Original ArticleAdvantages and Disadvantages of Combined Chemotherapy with Carmustine Wafer and Bevacizumab in Patients with Newly Diagnosed Glioblastoma: A Single-Institutional Experience
Introduction
The standard of care for patients with newly diagnosed glioblastoma (GBM) is maximal surgical tumor resection followed by 6 weeks of concurrent radiotherapy with temozolomide (Schering-Plough Corp., Kenilworth, New Jersey, USA), and additional adjuvant chemotherapy with temozolomide1 (the Stupp regimen). New therapeutic options have been developed such as simultaneous combined therapy with carmustine (BCNU) wafer and bevacizumab for newly diagnosed high-grade gliomas. Since 2013, BCNU and bevacizumab have been approved by the Japanese Ministry of Health, Labour and Welfare. Some studies have shown that the BCNU wafer prolongs patients' survival. On the other hand, bevacizumab may not prolong overall survival (OS) but may increase progression-free survival (PFS) as shown in previous clinical trials (AVAglio [Avastin in Glioblastoma] and RTOG [Radiation Therapy Oncology Group] 0825).2, 3 However, there has been no previous clinical trial using combined therapy with both BCNU wafer and bevacizumab for newly diagnosed high-grade gliomas simultaneously.
Herein, we report our single-institutional experience with combined therapy with BCNU and bevacizumab in addition to the Stupp regimen for patients with newly diagnosed GBM. We focused on the synergistic effects of concomitant radiation, BCNU, bevacizumab, and temozolomide for patients with newly diagnosed GBM.
Section snippets
Patients
A total of 54 newly diagnosed patients with GBM underwent tumor resection at our institution between January 2010 and December 2016. All patients in the control and combined therapy groups were treated between 2010 and 2012 and 2013 and 2016, respectively. All patients received standard therapy with the Stupp protocol (local irradiation with a total dose of 60 Gy for grade 4 tumors in 2-Gy fractions, 5 days per week, for 6 weeks) and temozolomide (75 mg/m2 orally) during the concurrent phase,
Results
During the follow-up period from January 2010 to December 2016, 54 patients with newly diagnosed GBMs were enrolled. Twenty-nine patients received combined therapy with BCNU wafer implantation during the operation, followed by temozolomide administration and bevacizumab treatment with concomitant radiation 3 weeks after the operation (Figure 1). There were no differences in the baseline characteristics of the patients in group A and B except the proportion of patients who underwent awake
Discussion
In our analysis, the OS in combined treatment group B was significantly longer than that in control group A (P = 0.027). One of the reasons for this difference may be the synergy between antitumoral agents, including BCNU wafer, temozolomide, and radiation therapy combined with the vascular endothelial growth factor (VEGF) antagonist bevacizumab. We hypothesize that bevacizumab itself does not have antitumoral effects, but that it improves the antitumoral actions of other drugs and radiation
References (43)
- et al.
Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain tumor treatment group
Lancet
(1995) - et al.
Cellular abnormalities of blood vessels as targets in cancer
Curr Opin Genet Dev
(2005) - et al.
Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization
Cell
(2009) - et al.
Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases
Cancer Cell
(2004) - et al.
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma
N Engl J Med
(2005) - et al.
Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma
N Engl J Med
(2014) - et al.
A randomized trial of bevacizumab for newly diagnosed glioblastoma
N Engl J Med
(2014) - et al.
Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group
J Clin Oncol
(2010) - et al.
The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial
J Neurooncol
(1995) - et al.
Local treatment of malignant brain tumors using implantable chemotherapeutic polymers
J Natl Compr Canc Netw
(2005)
Interstitial chemotherapy for malignant gliomas: the Johns Hopkins experience
J Neurooncol
Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study
Neurosurgery
Biology and therapy of glial tumors
Curr Opin Neurol Neurosurg
Phase I trial of polifeprosan 20 with carmustine implant plus continuous infusion of intravenous O6-benzylguanine in adults with recurrent malignant glioma: new approaches to brain tumor therapy CNS consortium trial
J Clin Oncol
A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma
Neuro Oncol
Executive Committee of the Gliadel Study Group. Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial
Acta Neurochir (Wien)
Molecular mechanisms of blood vessel growth
Cardiovasc Res
Determinants of tumor blood flow: a review
Cancer Res
Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy
Science
Heterogeneity of the tumor vasculature
Semin Thromb Hemost
Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment
Proc Natl Acad Sci U S A
Cited by (26)
Nonlinear optical response of cancer cells following conventional and nano-technology based treatment strategies: Results of chemo-, thermo- and radiation therapies
2022, Photodiagnosis and Photodynamic TherapyCitation Excerpt :Conventional techniques including chemotherapy, radiation therapy (RT), and hyperthermia, considerably effect the normal tissue [1–4]. Although traditional chemotherapy has been able to increase cancer survival rate, undesirable impacts on off-target tissues (skin reactions, mucositis, hypokalemia and neutropenia), limited absorption by the target tumors, and finally decreasing drug effectiveness, are considered as limitations of this treatment [1,2,5,6]. Like chemotherapy, radiation effects off-target tissues, which has manifestations such as: skin reactions, inflammation of the mucus, bone marrow inhibition and damaging chromosomes by producing free radicals [3,7].
Smart drug carrier based on polyurethane material for enhanced and controlled DOX release triggered by redox stimulus
2020, Reactive and Functional PolymersCitation Excerpt :Since chemotherapy of tumor was a useful method for highly efficient treatment of cancer, many chemotherapeutics were studied and made use of [1]. While most antitumor drugs were so hydrophobic that they were faced with several bottlenecks in chemotherapy application [2], such as low solubility [3,4], high toxicity [5,6], short circulation time in vivo [7,8] and so on [9,10]. To conquer these problems, researchers have developed series of nanocarriers by means of nanotechnology [11–13], including nanoparticles [14,15], polymersomes [16,17], nanogels [18,19] and micelles [20,21].
Pep-1&borneol–Bifunctionalized Carmustine-Loaded Micelles Enhance Anti-Glioma Efficacy Through Tumor-Targeting and BBB-Penetrating
2019, Journal of Pharmaceutical SciencesCitation Excerpt :Clinical reports, however, have revealed the following limitations of using CMS: (1) in vivo half-life of 15 ∼ 30 min, which makes it difficult to maintain effective concentrations in desired sites; (2) lack of selectivity for tumor cells, resulting in a large number of secondary effects, such as blood toxicity, bone marrow suppression, liver and kidney injury, among others; and (3) a short retention in the brain, which is difficult to exert the sustained anticancer efficacy. These adverse reactions greatly reduce the patient's compliance to treatment and their quality of life.4,5 Polymer micelles with a “shell-core” structure are self-assembled by suitable polymer materials to carry insoluble drugs in the aqueous phase.
Computational modelling of drug delivery to solid tumour: Understanding the interplay between chemotherapeutics and biological system for optimised delivery systems
2018, Advanced Drug Delivery ReviewsCitation Excerpt :Gliadel® wafer containing 3.85% carmustine was approved by FDA in 1996 to serve as an adjuvant therapy for high-grade malignant glioma [161], and it is still in clinical use for prolonged and localized treatment of recurrent gliomas [162,163]. Recent studies have focused on enhancing drug penetration and improving treatment efficacy through optimising the wafer structure [164] and coated drugs [165], combination with other treatment approaches [166], and the development of alternative micro/nano-structured implants [167]. A number of mathematical models for chemotherapeutic polymer implants have been developed.
Recent advances in cold atmospheric plasma (CAP) for breast cancer therapy
2023, Cell Biology International
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.