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Maciej M Mrugala

Advances and Challenges in the Treatment of Glioblastoma: A Clinician’s Perspective

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.



Introduction

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.

Figure 1A.

Figure 1A. 64 years old woman with recurrent GBM receiving therapy with bevacizumab. MRI of the brain in axial plane. FLAIR images (upper row) and post contrast images (lower row). Note extension of abnormal FLAIR signal (arrows) anteriorly to the resection cavity as well as in the contra lateral hemisphere after 3 months of therapy, suggesting non-enhancing tumor progression. Corresponding post contrast images obtained at the same time points indicate stable disease with two small foci of enhancement (arrows) unchanged in size.

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).

Figure 1B.

Figure 1B. 44 years old man with recurrent glioblastoma. MRI images (FLAIR, axial plane) of the brain. Note significant amount of tumor associated vasogenic edema (arrows) and the midline shift. After treatment with bevacizumab midline shift has almost completely resolved and the amount of edema significantly decreased leading to clinical improvement.

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).

Conclusions

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.

Acknowledgments

The author wishes to thank Piotr Zlomanczuk, Ph.D., for valuable comments.

Disclosure

The author reports no conflicts of interest.

Corresponding Address

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.

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[Discovery Medicine; ISSN: 1539-6509; Discov Med 15(83):221-230, April 2013. Copyright © Discovery Medicine. All rights reserved.]

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