bevacizumab Pseudoprogression 18 F-FET-PET/CT scan
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults and the 5-year survival rate is <5% in adults [1, 2]. According to the guidelines of the National Guideline Clearinghouse of the U.S. Department of Health & Human Services, the recommended therapy for a newly diagnosed GBM is surgical debulking provided that unacceptable neurologic deficit can be avoided, followed by adjuvant radiotherapy [3, 4]. Concomitant radiotherapy and temozolomide followed by adjuvant temozolomide for 6 courses have been shown to significantly prolong overall survival (OS) compared to radiotherapy alone [5, 6]. The median OS in patients treated with additional temozolomide is prolonged from 12.1 months to 14.6 months when compared to radiotherapy alone. In addition, the 2-year survival is improved from 10.4% with radiotherapy alone to 26.5% with radiotherapy and temozolomide . Due to their invasive growth pattern, GBM have a high relapse rate . According to the guidelines of the National Comprehensive Cancer Network (NCCN), the recommended therapy for a resectable locally relapsed GBM is resection with or without implantation of a carmustine wafer. However, there is no clearly defined standard therapy for relapsed unresectable GBM [8, 9]. In this case, the treatment decision depends on multiple parameters such as prior therapy, time to relapse, tumor grade, and performance status [8, 9]. Treatment options include repeated surgery, radiation, or chemotherapy . Chemotherapeutic regimes include either monotherapy with lomustine (CCNU), platinum compounds, or temozolomide [9, 11, 12]. Alternatively, medically fit and healthy patients can be treated with polychemotherapy using regimens such as procarbacin/CCNU/vincristin (PCV) . Two uncontrolled phase II studies showed that the monoclonal human anti-VEGF-antibody bevacizumab, alone or in combination with irinotecan, prolongs progression-free survival (PFS) and overall survival (OS) in patients with relapsed GBM compared to historical data [14, 15]. Based on this data, bevacizumab was approved by the US Food and Drug administration (FDA) for use in relapsed GBM. However, it is currently not approved by the European Medicines Agency (EMA) for relapsed GBM because of missing evidence that bevacizumab prolongs survival. In 2013, Johnson et al. published a population-based analysis in which they compared patients in the United States who eventually succumbed to GBM in 2006, 2008, and 2010 . The difference in survival between 2008 and 2010 was significantly better for patients treated with bevacizumab . This circumstantial evidence suggests that the improved median survival of GBM patients in the US might be due to the approval and use of bevacizumab, however a direct comparison of subpopulations is missing so far. Here we report on the successful long-term treatment of a relapsed GBM patient with bevacizumab as monotherapy for the last 26 months with an ongoing improvement in tumor volume and quality of life.
26 months after the diagnosis of relapsed GBM, our patient remains in an excellent general condition with a Karnofsky performance status of 100% without further adverse side effects to the current therapy. Under ongoing treatment with bevacizumab the patient is able to live a self-reliant, socially active life.
Despite therapeutic advances, the prognosis for patients with GBM is still poor . Nevertheless, a small fraction of patients with GBM (3–5%) survive longer that 36 months and they are referred to as long-term survivors . Young age, female gender, higher preoperative Karnofsky performance status, unilateral tumor, gross total resection, and adjuvant radiochemotherapy are associated with prolonged survival . Furthermore, there are some molecular markers, e.g. p53 mutation, MGMT promoter methylation, or isocitrate dehydrogenase 1 (IDH1) mutations that are frequently found in long-term survivors . Single amino acid mutations in IDH1 can lead to the loss of regular enzyme function . The mutated IDH1 converts α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), which causes genome-wide epigenetic changes in human gliomas . Patients harboring mutated IDH1 and corresponding epigenetic changes have a better prognosis than patients diagnosed with GBM with wild-type IDH1 [21, 23]. This is exemplified by the fact that treatment with bevacizumab as single agent in patients with relapsed GBM and IDH1 mutation results in a significant better PFS and OS compared to patients without IDH1 mutation (PFS 3.23 vs. 1.37 months, p = 0.05; and OS 10.16 vs. 4.90 months, p = 0.09) .
The MGMT promoter methylation is known to play an important role in the cellular response to alkylating agents such as temozolomide [5, 25]. Significantly more long-term survivors harbor MGMT promoter methylation compared to patients that survive shorter than 18 months . Furthermore, Capdevila and colleagues showed, that patients with methylated MGMT promoter status derive greater benefit from neoadjuvant temozolomide treatment than those without methylated MGMT promoter status . Concerning bevacizumab, a previously published single-arm study showed that patients with a relapsed GBM treated with the combination of bevacizumab and fotemustin had an improved PFS when the MGMT promoter was methylated , however the difference to historical controls was not statistically significant. An alternative single-arm study used bevacizumab in combination with temozolomide after radiotherapy in newly diagnosed GBM patients . In this study, patients with MGMT promoter methylation had an improved median OS and PFS compared to patients without MGMT promoter methylation . The patients of the MGMT unmethylated group appeared to have a poor outcome, possibly caused by the reduced effectiveness of temozolomide.
Since the approval of bevacizumab for relapsed GBM by the FDA, there is an ongoing attempt to improve the anti-tumor effect of bevacizumab using combination therapies. Several studies have analyzed the combination of bevacizumab with various chemotherapeutic agents that are recommended as second-line therapy for relapsed unresectable GBM. In these studies, bevacizumab was combined with irinotecan [14, 29, 30], oral etoposide , temozolomide , carboplatin and etoposide , or carboplatin and irinotecan . All these combination therapies were effective treatments for relapsed GBM, but did not improve the outcome over the level observed with bevacizumab alone.
The presented case shows that monotherapy with bevacizumab can substantially prolong survival and improve quality of life in patients with relapsed GBM. This argues that a better understanding of the clinical or molecular parameters that define the patient population that will profit from bevacizumab monotherapy is urgently needed. At this point, it is not clear whether a definite correlation exists between improved PFS and OS in patients treated with bevacizumab as monotherapy and their MGMT methylation status. The patient’s current survival time of 26 months from start of monotherapy with bevacizumab after relapsed GBM exceeds all expectations and surpasses to our knowledge survival rates of other studies or reports. The patient remains in an excellent general condition under ongoing treatment with bevacizumab. At this point, we have no explanation for this successful course, particularly taking into consideration the reduced Karnofsky performance status of 50% at time of relapse, male gender and unmethylated MGMT promoter as negative prognostic survival markers. Therefore, additional clinical trials and an improved molecular characterization of these cases might help to identify patient populations that will likely benefit from an anti-VEGF therapy.
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