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.
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.
- Dolecek TA, Propp JM, Stroup NE, Kruchko C: CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol 2012,14(Suppl 5):v1–49. 10.1093/neuonc/nos218PubMed CentralPubMedView ArticleGoogle Scholar
- Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M, Sabel M, Steinbach JP, Heese O, Reifenberger G, et al.: Long-term survival with glioblastoma multiforme. Brain 2007, 130: 2596–2606. 10.1093/brain/awm204PubMedView ArticleGoogle Scholar
- Kristiansen K, Hagen S, Kollevold T, Torvik A, Holme I, Nesbakken R, Hatlevoll R, Lindgren M, Brun A, Lindgren S, et al.: Combined modality therapy of operated astrocytomas grade III and IV. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: a prospective multicenter trial of the Scandinavian Glioblastoma Study Group. Cancer 1981, 47: 649–652. 10.1002/1097-0142(19810215)47:4<649::AID-CNCR2820470405>3.0.CO;2-WPubMedView ArticleGoogle Scholar
- Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, et al.: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 1980, 303: 1323–1329. 10.1056/NEJM198012043032303PubMedView ArticleGoogle Scholar
- Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, et al.: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009, 10: 459–466. 10.1016/S1470-2045(09)70025-7PubMedView ArticleGoogle Scholar
- Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005, 352: 987–996. 10.1056/NEJMoa043330PubMedView ArticleGoogle Scholar
- Ohgaki H, Kleihues P: Genetic pathways to primary and secondary glioblastoma. Am J Pathol 2007, 170: 1445–1453. 10.2353/ajpath.2007.070011PubMed CentralPubMedView ArticleGoogle Scholar
- Stupp R, Roila F: Malignant glioma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009,20(Suppl 4):126–128.PubMedGoogle Scholar
- Weller M, Cloughesy T, Perry JR, Wick W: Standards of care for treatment of recurrent glioblastoma–are we there yet? Neuro Oncol 2013, 15: 4–27. 10.1093/neuonc/nos273PubMed CentralPubMedView ArticleGoogle Scholar
- Stupp R, Hegi ME, van den Bent MJ, Mason WP, Weller M, Mirimanoff RO, Cairncross JG: Changing paradigms–an update on the multidisciplinary management of malignant glioma. Oncologist 2006, 11: 165–180. 10.1634/theoncologist.11-2-165PubMedView ArticleGoogle Scholar
- Scoccianti S, Detti B, Sardaro A, Iannalfi A, Meattini I, Leonulli BG, Borghesi S, Martinelli F, Bordi L, Ammannati F, Biti G: Second-line chemotherapy with fotemustine in temozolomide-pretreated patients with relapsing glioblastoma: a single institution experience. Anticancer Drugs 2008, 19: 613–620. 10.1097/CAD.0b013e3283005075PubMedView ArticleGoogle Scholar
- Brandes AA, Tosoni A, Franceschi E, Blatt V, Santoro A, Faedi M, Amista P, Gardiman M, Labianca R, Bianchini C, et al.: Fotemustine as second-line treatment for recurrent or progressive glioblastoma after concomitant and/or adjuvant temozolomide: a phase II trial of Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Cancer Chemother Pharmacol 2009, 64: 769–775. 10.1007/s00280-009-0926-8PubMed CentralPubMedView ArticleGoogle Scholar
- Cairncross G, Macdonald D, Ludwin S, Lee D, Cascino T, Buckner J, Fulton D, Dropcho E, Stewart D, Schold C Jr, et al.: Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1994, 12: 2013–2021.PubMedGoogle Scholar
- Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, et al.: Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009, 27: 4733–4740. 10.1200/JCO.2008.19.8721PubMedView ArticleGoogle Scholar
- Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen 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: 740–745. 10.1200/JCO.2008.16.3055PubMed CentralPubMedView ArticleGoogle Scholar
- Johnson DR, Leeper HE, Uhm JH: Glioblastoma survival in the United States improved after Food and Drug Administration approval of bevacizumab: a population-based analysis. Cancer 2013, 119: 3489–3495.PubMedView ArticleGoogle Scholar
- Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, Bertorelle R, Bartolini S, Calbucci F, Andreoli A, et al.: MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol 2008, 26: 2192–2197. 10.1200/JCO.2007.14.8163PubMedView ArticleGoogle Scholar
- Dunet V, Rossier C, Buck A, Stupp R, Prior JO: Performance of 18F-fluoro-ethyl-tyrosine (18F-FET) PET for the differential diagnosis of primary brain tumor: a systematic review and Metaanalysis. J Nucl Med 2012, 53: 207–214. 10.2967/jnumed.111.096859PubMedView ArticleGoogle Scholar
- Goodenberger ML, Jenkins RB: Genetics of adult glioma. Cancer Genet 2012, 205: 613–621. 10.1016/j.cancergen.2012.10.009PubMedView ArticleGoogle Scholar
- Zhang GB, Cui XL, Sui DL, Ren XH, Zhang Z, Wang ZC, Lin S: Differential molecular genetic analysis in glioblastoma multiforme of long- and short-term survivors: a clinical study in Chinese patients. J Neurooncol 2013, 113: 251–258. 10.1007/s11060-013-1102-xPubMedView ArticleGoogle Scholar
- Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, et al.: IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009, 360: 765–773. 10.1056/NEJMoa0808710PubMed CentralPubMedView ArticleGoogle Scholar
- Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, Campos C, Fabius AW, Lu C, Ward PS, et al.: IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 2012, 483: 479–483. 10.1038/nature10866PubMed CentralPubMedView ArticleGoogle Scholar
- Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J, Ducray F, El Hallani S, Boisselier B, Mokhtari K, Hoang-Xuan K, Delattre JY: Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 2009, 27: 4150–4154. 10.1200/JCO.2009.21.9832PubMedView ArticleGoogle Scholar
- Lv S, Teugels E, Sadones J, Quartier E, Huylebrouck M, DUF S, LEM M, DEW O, Salmon I, Michotte A, et al.: Correlation between IDH1 gene mutation status and survival of patients treated for recurrent glioma. Anticancer Res 2011, 31: 4457–4463.PubMedGoogle Scholar
- Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, et al.: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005, 352: 997–1003. 10.1056/NEJMoa043331PubMedView ArticleGoogle Scholar
- Capdevila L, Cros S, Ramirez JL, Sanz C, Carrato C, Romeo M, Etxaniz O, Hostalot C, Massuet A, Cuadra JL, et al.: Neoadjuvant cisplatin plus temozolomide versus standard treatment in patients with unresectable glioblastoma or anaplastic astrocytoma: a differential effect of MGMT methylation. J Neurooncol 2014, 117: 77–84. 10.1007/s11060-013-1352-7PubMedView ArticleGoogle Scholar
- Soffietti R, Trevisan E, Bertero L, Cassoni P, Morra I, Fabrini MG, Pasqualetti F, Lolli I, Castiglione A, Ciccone G, Ruda R: Bevacizumab and fotemustine for recurrent glioblastoma: a phase II study of AINO (Italian Association of Neuro-Oncology). J Neurooncol 2014, 116: 533–541. 10.1007/s11060-013-1317-xPubMed CentralPubMedView ArticleGoogle Scholar
- Lai A, Tran A, Nghiemphu PL, Pope WB, Solis OE, Selch M, Filka E, Yong WH, Mischel PS, Liau LM, et al.: Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol 2011, 29: 142–148. 10.1200/JCO.2010.30.2729PubMed CentralPubMedView ArticleGoogle Scholar
- Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, et al.: Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 2007, 13: 1253–1259. 10.1158/1078-0432.CCR-06-2309PubMedView ArticleGoogle Scholar
- Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, et al.: Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007, 25: 4722–4729. 10.1200/JCO.2007.12.2440PubMedView ArticleGoogle Scholar
- Reardon DA, Desjardins A, Vredenburgh JJ, Gururangan S, Sampson JH, Sathornsumetee S, McLendon RE, Herndon JE 2nd, Marcello JE, Norfleet J, et al.: Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study. Br J Cancer 2009, 101: 1986–1994. 10.1038/sj.bjc.6605412PubMed CentralPubMedView ArticleGoogle Scholar
- Desjardins A, Reardon DA, Coan A, Marcello J, Herndon JE 2nd, Bailey L, Peters KB, Friedman HS, Vredenburgh JJ: Bevacizumab and daily temozolomide for recurrent glioblastoma. Cancer 2012, 118: 1302–1312. 10.1002/cncr.26381PubMedView ArticleGoogle Scholar
- Francesconi AB, Dupre S, Matos M, Martin D, Hughes BG, Wyld DK, Lickliter JD: Carboplatin and etoposide combined with bevacizumab for the treatment of recurrent glioblastoma multiforme. J Clin Neurosci 2012, 17: 970–974.View ArticleGoogle Scholar
- Reardon DA, Desjardins A, Peters KB, Gururangan S, Sampson JH, McLendon RE, Herndon JE 2nd, Bulusu A, Threatt S, Friedman AH, et al.: Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naive, recurrent glioblastoma. J Neurooncol 2012, 107: 155–164. 10.1007/s11060-011-0722-2PubMed CentralPubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.