Glioblastoma: Multidisciplinary treatment approaches

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most common and most malignant primary tumor of the central nervous system (CNS) (Figure 1). According to the Central Brain Tumor Registry of the United States (CBTRUS) 2007-2011, 52.751 of 343.171 brain tumors (15.37%) were GBM, representing 45.6% of all malignant primary brain tumors.¹

During the early 19th century, glioblastoma was considered GBM of mesenchymal origin and was defined as a sarcoma. In 1863, Rudolf Virchow demonstrated its glial origin,² and in 1914 Mallory proposed the term glioblastoma multiforme. However, it was not until 1925 that Globus and Strass presented a complete description of the neoplasm, at which point the most common term became spongioblastoma multiforme. Finally, in 1926, Bailey and Cushing successfully reintroduced the term originally proposed by Mallory: glioblastoma multiforme.

There are two types of GBM, each distinguished by origin and molecular phenotype: primary, which represents the majority of GBM patients and develops rapidly over the course of several weeks; and secondary, which presents as lower-grade gliomas and eventually progresses to grade IV. Once a patient is diagnosed with GBM, the overall median survival time for those treated with the Stupp scheme is approximately 15 months.³

Technology

Treatment protocols for GBM combine surgery followed by concurrent radiation therapy with temozolamide and adjuvant temozolamide (TMZ). These approaches provide palliation and moderate survival benefit.^3-5

Clinical Applications

Surgery

In multidisciplinary regimens, glioma resection remains the mainstay given its central role in establishing a histologic diagnosis and in relieving symptoms of mass effect by mechanical cytoreduction. The objective is to provide maximal tumor resection with preservation or restoration of neurologic function.^6,7 Unfortunately, patients nearly always experience tumor recurrence, as these tumors invade and infiltrate surrounding normal tissue, making curative resection unlikely.

Advanced Surgical Techniques

The best established technique for assessing the eloquent cortex to guide resection is direct cortical stimulation (DCS).^8,9 With this approach, low-current stimulation of the brain creates a transient localized lesion, and testing of language function during DCS can help assess the site of importance in language function. The mapping of motor and language areas of the brain has allowed for more aggressive resections of high-grade gliomas by minimizing the risk of potential deficits.

In fluorescence-guided resections, 5 aminolevulinic acid (5-ALA) is used as an orally administered prodrug, which is metabolized intracellularly to protoporphyrin IX and emits a red-violet fluorescent signal evidenced by blue light. This agent accumulates in certain tumor types and, thus, can help differentiate tumor from normal surrounding brain tissue.¹⁰

Image-guided surgical techniques have helped safely assist the extent of surgery in eloquent cortical areas where resection is frequently abandoned before gross total resection to avoid neurologic deficits. This is the reason for neuro-navigation based on preoperative functional MRI (fMRI), the most common noninvasive tool that can provide additional information on the anatomical relationship between borders of the tumor, specifically infiltrating tumors and eloquent areas.^11-14 Motor mapping can be performed either with the patient awake or under general anesthesia, while speech mapping requires the use of an awake anesthesia technique, at least during the mapping portion. Concomitant with neuronal activity is an increase of blood flow through local cerebral vessels. These changes in cerebral blood flow can be visualized by a method of fMRI that measures variations in the area of interest that are dependent on blood oxygen level.

Chemoradiotherapy

After surgery, chemoradiotherapy is considered the standard treatment. During the delineation and planning of radiotherapy treatment, the radiation oncology team uses acronyms like GTV (gross tumor volume), CTV (clinical target volume) and PTV (planning target volume). The doses and treatment phases are based on protocols determined by the European Organization for Research and Treatment of Cancer (EORTC) and the Radiation Therapy Oncology Group (RTOG). Based on the RTOG guidelines, the initial volumes (T2/FLAIR + gross/residual tumor plus resection cavity) receive 4600 cGy/23 fractions followed by a boost to 1400 cGy/7 fractions to gross/residual tumor plus resection cavity. In a study by Kelly et al,¹⁵ the isolated tumor cells were noted to extend to cover T2 changes and beyond on MRI, which was confirmed with serial stereotactic biopsies; this is the reason for the definition of the initial GTV treated to lower doses (eg, 46 Gy). These PTV are based on the 1980 study by Hochberg and Pruitt¹⁶ that showed, using computed tomography (CT), 78% of recurrences were within 2 cm of the margin of the initial tumor bed, and 58% were within 1 cm. This pattern was validated by Wallner et al.¹⁷ These data are the basis for the definition of the boost to GTV treated to higher doses (eg, 60 Gy). According to the EORTC, only a treatment volume receives 60 Gy in 30 fractions. The GTV corresponds to the surgical resection cavity plus any residual enhancing tumor (postcontrast T1-weighted MRI scans); the CTV comprises the GTV plus a margin of 20 mm; and finally, PTV is equal to CTV plus a margin of 3-5 mm.

Better results have been obtained with a combination of RT and temozolamide (TMZ), with standard dosing for concomitant TMZ therapy being 75 mg/m2/d given daily during radiation therapy (RT) followed by 150-200 mg/m2/d for 5 days every 28 days for a total of 6 cycles.³ The RTOG-0525, which consisted of 833 patients, did not show a statistically significant difference between a conventional TMZ regimen and a dose-dense TMZ protocol. The overall survival (OS) was 16.6 vs. 14.9 months, and progression-free survival (PFS) was 5.5 vs. 6.7 months, respectively. The dose-dense protocol increased grade 3 toxicities from 34% to 53% (Figure 2).

In an attempt to shorten treatment duration in older patients, hypofractionated radiation therapy (HFRT), which gives a higher radiation dose per fraction in fewer total fractions over a shorter period (eg, 40 Gy in 15 fractions over 3 weeks), has been shown to be equivalent in older patients to the standard of 60 Gy in 30 fractions over 6 weeks.¹⁸

Stereotactic radiosurgery (SRS) has been used as a boost after conventional treatment or in cases of recurrence.^19,20 Some authors theorize that SRS could be useful as a local radiation boost to the “worst” part of the tumor, which could be identified with MR perfusion imaging, or in areas with the highest creatine to coline ratio on MR spectrocospy; however, some publications have shown no benefits^21,22 (Figure 3). There is no level I evidence that supports the addition of SRS as an initial treatment. Level II evidence suggests a modest survival benefit after SRS in selected patients; on the other hand, attempts to deliver a higher cumulative dose of 70.4 Gy using hyperfractionation schemes also failed to show a survival advantage.²³ With the implementation of TMZ into standard GBM therapy, the role of SRS in both newly diagnosed and recurrent GBM continues to be investigated. Clinical oncologists should consider different schemes (Table 1) in treatment regimens with TMZ (recurrence), which can be monitored closely, considering the advances in imaging techniques, localization, chemotherapy (CHT), biological agents and radiosensitizers.

Chemotherapy

CHT includes alkylating agents, nitrosoureas, procarbazine, topoisomerase inhibitors, platinoids, vincristine, and estrogen receptor antagonists.^24-32 Before TMZ therapy, the role of CHT in GBM was controversial. A meta-analysis of 12 randomized trials (> 3000 patients) showed an increase in 1-year survival from 40% to 46% with CHT.³³ TMZ is an alkylating agent stable only at acidic pH.³⁴ This prodrug undergoes rapid chemical conversion in the systemic circulation at physiological pH to the active compound, which will react with water. This results in an unstable cation, which transfers a methyl group to the DNA, causing the cytotoxic effect of temozolomide because it depletes the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). In 2009, bevacizumab, an anti-VEGF inhibitor, was approved for the treatment of recurrent glioblastoma. It has been administrated as a single agent or in combination with cytotoxic therapy; however, neither regimen has been shown to prolong OS.

Molecular Diagnostics

Molecular diagnostics are important because low levels of MGMT in tumor tissue are associated with longer survival among patients with GBM.^35-36 Approximately 45% of patients with newly diagnosed GBM have methylation of the MGMT promoter that responds better to TMZ.³⁷

Recently, a paper by Parsons and colleagues³⁸ demonstrated the existence of a glioma-associated mutation in isocitrate dehydrogenase-1 (IDH1) in 12% of patients with GBM. IDH is an enzyme involved in oxidative metabolism.³⁹ Mutations in IDH1 were associated with younger age, secondary GBMs (grade IV tumors that arise from biopsy-proven, lower-grade predecessors), and increased OS. IDH1 mutations have been found more frequently in secondary GBM (sGBM) compared with primary GBM (pGBM); patients with GBM with IDH1 mutations have improved survival (45.6 vs 13.2 months).^40,41 Additionally, Sanson and colleagues⁴² found improved progression-free survival (PFS) of 55 months in patients with IDH1 mutation vs 8.8 months in those without mutation. Secondary GBM is characterized by IDH1, TP53, and ATRX mutations, while primary GBM frequently show molecular alterations in EGFR, PDGFRA, PTEN, TP53, NF1, and CDKN2A/B, as well as TERT promoter mutations, but not IDH mutations.

Another molecular prognosticator is alpha thalassemia/mental retardation syndrome X-linked (ATRX), a gene that produces a protein involved in chromatin remodeling. Jiao et al⁴³ showed that ATRX mutations appear in 57% of patients with secondary GBM, and are rare in primary GBM (4%), noting that nearly half of adult-infiltrating gliomas that harbored an ATRX mutation also contained an IDH1 mutation.⁴⁴

Electrical Fields

Tumor-treating fields (TTF) are low- intensity, medium-frequency, alternating electric fields administered using insulated electrodes on the skin surrounding the region of a malignant tumor (Figure 4). This disrupts cancer cell mitosis. TTF selectively affects dividing cells while quiescent cells are left intact, acting in 2 modes: arrest of cell proliferation and destruction of cells while undergoing division.⁴⁵

In 2011, the NovoTTF-100A system (Novocure Ltd., Haifa, Israel) was approved by the U.S. Food and Drug Administration for treating recurrent glioblastoma. While a phase 3 clinical trial comparing stand-alone TTF with TMZ for recurrent glioblastoma failed to demonstrate a significant difference in OS between both groups,⁴⁶ it is important to mention that a comparative subgroup analysis of the original trial demonstrated that TTF accounted for a proportion of the responders to treatment than the conventional CHT group, with a median response duration of 7.3 vs 5.6 months.⁴⁷ At interim analysis, the EF-14 Trial,¹¹⁷ which enrolled 700 patients from the United States, Europe, South Korea, and Israel, showed that 315 patients who received TMZ and treatment with the NovoTTF-100A system (now called Optune) survived an average of 19.6 months vs. 16.6 months for those receiving only TMZ. Additionally, patients treated with Optune had an increased PFS of 3 months compared to those who did not (7.1 vs 4.0 months). The OS at 2 years was 43% with Optune and TMZ, and 29% with TMZ alone.This phase 3 clinical trial was terminated at interim analysis due to early success, and was presented at the Society of Neuro-Oncology (SNO) 2014 Annual Meeting in Miami, Florida, by Dr. Roger Stupp.

Toxicity

The presence of neurological deficits following neurosurgery is declining, thanks to advances in tumor localization and delineation, functional imaging, and operative techniques. Despite these advances, some tumor localizations remain a common cause of cranial nerve injury.

Common radiation-induced adverse effects include: fatigue, anorexia, alopecia, erythema of the scalp, serous otitis, nausea, vomiting, exacerbation of neurologic deficits, headaches and seizures. Considering the poor prognosis of these patients, reports of long-term complications in high-grade gliomas (other than radiation necrosis) are rare.

CHT is generally neurotoxic,⁵⁴ but the CNS is protected when the blood-brain barrier is intact. Therefore, signs of encephalopathy such as headaches, altered cognition, or arousal with or without seizures are rare after systemic administration of conventional CHT doses. The use of glucocorticosteroids,⁵⁵ opioids and antiepileptics may result in behavioral and mental changes, anxiety, nervousness, insomnia, or euphoria. The toxicity caused by TTF is low and consists mainly of skin reactions at the site of the electrodes.

Diagnosis of Recurrence

Tumor recurrence occurs in almost all patients, and standards of care are incompletely defined in recurrent or progressive glioblastoma. All therapeutic modalities mentioned above can be used again, modified as needed with each case. However, one should note that the appearance of enhancing lesions on MR imaging within the first 6 months after completing chemoradiation therapy poses a challenge as it can reflect true progression (TP) or treatment-related changes known as pseudoprogression (PSP). Criteria for response and progression in GBM should be discussed 3 to 6 months after completing chemoradiation, as many patients show increased contrast enhancement and T2/FLAIR hyperintensity in the radiation treatment field. As a result, MR imaging every 3 months remains the gold standard for diagnosing response or progression in GBM. Given the uncertainty of PSP and TP, it is important to consider criteria such as the MacDonald criteria and RANO criteria (Table 2). MacDonald criteria does not take PSP into account when defining disease progression, whereas the more contemporary RANO criteria defines progression as the development of a new area of enhancement outside of the prior radiation field at < 12 weeks after completion of chemoradiotherapy, confirmed by biopsy or clinical decline. Currently, the best standardized tool for evaluating response or progression is the RANO criteria.

Conventional MRI, such T1-weighted, gadolinium-enhanced (T1-Gad); T2-weighted; or fluid-attenuated inversion recovery (FLAIR) sequences, do not differentiate recurrent tumors from radiation injury. Advanced MRI techniques such as MR spectroscopy (MRS), perfusion-weighted imaging (PWI), and diffusion-weighted imaging (DWI); and biological imaging such as positron emission tomography (PET), have shown promise in differentiating glioma recurrence or progression from treatment changes.⁵⁶ Several studies evaluating the use of either MR spectroscopy or MR perfusion found that relative cerebral blood volume (rCBV),^57-61 as well as Cho/Cr and Cho/NAA ratios,^62-68 are good predictors of recurrent tumor. The Cho/NAA and NAA/Cr ratios⁴⁴ are good for differentiating tumor recurrence from radiation necrosis, and higher Cho/NAA ratios were associated with a greater probability of tumor infiltration and recurrence.^41,45 With PET techniques, imaging with radiolabeled amino acids offers a powerful approach for noninvasive evaluation of brain tumors. Recent studies demonstrated that [11 C]-methionine (MET), O-2-[18 F]-fluoroethyl-L -thyrosine (FET), as well as 3,4-dihydroxy-6-[18 F]-fluoro-L-phenyl-alanine (FDOPA) could be good techniques for detecting glioma recurrence and complementing MRI.^69-77 Amino acid PET can detect a metabolically active tumor, and this amino acid uptake in patients with suspected glioma recurrence may be useful in guiding new treatment options to optimize effects in patients with recurrent malignant GBM.

Treatment Options for Tumor Recurrence

The option of repeating surgery in patients with progressive or recurrent glioblastoma remains controversial. Some retrospective studies proposed a survival benefit after reoperation^78-81 taking into account age, Karnofsky (KPS) and Eastern Cooperative Oncology Group (ECOG) scales, MGMT promotor methylation, tumor volume, localization, extent of resection, ependymal involvement and tumor in noneloquent areas, while others did not.^82-84 Ringel et al⁸⁵ assessed 503 patients undergoing 1 to 4 re-resections for recurrent GBM with a median OS of 25.0 months after initial surgical treatment, and 11.9 months after first re-resection.

Re-irradiation is a similarly controversial option for patients with recurrent glioblastoma; total doses between 30-36 Gy in 2-3.5 Gy fractions with or without intensity modulation have been used.^86,87 In an attempt to retreat larger volumes of recurrent disease with higher doses, the departments of human oncology, medical physics, and biostatistics at the University of Wisconsin, explored pulsed reduced-dose-rate radiation therapy (PRDR), in which the dose-rate effect is most dramatic between 0.01 and 1 Gy/min compared to conventional radiation therapy, in which a dose of 2 Gy is delivered at a dose rate of 4-6 Gy/min. The Wisconsin reirradiation experience consisted of PRDR in a series of 0.2-Gy pulses separated by 3-min intervals, creating a dose rate of 0.0667 Gy/min, reducing the linac dose rate to 1 Gy/min during each 0.2-Gy pulse, which would enhance the therapeutic ratio, taking advantage of the sublethal damage repair of normal tissue and the phenomenon known as low-dose hyper-radiosensitivity (LDHRS) of the tumor.¹¹⁸ On the other hand, SRS can be considered in patients with small volume and well-defined disease.⁸⁸ Given that GBM recurrences are predominantly local, proponents of using SRS note that it allows for dose escalation with a rapid fall-off of gradient doses limiting exposure to organs at risk (OARs). Skeptics report that GBM is a highly infiltrative disease that extends beyond the apparent margins, making the use of a highly conformal technique inadvisable. In 2014, Larson et al reviewed the literature and found 9 studies describing the use of Gamma Knife (Leksell Gamma Knife; Elekta, Stockholm, Sweden) radiosurgery for recurrent GBM,⁸⁹ with a median OS range of 9-17.9 months from salvage SRS, and a median progression-free survival (PFS) range of 4.6-14.9 months.^90-98

Beyond chemotherapy with alkylating agents (TMZ or nitrosoureas), other classical non-alkylating chemotherapeutics have been studied, including carboplatin (CABARET trial) and irinotecan (BRAIN trial). Evaluated in randomized phase 2 trials as add-ons to bevacizumab,^99,100 these agents showed no difference in outcome, and caused additional toxicity.

Another therapeutic option to consider is an intravenous humanized anti-VEGF monoclonal antibody that impairs angiogenesis by targeteing the VEGF ligand (bevacizumab). The induction of VEGF by ionizing radiation enhances blood vessel protection and, subsequently, tumor resistance. Anti-VEGF therapies block this protection, and enhance the effect of therapeutic radiation,^101,102 but the future role of bevacizumab is uncertain since the EORTC 26101 trial failed to demonstrate superiority for OS of lomustine plus bevacizumab over lomustine alone.¹⁰³

Extracranial Metastatic Disease

The first case of extracranial metastasis was reported by Davis in 1928,¹⁰⁴ with a GBM disseminated to the lung, chest wall and soft tissue of an arm. Extracranial metastasis is a unique but rare manifestation of GBM reported in < 2% of cases,^105-112 with only 83 cases published between 1928 and 2009. This rarity is related to patients’ short period of life, with a median OS of 10.5 months, a median time from symptom onset to diagnosis of primary GBM of 2.5 months, a diagnosis to extracranial metastasis detection time of 8.5 months, and metastasis to death time of 1.5 months.^113,114 The infrequency of this extracranial demonstration is perhaps due to intrinsic biological obstacles that prevent tumor GBM cells from infiltrating and surviving beyond the neural environment, such as the blood–brain barrier, absence of a lymphatic system within the brain and spinal cord to allow systemic dissemination, thickened basement membrane of blood vessels, and thickened dura mater around intracranial veins that prevents tumor cell penetration.

Conclusion

In general, overall survival of GBM patients has improved little over time, despite advances in molecular diagnostics, neurosurgery, radiation therapy, chemotherapies, imaging techniques, and immunotherapy, and continues to pose a difficult challenge for patients, family and clinicians. Life expectancy in patients with unmethylated MGMT is 14.8% and 8.3% at 2 and 5 years, respectively, vs. 48.9% and 13.8% in those with MGMT promoter methylation.¹¹⁵ In 2009, the randomized phase 3 study of a 5-year analysis of the EORTC-NCIC trial¹¹⁹ showed that OS in 573 patients was 27.2%, 16.0%, 12.1% and 9.8% at 2, 3, 4 and 5 years, respectively, with radiotherapy and TMZ, vs. 10.9%, 4.4%, 3.0% and 1.9% with radiotherapy alone. The methylation of the MGMT promoter was the strongest predictor of results with TMZ. Research must continue to guide treatment based on current developments, taking into account prognostic factors to offer patients a greater quantity and/or quality of life.

While standard treatment for intracranial GBM is surgical resection followed by concurrent radiotherapy and chemotherapy,¹¹⁶ treatment strategies for metastatic disease are sparse, and optimal treatment has not been determined. Clinical trials¹²⁰ are attempting to establish the most appropriate therapy for recurrent GBM. In the case of metastatic lesions, it would be an interesting option to recruit patients for clinical trials to establish the most promising treatment; however, the rarity of this condition and its prognosis would hamper success.

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