Abstract: Glioblastoma (GBM) is the most deadly form of human cancer. Most patients diagnosed with this WHO grade IV malignant glioma survive about 12 months. Despite international efforts, treatment of GBM remains one of the most challenging tasks in clinical oncology. While new molecular pathways active in the biology and invasiveness of glioma are being constantly discovered, translation of basic science achievements into clinical practice is rather slow. Advances in surgical approaches, radiotherapy, and chemotherapy are contributing to incremental improvements in survival of the patients with GBM and improved quality of life. Yet much more significant strides need to be made before we can witness positive outcomes, similar to those seen in certain other cancers that can now be treated successfully. This review will discuss standard of care approach to GBM therapy in a newly diagnosed and recurrent setting. It will summarize the recent developments in management of this disease as well as future directions, keeping a practicing clinician in mind.
Malignant gliomas are heterogeneous, highly invasive primary brain tumors. Glioblastoma multiforme (GBM), classified by World Health Organization (WHO) as a grade IV glioma is particularly aggressive. Most patients diagnosed with this tumor die within one year from the diagnosis and only 5% survive more than 5 years despite aggressive therapies (CBTRUS, 2011). Over the last decade, a variety of different treatments were explored with very limited success. Major challenges in therapy of GBM are associated with the location of the disease and its complex and heterogeneous biology (Kesari, 2011). Most treatments cannot reach all the tumor cells. Surgery is frequently inadequate given the diffuse nature of the tumor and inability to remove it in its entirety without causing harm to the healthy brain. Although in newly diagnosed patients the extent of the resection carries prognostic value (Stummer et al., 2000; 2008), certain tumor locations such as eloquent cortex, basal ganglia, or brain stem are not amenable to surgical intervention and these patients typically exhibit worse prognosis. Similarly, chemotherapy approaches are associated with several limitations. Many chemotherapeutics are not able to cross the blood-brain barrier and consequently drug delivery to the brain parenchyma and the tumor itself is significantly impaired. Even the agents most active in glioma therapy achieve relatively low concentrations in the tissues surrounding the tumor (Ostermann et al., 2004; Portnow et al., 2009). There are several factors that influence drug access to the central nervous system (CNS): size of the molecule, lipophilicity, integrity of the blood-brain barrier that is typically damaged by the invasive GBM, and lastly presence of the active efflux pumps (Neuwelt et al., 2011). Hypoxic tumor environment is another factor that makes GBM resistant to chemotherapy (Haar et al., 2012). Moreover, many patients with CNS tumors receive concomitant medications such as steroids and anti-epileptic drugs that may reduce the efficacy of the chemotherapeutics and potentially exacerbate their side effects (Kuhn, 2002). One of the most challenging problems in therapy of GBM is its extremely complex and heterogeneous molecular biology. Consequently, “the same treatment for all” approach does not work well in this disease. Activation of numerous signaling pathways that are frequently redundant requires multi-targeted therapy. Testing different agents for safety and efficacy requires large cohorts of patients which is difficult to accomplish in this rare disease. Better pre-clinical testing, novel study designs and collaborative international efforts are needed to accelerate progress in neuro-oncology and improve outcomes in patients with GBM. This review will discuss current approach to this disease and select promising novel treatments that are entering clinical arena.
The Scope of the Problem — Epidemiology and Risk Factors
The incidence rate of primary malignant brain and CNS tumors is about 6.5 cases per 100,000/year (2005-2009). The rate is higher in males (7.7 per 100,000/year) than females (5.4 per 100,000/year). The incidence of GBM is about 3.19 per 100,000/year in the United States. It is estimated that 24,620 new cases of malignant CNS tumors will be diagnosed in 2013 (CBTRUS, 2011). Average age at diagnosis is 64 years and age is one of the most important prognostic factors (Schwartzbaum et al., 2006). Survival decreases with each additional decade of life at the time of diagnosis.
Prevention does not really exist as the risk factors for developing glioma are poorly understood. Many environmental, dietary, and lifestyle influences were studied but no conclusive evidence has been produced to date. A subject of a hot debate is the cell phone use and the risk of brain tumors. Several large population studies were conducted, mostly in Europe and they provided conflicting evidence (Swerdlow et al., 2011). The largest INTERPHONE study conducted in 13 countries suggested trends of increasing risk for certain brain tumors but no statistically significant evidence. In contrast, Swedish studies led by Hardell et al. (2012) indicated that the risk of developing glioma in the part of the brain with the highest exposure to the non-ionizing electromagnetic field produced by the cell phone (temporal lobe) is higher (OR=1.71) with over 10 year exposure. These studies are very difficult to conduct due to the nature of exposure, rapidly changing mobile technology, and reliability of recall. Data for childhood tumors and long term (over 15 years) exposure are being accumulated. Meta-analysis of studies done in the U.S. provided similar conclusions to these cited in the INTERPHONE study, suggesting possible modest excess risk (Little et al., 2012).
The environmental exposure associated with the known increased risk of developing GBM is ionizing radiation. It has been shown that children treated with radiotherapy for leukemia and other cancers have a significantly increased risk for developing CNS tumors including malignant glioma (Neglia et al., 1991; 2006). Adults with more benign brain tumors such as meningiomas or low grade gliomas who are long term survivors and received radiotherapy as their initial treatment also exhibit higher risk for developing GBM.
In addition to the factors mentioned above, several genetic syndromes are strongly associated with gliomas. These are: neurofibromatoses (I and II), Turcot syndrome, and Li-Fraumeni syndrome. Mutations in TP53 gene as well as PTEN have been postulated to play an important role in glioma formation (Ohgaki et al., 2004).
Setting the Stage — Current Standard of Care for Newly Diagnosed GBM
The standard of care for patients with newly diagnosed GBM includes maximal safe resection of the tumor followed by 6 week course of radiotherapy (typical dose is around 60 Gy) with concomitant systemic therapy using alkylating agent temozolomide (TMZ) (75 mg/m2 daily), followed by the minimum of 6 months of adjuvant temozolomide (150-200 mg/m2 for 5 days every 28 days) (Stupp et al., 2005). Standard of care approach is generally uniform and does not take into account different molecular signatures of GBM. It is now well known that response to alkylating therapy with temozolomide differs among patients with the same histological diagnosis of GBM and depends on the methylation of the methylguanine methyltransferase (MGMT) promoter. Hegi et al. (2005) showed that patients with methylated MGMT not only have better prognosis but also respond better to alkylator therapy. Median survival of patients with methylation vs. lack of thereof is 21.7 vs.15.3 months. Despite these findings, almost all patients with newly diagnosed GBM receive irradiation with concomitant and adjuvant temozolomide. It is not yet routine to test MGMT status outside of the clinical trials and patients may receive expensive and toxic therapy with minimal benefit (unmethylated GBM). Another important problem associated with standard of care in GBM is duration of therapy with adjuvant temozolomide. Stupp et al. (2005) treated patients with 6 months of adjuvant temozolomide and survival data we are using are based on this study. Many practicing neuro-oncologists extend the duration of therapy, given excellent tolerability of temozolomide, typically for 12 months or even longer. The benefit of this approach is unknown and should be studied. Prolonged exposure to alkylating therapy increases the risk of myelodysplasia and adds to the cost of care which is problematic with unknown benefit (Baehring and Marks, 2012; Natelson and Pyatt, 2010). Recent advances in therapy of newly diagnosed GBM in elderly patients should change the clinical practice. Studies showed that temozolomide is non-inferior to radiotherapy alone in the treatment of elderly patients (65 years or older) with malignant glioma (Wick et al., 2012). In the same study event free survival (EFS) was longer in patients with methylated MGMT promoter who were receiving temozolomide, findings that can facilitate treatment decision making in this group of patients.
Standard of Care Is Not Always the Best Option — Clinical Trials in Newly Diagnosed
Whenever possible, patients with newly diagnosed GBM should be offered participation in a clinical trial. There are several ongoing clinical trials in newly diagnosed glioblastoma that are worth mentioning. Agents that are of great interest to neuro-oncologic community are inhibitors of vascular endothelial growth factor (VEGF) and its receptors. Following Food and Drug Administration (FDA) approval of bevacizumab (Avastin), a humanized monoclonal antibody against VEGF for treatment of recurrent GBM (Cohen et al., 2009; Vredenburgh et al., 2007), studies were designed to use this approach in the up-front setting currently. The initial results of one of the studies combining bevacizumab with standard of care in patients with newly diagnosed GBM indicate that addition of bevacizumab to radiotherapy/temozolomide provides clinically meaningful and statistically significant improvement in progression free survival (PFS), improved quality of life, and diminished steroid requirement (Cloughsey et al., 2013). These results are encouraging and if improvement in overall survival with this therapy is observed we may be witnessing another paradigm shift in neuro-oncology, similar to change in practice witnessed after publication of Stupp data in 2005. Other anti-angiogenic agents that are being tested in newly-diagnosed GBM include an integrin inhibitor cilengitide (Nabors et al., 2012) and oral pan-VEGF inhibitor cediranib (Batchelor et al., 2007; Dietrich et al., 2009).
Another very promising approach to therapy of GBM is the vaccine against epidermal growth factor receptor (EGFR) and specifically its variant III (EGFRvIII). Phase II data from prior studies are encouraging. The median overall survival for patients with the newly diagnosed GBM expressing EGFRvIII was 22.8 months in the study published by Sampson et al. (2009). The treatment was well tolerated. This and other studies established the EGFRvIII mutation as a safe and immunogenic tumor-specific target for immunotherapy in GBM. The downside of this approach is the fact that only up to 30% GBMs overexpress EGFRvIII, therefore this approach, even if successful, will not be generalizable. A departure from a conventional approach to cancer therapy is introduction of tumor treating fields (TTF) recently made available for therapy of the recurrent GBM (Stupp et al., 2012). NovoTTF-110A system (Novocure, Ltd., Haifa, Israel), a device generating medium frequency electrical field (100-300 kHz) is now being tested in newly diagnosed GBM in combination with standard of care. A large, international study will enroll over 700 patients to identify if this approach can offer benefit to patients with GBM (Table 1) Gene therapy is also being considered for therapy of malignant glioma. Adair and colleagues in an elegant study achieved chemoprotection of hematopoietic stem cells using mutant methylguanine methyltransferase (P140K). Following transplantation of the modified (chemoprotected) autologous stem cells they were able to treat patients with newly diagnosed GBM with a combination of high dose TMZ and O-6 benzylguanine (O-6BG), a potent MGMT inhibitor. The longest surviving patient in this study is now 40+ months from the initial diagnosis and the side effects associated with this therapy were moderate and reversible (Adair et al., 2012).
Outside of enrolling patients in clinical trials, we must also recognize the importance of further study of the biology of this heterogeneous disease. Identifying different molecular signatures within GBMs and understanding their prognostic and predictive value will permit customized therapy with chances for the best outcomes. MGMT, IDH1 (isocitrate dehydrogenase), and other markers will soon enter clinics and tumor samples are already routinely tested for these mutations at major neuro-oncologic centers. Physicians taking care of patients with GBM should be aware of their prognostic and predictive value. Novel, non-invasive tools allowing predictions are also being developed. Rockne et al. (2010) proposed a mathematical model that facilitates, based on standard clinical pre-treatment MRIs, estimation of the tumor growth in time and its response to radiotherapy.
When the Tumor Comes Back — Challenges of Managing GBM in Recurrent Setting
After initial therapy fails, therapeutic options are limited and generally not effective. There is no standard of care for recurrent GBM. Median time to progression at this stage is about 10 weeks and overall survival ~30 weeks (Wong et al., 1999). Clinicians typically offer surgical intervention when it is believed to be feasible although there is no data indicating that second surgery in GBM offers significant survival benefit (Barker et al., 1998). Surgical resection, however, can be helpful diagnostically, especially in cases where pseudoprogression or radiation necrosis is suspected. In many instances, surgery can also serve as a vehicle to introduce chemotherapy wafers. Carmustine impregnated wafers (Gliadel, Eisai, Inc., USA) have been shown to increase time to progression in patients with recurrent GBM (Westphal et al., 2003). The effect is rather modest, yet, this treatment modality can be attractive in patients who cannot tolerate toxicity associated with systemic chemotherapy.
At present, in the recurrent setting, re-irradiation is more frequently employed. Historically, second course of radiotherapy was believed to be too toxic and was rarely recommended. With advances in technology, re-irradiation is safe and can provide survival benefit (Butowski et al., 2006). Several groups have shown that fractionated stereotactic radiotherapy can benefit patients with recurrent GBM (Torok et al., 2011; Vordermark et al., 2005). In the study by Torok et al. (2011) overall survival following re-irradiation was 79% at 6 months and 30% at 1 year. Chemotherapy options have been and continue to be quite limited. A variety of agents have been used in this setting with rather disappointing results. Drugs typically employed include temozolomide (MacDonald, 2001; Strik et al., 2008; Taal et al., 2012; Wick et al., 2009), nitrosoureas (BCNU, CCNU) (Wilson et al., 1976), platinoids (Francesconi et al., 2010 Jeremic et al., 1992; Mrugala et al., 2012; Prados et al., 1996; Watanabe et al., 2002), topoisomerase inhibitors (irinotecan, etoposide) (Korones et al., 2006; Santisteban et al., 2009), procarbazine and vincristine (part of PCV regimen with lomustine) (Boiardi, 2001; Kappelle et al., 2001; Schmidt et al., 2006), and tamoxifen (Brandes et al., 1999). National Comprehensive Cancer Network (NCCN) guidelines provide a good overview of therapies that can be considered in the recurrent setting (www.nccn.org).
Temozolomide, an alkylating agent used primarily in the newly diagnosed GBM patients, has been evaluated in the recurrent setting, given its good blood-brain-barrier penetration and acceptable toxicity profile. Studies were conducted to evaluate different dosing regimens of TMZ to increase dose intensity and achieve maximum MGMT suppression. In two phase II studies using 7-days-on/7-days-off regimen modest efficacy without substantial hematologic toxicity was noted (Wick et al., 2004). In one study overall response rate was 10% with PFS-6 rate of 48% and median PFS of 21 weeks (Wick et al., 2004). In another study using the same drug schedule the PFS-6 rate was 44% and PFS was 24 weeks (Wick et al., 2007). Other schedules of TMZ have also been tested, particularly the so called metronomic schedule (50 mg/m2 continuous dosing) (Hau et al., 2007).
Bevacizumab, an anti-VEGF inhibitor, has been approved by FDA for use in recurrent GBM in 2009 (Cohen et al., 2009). Since its introduction to neuro-oncologic menu, physicians started using it either as a single agent or in combination with cytotoxic drugs. Available clinical trial data currently does not provide convincing evidence that combination therapy is superior to single agent approach (Zhang et al., 2012). Yet, followers of “vascular normalization theory” (Chi et al., 2009; Sorensen et al., 2009) employ combination therapy in this setting. Bevacizumab has been used in combination with irinotecan (Vredenburgh et al., 2007), carboplatin (Mrugala et al., 2012; Reardon et al., 2011), etoposide (Francesconi et al., 2010), and CCNU (www.clinicaltrials.gov, NCT01067469). The timing of cytotoxic therapy in relation to bevacizumab might be crucial to take advantage of the so called “vascular normalization window” (Jain et al., 2007). Additional studies are needed to establish if bevacizumab paired with other agents can benefit patients with GBM. One of the major dilemmas in bevacizumab therapy era is the duration of therapy. Most patients are treated until progression and since this agent is used primarily in the recurrent disease, patients remain on it on average for 4-6 months (Friedman et al., 2009; Kreisl et al., 2009). Those without progression, however, are frequently kept on the drug indefinitely, with potential for serious adverse effects, including rare progression to a more invasive tumor type (Figure 1A) (Norden et al., 2008; de Groot et al., 2010; Paez-Ribes et al., 2009; Mrugala et al., 2009). Given powerful anti-edema properties (and steroid sparing effect) of bevacizumab and other anti-VEGF agents (Figure 1B), their discontinuation might be associated with the “rebound effect,” leading to clinical progression (Batchelor et al., 2007). This is one of the major reasons why clinicians are weary of stopping the drug. In addition, prolonged treatment with bevacizumab might be associated with a modest survival benefit (Reardon et al., 2012). A large number of agents, especially targeted molecular therapies have been evaluated in recurrent GBM. Agents tested include inhibitors of the receptor tyrosine kinases like EGFR (endothelial growth factor receptor), VEGFR (vascular endothelial growth factor receptor), and PDGFR (platelet derived growth factor receptor). Signal transduction pathways inhibitors directed against mTOR, PI3K, histone deacetylase (HDAC), and farnesyltransferase have also been evaluated. Most of these therapies have been associated with poor outcomes (Table 2). Based on the lessons learned in newly diagnosed GBM, anti-EGFRvIII vaccine approach is also being tested in the recurrent setting. The ReACT study, currently ongoing, randomizes first or second recurrence patients to receive either bevacizumab plus the vaccine or placebo (for bevacizumab naïve patients) or bevacizumab plus the vaccine for anti-VEGF refractory tumors (www.clinicaltrials.gov, NCT01498328).
An outside-the-box approach to therapy of GBM in the recurrent setting is utilization of medium frequency electrical fields. The novel device known as NovoTTF-100A (Novocure, New Hampshire, USA) — was introduced to therapy of malignant glioma in 2011. Tumor treating fields (TTFs) work by arresting dividing cells in mitosis. Data from the largest to date study using this therapy in recurrent GBM was published by Stupp et al. (2012). Researchers found that TTFs provided similar efficacy to chemotherapy agents typically used in this setting. Adverse effect profile favored TTFs and quality of life was found to be better in patients treated with this modality as opposed to systemic therapy. Based on these results and preliminary data indicating that TTFs might potentiate effects of chemotherapy (Kirson et al., 2009), the study in newly diagnosed GBM was designed and is currently being conducted (www.clinicaltrials.gov, NCT00916409) (Table 1).
Glioblastoma remains a challenging disease to treat. Even with the recent advances in the understanding of the molecular heterogeneity of the disease and its prognostic and predictive value, customized therapy for GBM is not quite possible. With the introduction of anti-VEGF agents, we now have the tools to improve patients’ quality of life and extend progression free survival. Novel modalities, such as NovoTTF-100A device, are entering the field of neuro-oncology and may offer an alternative to more toxic, systemic therapies. Gene therapy might allow for high-dose chemotherapy with limited toxicity. The search for new agents and better clinical trial designs are mandatory.
This review does not discuss all therapeutic approaches to GBM; it attempts to highlight the more clinically relevant aspects of the subject. Some challenges facing clinicians treating patients with malignant glioma are summarized in Table 3.
The author wishes to thank Piotr Zlomanczuk, Ph.D., for valuable comments.
The author reports no conflicts of interest.
Maciej M. Mrugala, M.D., Ph.D., M.P.H., University of Washington and Fred Hutchinson Cancer Research Center, 1959 NE Pacific Street, Seattle, Washington 98195, USA.
Adair JE, Beard BC, Trobridge GD, Neff T, Rockhill JK, Silbergeld DL, Mrugala MM, Kiem HP. Extended survival of glioblastoma patients after chemoprotective HSC gene therapy. Sci Transl Med 4(133):133ra157, 2012.
Baehring JM, Marks PW. Treatment-related myelodysplasia in patients with primary brain tumors. Neuro Oncol 14(5):529-540, 2012.
Barker FG, 2nd, Chang SM, Gutin PH, Malec MK, Mcdermott MW, Prados MD, Wilson CB. Survival and functional status after resection of recurrent glioblastoma multiforme. Neurosurgery 42(4):709-720; discussion 720-703, 1998.
Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11(1):83-95, 2007.
Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, Eichler AF, Drappatz J, Hochberg FH, Benner T, Louis DN, Cohen KS, Chea H, Exarhopoulos A, Loeffler JS, Moses MA, Ivy P, Sorensen AG, Wen PY, Jain RK. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor patients with recurrent glioblastoma. J Clin Oncol 28(17):2817-2823, 2010.
Boiardi A. PCV chemotherapy for recurrent glioblastoma multiforme. Neurology 56(12):1782, 2001.
Brandes AA, Ermani M, Turazzi S, Scelzi E, Berti F, Amista P, Rotilio A, Licata C, Fiorentino MV. Procarbazine and high-dose tamoxifen as a second-line regimen in recurrent high-grade gliomas: a phase II study. J Clin Oncol 17(2):645-650, 1999.
Brandsma D, Stalpers L, Taal W, Sminia P, Van Den Bent MJ. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 9(5):453-461, 2008.
Brandsma D, Van Den Bent MJ. Pseudoprogression and pseudoresponse in the treatment of gliomas. Curr Opin Neurol 22(6):633-638, 2009.
Butowski NA, Sneed PK, Chang SM. Diagnosis and treatment of recurrent high-grade astrocytoma. J Clin Oncol 24(8):1273-1280, 2006.
CBTRUS (Central Brain Tumor Registry of the United States). CBTRUS Statistical Reoprt: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004-2007. Central Brain Tumor Registry of the United States, Hinsdale, Illinois, USA, 2011.
Chang, S M, Wen P, Cloughesy T, Greenberg H, Schiff D, Conrad C, Fink K, Robins HI, De Angelis L, Raizer J, Hess K, Aldape K, Lamborn KR, Kuhn J, Dancey J, Prados MD; North American Brain Tumor Consortium and the National Cancer Institute. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23(4):357-361, 2005.
Cloughesy TF, Wen PY, Robins I, Chang SM, Morris D, Groves KL, Fink KL, Junck L, Schiff D, Abrey L, Gilbert MR, Lieberman F, Kuhn J, DeAngelis LM, Mehta M, Raizer JJ, Yung WK, Aldape K, Wright J, Lamborn KR, Prados MD. Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J Clin Oncol 24(22):3651-3656, 2006.
Cohen MH, Shen YL, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 14(11):1131-1138, 2009.
de Groot JF, Fuller G, Kumar AJ, Piao Y, Eterovic K, Ji Y, Conrad CA. Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol 3:233-242, 2010.
Dietrich J, Wang D, Batchelor TT. Cediranib: profile of a novel anti-angiogenic agent in patients with glioblastoma. Expert Opin Investig Drugs 18(10):1549-1557, 2009.
Franceschi E, Cavallo G, Lonardi S, Magrini E, Tosoni A, Grosso D, Scopece L, Blatt V, Urbini B, Pession A, Tallini G, Crinò L, Brandes AA. Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperative de Neuro-Oncologia (GICNO). Br J Cancer 96(7):1047-1051, 2007.
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 17(8):970-974, 2010.
Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27(28):4733-4740, 2009.
Galanis E, Jaeckle KA, Maurer MJ, Reid JM, Ames MM, Hardwick JS, Reilly JF, Loboda A, Nebozhyn M, Fantin VR, Richon VM, Scheithauer B, Giannini C, Flynn PJ, Moore DF Jr, Zwiebel J, Buckner JC. Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study. J Clin Oncol 27(12):2052-2058, 2009.
Galanis E, Buckner JC, Maurer MJ . Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 23(23):5294-5304, 2005.
Gilbert MR, Kuhn J, Lamborn KR, Lieberman F, Wen PY, Mehta M, Cloughsey T, Lassman AB, Deangelis LM, Chang S, Prados M. Cilengitide in patients with recurrent glioblastoma: the results of NABTC 03-02, a phase II trial with measures of treatment delivery. J Neurooncol 106(1):147-153, 2012.
Haar CP, Hebbar P, Wallace GCT, Das A, Vandergrift WA, 3rd, Smith JA, Giglio P, Patel SJ, Ray SK, Banik NL. Drug resistance in glioblastoma: a mini review. Neurochem Res 37(6):1192-1200, 2012.
Hardell L, Carlberg M, Hansson Mild K. Use of mobile phones and cordless phones is associated with increased risk for glioma and acoustic neuroma. Pathophysiology, epub ahead of print, Dec. 20, 2012.
Hau P, Koch D, Hundsberger T, Marg E, Bauer B, Rudolph R, Rauch M, Brenner A, Rieckmann P, Schuth J, Jauch T, Koch H, Bogdahn U. Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma. Neurology 68(9):688-690, 2007.
Hegi ME, Diserens AC, Gorlia T, Hamou MF, De Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997-1003, 2005.
Jain RK, Di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumours. Nat Rev Neurosci 8(8):610-622, 2007.
Jeremic B, Grujicic D, Jevremovic S, Stanisavljevic B, Milojevic L, Djuric L, Mijatovic L. Carboplatin and etoposide chemotherapy regimen for recurrent malignant glioma: a phase II study. J Clin Oncol 10(7):1074-1077, 1992.
Kappelle AC, Postma TJ, Taphoorn MJ, Groeneveld GJ, Van Den Bent MJ, Van Groeningen CJ, Zonnenberg BA, Sneeuw KC, Heimans JJ. PCV chemotherapy for recurrent glioblastoma multiforme. Neurology 56(1):118-120, 2001.
Kesari S. Understanding glioblastoma tumor biology: the potential to improve current diagnosis and treatments. Semin Oncol 38(Suppl 4):S2-S10, 2011.
Kirson ED, Schneiderman RS, Dbaly V, Tovarys F, Vymazal J, Itzhaki A, Mordechovich D, Gurvich Z, Shmueli E, Goldsher D, Wasserman Y, Palti Y. Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). BMC Med Phys 9:1, 2009.
Korones DN, Smith A, Foreman N, Bouffet E. Temozolomide and oral VP-16 for children and young adults with recurrent or treatment-induced malignant gliomas. Pediatr Blood Cancer 47(1):37-41, 2006.
Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27(5):740-745, 2009.
Kreisl TN, Kotliarova S, Butman JA, Albert PS, Kim L, Musib L, Thornton D, Fine HA. A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas. Neuro Oncol 12(2):181-189, 2010.
Kuhn JG. Influence of anticonvulsants on the metabolism and elimination of irinotecan. A North American Brain Tumor Consortium preliminary report. Oncology (Williston Park) 16(8 Suppl 7):33-40, 2002.
Little MP, Rajaraman P, Curtis RE, Devesa SS, Inskip PD, Check DP, Linet MS. Mobile phone use and glioma risk: comparison of epidemiological study results with incidence trends in the United States. BMJ 344:e1147, 2012.
MacDonald DR. Temozolomide for recurrent high-grade glioma. Semin Oncol 28(4 Suppl 13):3-12, 2001.
Mrugala MM, Crew LK, Fink JR, Spence AM. Carboplatin and bevacizumab for recurrent malignant glioma. Oncol Lett 4(5):1082-1086, 2012.
Mrugala MM, Rudnick JD, Rockhill JK, Recht LD. Does bevacizumab increase the risk of leptomeningeal gliomatosis? Society for Neuro-Oncology, New Orleans, LA, 2009. Neuro-Oncology 11(5):634, 2009
Nabors LB, Mikkelsen T, Hegi ME, Ye X, Batchelor T, Lesser G, Peereboom D, Rosenfeld MR, Olsen J, Brem S, Fisher JD, Grossman SA. A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306). Cancer 118(22):5601-5607, 2012.
Natelson EA, Pyatt D. Temozolomide-induced myelodysplasia. Adv Hematol 2010:760402, 2010.
Neglia JP, Meadows AT, Robison LL, Kim TH, Newton WA, Ruymann FB, Sather HN, Hammond GD. Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med 325(19):1330-1336, 1991.
Neglia JP, Robison LL, Stovall M, Liu Y, Packer RJ, Hammond S, Yasui Y, Kasper CE, Mertens AC, Donaldson SS, Meadows AT, Inskip PD. New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 98(21):1528-1537, 2006.
Neuwelt EA, Bauer B, Fahlke C, Fricker G, Iadecola C, Janigro D, Leybaert L, Molnar Z, O’donnell ME, Povlishock JT, Saunders NR, Sharp F, Stanimirovic D, Watts RJ, Drewes LR. Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci 12(3):169-182, 2011.
Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70(10):779-787, 2008.
Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schuler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lutolf UM, Kleihues P. Genetic pathways to glioblastoma: a population-based study. Cancer Res 64(19):6892-6899, 2004.
Ostermann S, Csajka C, Buclin T, Leyvraz S, Lejeune F, Decosterd LA, Stupp R. Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res 10(11):3728-3736, 2004.
Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D, Casanovas O. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 3 15(3):220-231, 2009.
Pitz MW, Hosseini B, Guilbert K, Lister D, Mihalcioiu CL, Eisenstat DD. Extended duration temozolomide in patients with glioblastoma multiforme. Proceedings of the American Society of Clinical Oncology, June 4-8, 2010; Chicago, IL. J Clin Oncol 28(Suppl 15):e12538 [abstract], 2010.
Portnow J, Badie B, Chen M, Liu A, Blanchard S, Synold TW. The neuropharmacokinetics of temozolomide in patients with resectable brain tumors: potential implications for the current approach to chemoradiation. Clin Cancer Res 15(22):7092-7098, 2009.
Prados MD, Warnick RE, Mack EE, Chandler KL, Rabbitt J, Page M, Malec M. Intravenous carboplatin for recurrent gliomas. A dose-escalating phase II trial. Am J Clin Oncol 19(6):609-612, 1996.
Reardon DA, Desjardins A, Peters KB, Gururangan S, Sampson JH, Mclendon RE, Herndon JE, 2nd, Bulusu A, Threatt S, Friedman AH, Vredenburgh JJ, Friedman HS. Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naive, recurrent glioblastoma. J Neurooncol 107(1):155-164, 2011.
Reardon DA, Herndon JE, 2nd, Peters KB, Desjardins A, Coan A, Lou E, Sumrall AL, Turner S, Lipp ES, Sathornsumetee S, Rich JN, Sampson JH, Friedman AH, Boulton ST, Bigner DD, Friedman HS, Vredenburgh JJ. Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients. Br J Cancer 107(9):1481-1487, 2012.
Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O’Neill A, Plotkin S, Glantz M, Ravin P, Raizer JJ, Rich KM, Schiff D, Shapiro WR, Burdette-Radoux S, Dropcho EJ, Wittemer SM, Nippgen J, Picard M, Nabors LB. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 26:5610-5617, 2008.
Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, Wikstrand CJ, Van Duyn LB, Dancey JE, McLendon RE, Kao JC, Stenzel TT, Ahmed Rasheed BK, Tourt-Uhlig SE, Herndon JE 2nd, Vredenburgh JJ, Sampson JH, Friedman AH, Bigner DD, Friedman HS. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22(1):133-142, 2004.
Rockne R, Rockhill JK, Mrugala M, Spence AM, Kalet I, Hendrickson K, Lai A, Cloughesy T, Alvord EC, Jr, Swanson KR. Predicting the efficacy of radiotherapy in individual glioblastoma patients in vivo: a mathematical modeling approach. Phys Med Biol 55(12):3271-3285, 2010.
Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon JE 2nd, Lally-Goss D, Mcgehee-Norman S, Paolino A, Reardon DA, Friedman AH, Friedman HS, Bigner DD. An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther 8(10):2773-2779, 2009.
Santisteban M, Buckner JC, Reid JM, Wu W, Scheithauer BW, Ames MM, Felten SJ, Nikcevich DA, Wiesenfeld M, Jaeckle KA, Galanis E. Phase II trial of two different irinotecan schedules with pharmacokinetic analysis in patients with recurrent glioma: North Central Cancer Treatment Group results. J Neurooncol 92(2):165-175, 2009.
Schmidt F, Fischer J, Herrlinger U, Dietz K, Dichgans J, Weller M. PCV chemotherapy for recurrent glioblastoma. Neurology 66(4):587-589, 2006.
Schwartzbaum JA, Fisher JL, Aldape KD, Wrensch M. Epidemiology and molecular pathology of glioma. Nat Clin Pract Neurol 2(9):494-503; quiz 491 p following 516, 2006.
Sorensen AG, Batchelor TT, Zhang WT, Chen PJ, Yeo P, Wang M, Jennings D, Wen PY, Lahdenranta J, Ancukiewicz M, Di Tomaso E, Duda DG, Jain RK. A “vascular normalization index” as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res 69(13):5296-5300, 2009.
Strik HM, Buhk JH, Wrede A, Hoffmann AL, Bock HC, Christmann M, Kaina B. Rechallenge with temozolomide with different scheduling is effective in recurrent malignant gliomas. Mol Med Report 1(6):863-867, 2008.
Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ. Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 93(6):1003-1013, 2000.
Stummer W, Reulen HJ, Meinel T, Pichlmeier U, Schumacher W, Tonn JC, Rohde V, Oppel F, Turowski B, Woiciechowsky C, Franz K, Pietsch T. Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62(3):564-576; discussion 564-576, 2008.
Stupp R, Mason WP, Van Den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987-996, 2005.
Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbaly V, Ram Z, Villano JL, Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, et al. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer 48(14):2192-2202, 2012.
Swerdlow AJ, Feychting M, Green AC, Leeka Kheifets LK, Savitz DA. Mobile phones, brain tumors, and the interphone study: where are we now? Environ Health Perspect 119(11):1534-1538, 2011.
Taal W, Segers-Van Rijn JM, Kros JM, Van Heuvel I, Van Der Rijt CC, Bromberg JE, Sillevis Smitt PA, van den Bent MJ. Dose dense 1 week on/1 week off temozolomide in recurrent glioma: a retrospective study. J Neurooncol 108(1):195-200, 2012.
Torok JA, Wegner RE, Mintz AH, Heron DE, Burton SA. Re-irradiation with radiosurgery for recurrent glioblastoma multiforme. Technol Cancer Res Treat 10(3):253-258, 2011.
van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, Clement PM, Frenay M, Campone M, Baurain JF, Armand JP, Taphoorn MJ, Tosoni A, Kletzl H, Klughammer B, Lacombe D, Gorlia T. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol 27(8):1268-1274, 2009.
Vordermark D, Kolbl O, Ruprecht K, Vince GH, Bratengeier K, Flentje M. Hypofractionated stereotactic re-irradiation: treatment option in recurrent malignant glioma. BMC Cancer 5:55, 2005.
Vredenburgh JJ, Desjardins A, Herndon JE, 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25(30):4722-4729, 2007.
Watanabe K, Kanaya H, Fujiyama Y, Kim P. Combination chemotherapy using carboplatin (JM-8) and etoposide (JET therapy) for recurrent malignant gliomas: a phase II study. Acta Neurochir (Wien) 144(12):1265-1270; discussion 1270, 2002.
Wen PY, MacDonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28(11):1963-1972, 2010.
Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, Whittle IR, Jaaskelainen J, Ram Z. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol 5(2):79-88, 2003.
Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, Nikkhah G, Papsdorf K, Steinbach JP, Sabel M, Combs SE, Vesper J, Braun C, Meixensberger J, Ketter R, Mayer-Steinacker R, Reifenberger G, Weller M. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 13(7):707-715, 2012.
Wick A, Pascher C, Wick W, Jauch T, Weller M, Bogdahn U, Hau P. Rechallenge with temozolomide in patients with recurrent gliomas. J Neurol 256(5):734-741, 2009.
Wick W, Steinbach JP, Kuker WM, Dichgans J, Bamberg M, Weller M. One week on/one week off: a novel active regimen of temozolomide for recurrent glioblastoma. Neurology 62(11):2113-2115, 2004.
Wick A, Felsberg J, Steinbach JP, Herrlinger U, Platten M, Blaschke B, Meyermann R, Reifenberger G, Weller M, Wick W. Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol 25(22):3357-3361, 2007.
Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol 28(7):1168-1174, 2010.
Wilson CB, Gutin P, Boldrey EB, Drafts D, Levin VA, Enot KJ. Single-agent chemotherapy of brain tumors. A five-year review. Arch Neurol 33(11):739-744, 1976.
Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, Levin VA, Yung WK. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17(8):2572-2578, 1999.
Zhang G, Huang S, Wang Z. A meta-analysis of bevacizumab alone and in combination with irinotecan in the treatment of patients with recurrent glioblastoma multiforme. J Clin Neurosci 19(12):1636-1640, 2012.
[Discovery Medicine; ISSN: 1539-6509; Discov Med 15(83):221-230, April 2013. Copyright © Discovery Medicine. All rights reserved.]