Management of Specific Tumors

Chapter 5

Options

Abstract

1. Introduction

77

Management of Refractory/

Aggressive Pituitary Adenomas

Congxin Dai, Xiaohai Liu, Sihai Ma, Ming Feng, Xinjie Bao,

Tumors of central nervous system (CNS) account for a small portion of tumors of human body, which includes tumors occurring in the parenchyma of brain and spinal cord as well as their coverings. This chapter covers some new development in some major brain tumors in both pediatric and adult populations, as well as some

Keywords: refractory pituitary adenoma, macroadenoma and microadenoma,

The anterior pituitary gland (adenohypophysis) is an important organ for human development and physiological functions (so called "Master Gland"), which comprises several different cell types, responsible for the synthesis and secretion of a specific hormone or group of specific hormones (plurihormonal), such as growth hormone (GH), adrenocorticotrophic hormone (ACTH), and prolactin (PRL). Each of these cell types may give rise to a discrete pituitary adenoma (PA) subtype that is

As one of the most common pituitary neuroendocrine tumors, pituitary adenomas (PAs) constitute the overwhelming majority of tumors arising in the pituitary gland and account for 10–15% intracranial neoplasms. Incidental microadenoma (smaller than 10 mm in diameter) may occur in up to 27% of pituitary glands examined at autopsy, and up to one-fifth of the human population has pituitary

Majority of PAs are benign and slow growing; however, up to 10% of PAs are aggressive with invasive growth and can exhibit clinical abnormal behavior with high rates of recurrences [1]. Based on the recent WHO classification in 2017, a more detailed tumor classification by immunohistochemical stain (IHC) was proposed, which identifies a subset of PAs with aggressive clinical behavior characterized by clinical recurrence, which includes PAs with elevated Ki-67 proliferation

uncommon but diagnostic and management challenging tumors.

either hormonal active (functional) or inactive (nonfunctional).

abnormalities on magnetic resonance imaging (MRI).

trans-sphenoidal adenomectomy, targeting therapy

Kan Deng, Yong Yao, Renzhi Wang, DX. Feng, E. Fonkem,

Review of Current Treatment

Frank Y. Shan and Jason H. Huang

#### Chapter 5

## Management of Refractory/ Aggressive Pituitary Adenomas Review of Current Treatment Options

Congxin Dai, Xiaohai Liu, Sihai Ma, Ming Feng, Xinjie Bao, Kan Deng, Yong Yao, Renzhi Wang, DX. Feng, E. Fonkem, Frank Y. Shan and Jason H. Huang

#### Abstract

Tumors of central nervous system (CNS) account for a small portion of tumors of human body, which includes tumors occurring in the parenchyma of brain and spinal cord as well as their coverings. This chapter covers some new development in some major brain tumors in both pediatric and adult populations, as well as some uncommon but diagnostic and management challenging tumors.

Keywords: refractory pituitary adenoma, macroadenoma and microadenoma, trans-sphenoidal adenomectomy, targeting therapy

#### 1. Introduction

The anterior pituitary gland (adenohypophysis) is an important organ for human development and physiological functions (so called "Master Gland"), which comprises several different cell types, responsible for the synthesis and secretion of a specific hormone or group of specific hormones (plurihormonal), such as growth hormone (GH), adrenocorticotrophic hormone (ACTH), and prolactin (PRL). Each of these cell types may give rise to a discrete pituitary adenoma (PA) subtype that is either hormonal active (functional) or inactive (nonfunctional).

As one of the most common pituitary neuroendocrine tumors, pituitary adenomas (PAs) constitute the overwhelming majority of tumors arising in the pituitary gland and account for 10–15% intracranial neoplasms. Incidental microadenoma (smaller than 10 mm in diameter) may occur in up to 27% of pituitary glands examined at autopsy, and up to one-fifth of the human population has pituitary abnormalities on magnetic resonance imaging (MRI).

Majority of PAs are benign and slow growing; however, up to 10% of PAs are aggressive with invasive growth and can exhibit clinical abnormal behavior with high rates of recurrences [1]. Based on the recent WHO classification in 2017, a more detailed tumor classification by immunohistochemical stain (IHC) was proposed, which identifies a subset of PAs with aggressive clinical behavior characterized by clinical recurrence, which includes PAs with elevated Ki-67 proliferation

index, sparsely granulated somatotroph PAs, Lactotroph PAs in men, silent corticotroph PAs, Crooke cell PAs, and plurihormonal PAs with PIT-1 positivity. PIT-1 is one of the pituitary transcription factors, sometimes to be used to clarify the PAs' tumor linages.

cavernous sinus (14.7%) [10]. In 2016, a systematic review and evidence-based guideline for the residual or recurrent NFPAs was produced by Congress of Neurological Surgeons, and the repeat resection is recommended as level III recommenda-

Management of Refractory/Aggressive Pituitary Adenomas Review of Current Treatment Options

Based on the previous studies and our experience, endoscopic surgery is better than the microscopic surgery for recurrent pituitary adenomas; however, these findings are needed to be verified by the large-scale prospective randomized controlled trials. Therefore, maximum tumor resection, meanwhile preserving nerve function is the goal to achieve local control and decompress vital structures for

Despite the success of trans-sphenoidal surgery or maximum tumor resection, most refractory PAs will regrow or recur; therefore, other therapeutic approaches are usually necessary. If surgical and/medical therapy failed to control the tumor growth, radiation therapy (RT) is currently the next treatment option [1]. There are several RT options for patients with refractory PAs. Fractionated external beam radiation therapy (EBRT) has been used for several decades and has shown good clinical safety and efficacy [12]. Stereotactic radiosurgery (SRS) is the delivery of a high single dose of radiation under conditions of accurate positioning. Recently, SRS has been gaining popularity due to the minimizing exposure of normal brain tissue to radiation. SRS has been preferred over fractionated photon beam because of the convenience of single day therapy and the potential for the faster effect on tumor [13]. A variety of SRS including Gamma Knife, CyberKnife, and proton-beam RT are available to deliver stereotactic RT. However, some refractory PAs are not candidates for stereotactic RT because of the tumor size (>3 cm), or tumor location near the optic apparatus and brainstem (<5 mm) [14]. Risks associated with RT include hypopituitarism, optic neuropathy, and other cranial

Comparing EBRT and SRS may help to guide decision making for patients with residual or recurrent pituitary tumors. Kong et al. [15] compared the efficacy and safety of SRS and EBRT for the treatment of 125 patients with PAs. Although no significant difference was found in either biochemical remission or tumor growth control, the time to biochemical remission after SRS was much shorter than EBRT

To better understand the effects of SRS for Cushing disease (CD), Mehta et al. [16] performed an international, multicenter, retrospective cohort analysis, 278 patients with CD received SRS was retrospective cohort analyzed, and found that the overall rate of durable control of hypercortisolism was 64% for 10 years, and the adverse radiation effects included hypopituitarism (25%) and cranial neuropathy

Medical therapy plays an increasingly important role in the management of PAs.

Both conventional radiotherapy and stereotactic RT have shown a good tumoristatic effect on typical PAs; however, they may be largely ineffective and rarely maintain a long-term remission in refractory PAs. As a matter of fact, one of the aggressive PAs with high recurrent potential, silent corticotroph PAs, is with high sensitivity to radiation, so RT can be a good option for patients with those kind of PAs.

Temozolomide (TMZ), an orally administered alkylating chemotherapy, is

tions for the treatment of symptomatic recurrent or residual NFPAs [11].

those refractory PAs with compressive symptoms.

DOI: http://dx.doi.org/10.5772/intechopen.81464

neuropathies, which should be concerned and avoided [12].

3. Radiation therapy

(26 months vs. 63 months).

(3%) were observed.

4. Medical therapy

79

Clinically, a subset of aggressive PAs characterized with high Ki-67 index, rapid growth, frequent recurrence, and resistant to conventional treatments is defined as refractory PAs [2]. These refractory PAs often have a very poor prognosis and even with an occasionally fatal outcome; however, there is no general agreement about how to manage the patient with refractory PAs. For neurosurgeons and clinicians, it is difficult to optimally choose the therapeutic options in treatment of refractory PAs in order to improve the prognoses of these patients; it is very important and necessary to review the emerging treatments for refractory PAs. This chapter is going to review some current treatment options for those refractory PAs.

#### 2. Management of refractory PAs by surgical treatment

Typically, multimodal approaches are required for managing refractory PAs. Except prolactin-secreting adenomas (prolactinomas), which should be first treated with dopamine agonists (DAs), the primary treatment option is usually surgery, even surgery is usually unable to cure or control the refractory PAs [3]. However, the therapeutic goals of surgery are maximum reduction of tumor mass, decompression of visual pathways, best possible reduction of hormonal oversecretion, amelioration of clinical symptoms, and minimization of complications [4].

Most of the refractory PAs are largely invasive, infiltrating adjacent tissues; repeated surgery seldom achieves complete tumor excision. However, surgical resection is still necessary to relieve compressive symptoms [5].

Repeated trans-sphenoidal surgery is generally more difficult to perform than the initial operation due to the increased risk of morbidity and mortality. The comparison of microscopic craniectomy and endoscopic approach for recurrent or residual pituitary adenomas remains controversial.

Heringer performed a meta-analysis to evaluate effect of repeated transsphenoidal surgery in recurrent or residual pituitary adenomas and found that half of secreting tumors and more than half of nonfunctional pituitary adenomas (NFPAs) could achieve remission after surgery, and there is no difference between endoscopic and microscopic approach [6]. However, Esquenazi and his colleagues performed another meta-analysis to compare the effects of endoscopic and microscopic transsphenoidal surgery on recurrent and/or residual pituitary adenomas and found that endoscopic surgery led to modest increases in resection rates on residual or recurrent adenomas [7]. Do et al. [8] retrospectively analyzed 61 patients with recurrent or residual pituitary adenomas who underwent endoscopic endonasal surgery and found that the gross total resection was achieved in 31 patients (51.7%), indicating that endoscopic endonasal approach is a safe and effective option for recurrent pituitary adenomas. The results from another meta-analysis performed by Li also indicated that the endoscopic surgery is related to higher gross tumor removal and lower incidence of complications in patients with PA [9]. Almeida accessed the outcomes of reoperation for patients with residual or recurrent growth hormone-secreting PA from authors' institution, and no statistically significant difference was found in disease control rates between the reoperation and first-time neurosurgery. They further systematically reviewed 161 reoperations and 2189 first-time surgery cases retrieved from 29 papers and found that reoperation and first-time surgery had similar control rates for microadenomas, but the reoperation was related to substantially lower control rates for macroadenomas (27.5%) and tumors invading the

Management of Refractory/Aggressive Pituitary Adenomas Review of Current Treatment Options DOI: http://dx.doi.org/10.5772/intechopen.81464

cavernous sinus (14.7%) [10]. In 2016, a systematic review and evidence-based guideline for the residual or recurrent NFPAs was produced by Congress of Neurological Surgeons, and the repeat resection is recommended as level III recommendations for the treatment of symptomatic recurrent or residual NFPAs [11].

Based on the previous studies and our experience, endoscopic surgery is better than the microscopic surgery for recurrent pituitary adenomas; however, these findings are needed to be verified by the large-scale prospective randomized controlled trials. Therefore, maximum tumor resection, meanwhile preserving nerve function is the goal to achieve local control and decompress vital structures for those refractory PAs with compressive symptoms.

#### 3. Radiation therapy

index, sparsely granulated somatotroph PAs, Lactotroph PAs in men, silent corticotroph PAs, Crooke cell PAs, and plurihormonal PAs with PIT-1 positivity. PIT-1 is one of the pituitary transcription factors, sometimes to be used to clarify

2. Management of refractory PAs by surgical treatment

resection is still necessary to relieve compressive symptoms [5].

residual pituitary adenomas remains controversial.

78

Clinically, a subset of aggressive PAs characterized with high Ki-67 index, rapid growth, frequent recurrence, and resistant to conventional treatments is defined as refractory PAs [2]. These refractory PAs often have a very poor prognosis and even with an occasionally fatal outcome; however, there is no general agreement about how to manage the patient with refractory PAs. For neurosurgeons and clinicians, it is difficult to optimally choose the therapeutic options in treatment of refractory PAs in order to improve the prognoses of these patients; it is very important and necessary to review the emerging treatments for refractory PAs. This chapter is going to review some current treatment options for those refractory PAs.

Typically, multimodal approaches are required for managing refractory PAs. Except prolactin-secreting adenomas (prolactinomas), which should be first treated with dopamine agonists (DAs), the primary treatment option is usually surgery, even surgery is usually unable to cure or control the refractory PAs [3]. However, the therapeutic goals of surgery are maximum reduction of tumor mass, decompression of visual pathways, best possible reduction of hormonal oversecretion, amelioration of clinical symptoms, and minimization of complications [4]. Most of the refractory PAs are largely invasive, infiltrating adjacent tissues; repeated surgery seldom achieves complete tumor excision. However, surgical

Repeated trans-sphenoidal surgery is generally more difficult to perform than the initial operation due to the increased risk of morbidity and mortality. The comparison of microscopic craniectomy and endoscopic approach for recurrent or

Heringer performed a meta-analysis to evaluate effect of repeated transsphenoidal surgery in recurrent or residual pituitary adenomas and found that half of secreting tumors and more than half of nonfunctional pituitary adenomas (NFPAs) could achieve remission after surgery, and there is no difference between endoscopic and microscopic approach [6]. However, Esquenazi and his colleagues performed another meta-analysis to compare the effects of endoscopic and microscopic transsphenoidal surgery on recurrent and/or residual pituitary adenomas and found that endoscopic surgery led to modest increases in resection rates on residual or recurrent adenomas [7]. Do et al. [8] retrospectively analyzed 61 patients with recurrent or residual pituitary adenomas who underwent endoscopic endonasal surgery and found that the gross total resection was achieved in 31 patients (51.7%), indicating that endoscopic endonasal approach is a safe and effective option for recurrent pituitary adenomas. The results from another meta-analysis performed by Li also indicated that the endoscopic surgery is related to higher gross tumor removal and lower incidence

of complications in patients with PA [9]. Almeida accessed the outcomes of reoperation for patients with residual or recurrent growth hormone-secreting PA from authors' institution, and no statistically significant difference was found in disease control rates between the reoperation and first-time neurosurgery. They further systematically reviewed 161 reoperations and 2189 first-time surgery cases retrieved from 29 papers and found that reoperation and first-time surgery had similar control rates for microadenomas, but the reoperation was related to substantially lower control rates for macroadenomas (27.5%) and tumors invading the

the PAs' tumor linages.

Primary Intracranial Tumors

Despite the success of trans-sphenoidal surgery or maximum tumor resection, most refractory PAs will regrow or recur; therefore, other therapeutic approaches are usually necessary. If surgical and/medical therapy failed to control the tumor growth, radiation therapy (RT) is currently the next treatment option [1]. There are several RT options for patients with refractory PAs. Fractionated external beam radiation therapy (EBRT) has been used for several decades and has shown good clinical safety and efficacy [12]. Stereotactic radiosurgery (SRS) is the delivery of a high single dose of radiation under conditions of accurate positioning. Recently, SRS has been gaining popularity due to the minimizing exposure of normal brain tissue to radiation. SRS has been preferred over fractionated photon beam because of the convenience of single day therapy and the potential for the faster effect on tumor [13]. A variety of SRS including Gamma Knife, CyberKnife, and proton-beam RT are available to deliver stereotactic RT. However, some refractory PAs are not candidates for stereotactic RT because of the tumor size (>3 cm), or tumor location near the optic apparatus and brainstem (<5 mm) [14]. Risks associated with RT include hypopituitarism, optic neuropathy, and other cranial neuropathies, which should be concerned and avoided [12].

Comparing EBRT and SRS may help to guide decision making for patients with residual or recurrent pituitary tumors. Kong et al. [15] compared the efficacy and safety of SRS and EBRT for the treatment of 125 patients with PAs. Although no significant difference was found in either biochemical remission or tumor growth control, the time to biochemical remission after SRS was much shorter than EBRT (26 months vs. 63 months).

To better understand the effects of SRS for Cushing disease (CD), Mehta et al. [16] performed an international, multicenter, retrospective cohort analysis, 278 patients with CD received SRS was retrospective cohort analyzed, and found that the overall rate of durable control of hypercortisolism was 64% for 10 years, and the adverse radiation effects included hypopituitarism (25%) and cranial neuropathy (3%) were observed.

Both conventional radiotherapy and stereotactic RT have shown a good tumoristatic effect on typical PAs; however, they may be largely ineffective and rarely maintain a long-term remission in refractory PAs. As a matter of fact, one of the aggressive PAs with high recurrent potential, silent corticotroph PAs, is with high sensitivity to radiation, so RT can be a good option for patients with those kind of PAs.

#### 4. Medical therapy

Medical therapy plays an increasingly important role in the management of PAs. Temozolomide (TMZ), an orally administered alkylating chemotherapy, is

recommended as the first-line chemotherapy for aggressive pituitary tumors and pituitary carcinomas after the failure of standard therapies by the European Society of Endocrinology [17]. TMZ is considered the standard treatment in the management of gliomas. Since 2006, the first successful treatment of PA with TMZ was reported [18, 19], and TMZ treatment has also been widely used for patients with refractory PAs and carcinomas [20]. However, only about 50% of pituitary tumors are sensitive to TMZ treatment, and most of the refractory PAs failed to respond to TMZ and even acquired TMZ resistance after the effective response to TMZ [21]. Therefore, it is important to enhance the efficacy of TMZ and overcome the resistance of TMZ. Some molecular status of pituitary tumors, such as O<sup>6</sup> methylguanine-DNA-methyltransferase MGMT and MSH6, has been associated with temozolomide response [22]. It is reported that the PI3K/AKT/mTOR signaling pathway is upregulated in pituitary tumors, and the inhibition of this pathway may enhance the TMZ-mediated cytotoxicity [23].

infiltration is associated with the pituitary adenoma size and invasiveness, indicating that immunotherapy may be useful to restrict the tumor enlargement and invasiveness [46]. Blocking the interaction between the programmed cell death (PD-1) protein and one of its ligands, programmed death ligand 1 (PD-L1) is one of the novel strategies for cancer immunotherapy. The expression of PD-L1 is positively correlated with improved responses to anti-PD-1/PD-L1 blockade in many cancers [47]. Mei reported that the expression of (PD-L1) is significantly higher in human functioning adenomas compared to nonfunctioning adenomas, suggesting the existence of an immune response to pituitary tumors [48]. Therefore, these researches raise the possibility of considering immunotherapy for the

Management of Refractory/Aggressive Pituitary Adenomas Review of Current Treatment Options

Although various treatment options are available to manage these refractory pituitary tumors, the efficacy is limited. Therefore, the new therapeutic approaches and such randomized clinical trials are needed. It is hoped that further research may clarify the tumorigenesis and pathogenesis of refractory PAs, and additional alter-

None of the authors have potential financial conflicts of interests related to this article. The financial support for this study was provided by the National Natural Science Foundation of China (grant number: 81502639, 81501192), Scientific Research Project of Capital Health Development in 2018 (grant number: 2018-4-4018), and the Youth Scientific Research Fund in Peking Union Medical College Hospital (grant number: pumch-2016-2.20). The funding institutions had no role in the design of the study, data collection and analysis, the decision to

native treatments may be developed for these tumors in the near future.

refractory PAs.

DOI: http://dx.doi.org/10.5772/intechopen.81464

5. Conclusion

Declaration of interest

Abbreviations

TMZ temozolomide

CD Cushing disease CS Cushing's syndrome DA dopamine agonists

RT radiation therapy SRS stereotactic radiosurgery TSS trans-sphenoidal surgery

81

WHO World health organization IHC immunohistochemical stain ACTH adrenocorticotropic hormone

EBRT external beam radiation therapy EGFR epidermal growth factor receptor NFPA nonfunctional pituitary adenomas PD-L1 programmed death ligand 1 RPA refractory pituitary adenoma

VEGF vascular endothelial growth factor

publish, or the preparation of the manuscript.

Epidermal growth factor receptor (EGFR) is a cell growth factor, which regulates cell proliferation and hormone production in pituitary tumors [24]. EGFR is overexpressed in prolactinoma and ACTH-secreting pituitary adenomas, which may offer a potential therapeutic target for refractory pituitary tumors [25, 26]. As an EGFR inhibitor, gefitinib has shown antiproliferative and apoptotic effects in corticotroph tumor cell in vitro [25]. Lapatinib, a dual HER2/EGFR inhibitor, was shown to both suppressed PRL mRNA expression and secretion more than gefitinib in animal model of prolactinomas [27].

Although further clinical trials are needed, preclinical data suggest that the EGFR pathway may be an effective therapeutic targeting for patients with refractory pituitary tumors.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor in pituitary tumors. The previous studies indicated that angiogenesis is associated with adenoma development, local invasion, and recurrences [28–30]. Several researches reported that angiogenesis decrease tumor sizes in human and experimental pituitary tumors [31–33]. Ortiz has reported the first case of a bevacizumab-treated pituitary carcinoma with long-term stabilization of disease in 2012 [34]. Touma also presented one case of pituitary carcinoma treated successfully with concurrent chemoradiation therapy and bevacizumab with a long-term follow up [35]. However, the role of anti-VEGF therapy in pituitary tumors is still controversial due to the lack of large-scale clinical trial.

Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) cascades is key signaling pathways in tumorigenesis of pituitary adenoma [36]. The previous studies reported that the PI3K/AKT/mTOR pathway is upregulated and overactivated in pituitary adenomas, implicating an important role in tumor formation and progression of pituitary adenoma [37–39]. Inhibition of the PI3K/mTOR signaling pathway not only displays antitumor efficacy against pituitary tumor [40, 41] but also sensitizes pituitary adenoma cells to radiotherapy and chemotherapy [23, 42]. Donovan reported one patient with pituitary carcinoma, which is refractory to multiple surgery, radiation, and chemotherapy, after the treatment with mTOR inhibitor (everolimus) and radiation, and the clinical improvement and stability >6 months were achieved [43].

As a promising therapeutic approach, cancer immunotherapy has been attracting more and more attention recently. To date, immunotherapy has been applied for the treatment of many tumors including glioma, lung cancer, melanoma, prostate cancer, and B cell lymphoma [44]. In 2007, Hazrati and his colleagues have reported one case of a prolactinoma treated successfully with immunotherapy for the first time [45]. Lu has reported that CD68+ macrophage Management of Refractory/Aggressive Pituitary Adenomas Review of Current Treatment Options DOI: http://dx.doi.org/10.5772/intechopen.81464

infiltration is associated with the pituitary adenoma size and invasiveness, indicating that immunotherapy may be useful to restrict the tumor enlargement and invasiveness [46]. Blocking the interaction between the programmed cell death (PD-1) protein and one of its ligands, programmed death ligand 1 (PD-L1) is one of the novel strategies for cancer immunotherapy. The expression of PD-L1 is positively correlated with improved responses to anti-PD-1/PD-L1 blockade in many cancers [47]. Mei reported that the expression of (PD-L1) is significantly higher in human functioning adenomas compared to nonfunctioning adenomas, suggesting the existence of an immune response to pituitary tumors [48]. Therefore, these researches raise the possibility of considering immunotherapy for the refractory PAs.

#### 5. Conclusion

recommended as the first-line chemotherapy for aggressive pituitary tumors and pituitary carcinomas after the failure of standard therapies by the European Society of Endocrinology [17]. TMZ is considered the standard treatment in the management of gliomas. Since 2006, the first successful treatment of PA with TMZ was reported [18, 19], and TMZ treatment has also been widely used for patients with refractory PAs and carcinomas [20]. However, only about 50% of pituitary tumors are sensitive to TMZ treatment, and most of the refractory PAs failed to respond to TMZ and even acquired TMZ resistance after the effective response to TMZ [21]. Therefore, it is important to enhance the efficacy of TMZ and overcome the resis-

methylguanine-DNA-methyltransferase MGMT and MSH6, has been associated with temozolomide response [22]. It is reported that the PI3K/AKT/mTOR signaling pathway is upregulated in pituitary tumors, and the inhibition of this pathway may

Epidermal growth factor receptor (EGFR) is a cell growth factor, which regulates cell proliferation and hormone production in pituitary tumors [24]. EGFR is overexpressed in prolactinoma and ACTH-secreting pituitary adenomas, which may offer a potential therapeutic target for refractory pituitary tumors [25, 26]. As an EGFR inhibitor, gefitinib has shown antiproliferative and apoptotic effects in corticotroph tumor cell in vitro [25]. Lapatinib, a dual HER2/EGFR inhibitor, was shown to both suppressed PRL mRNA expression and secretion more than gefitinib

Although further clinical trials are needed, preclinical data suggest that the EGFR pathway may be an effective therapeutic targeting for patients with refrac-

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor in pituitary tumors. The previous studies indicated that angiogenesis is associated with adenoma development, local invasion, and recurrences [28–30]. Several researches reported that angiogenesis decrease tumor sizes in human and experimental pituitary tumors [31–33]. Ortiz has reported the first case of a bevacizumab-treated pituitary carcinoma with long-term stabilization of disease in 2012 [34]. Touma also presented one case of pituitary carcinoma treated successfully with concurrent chemoradiation therapy and bevacizumab with a long-term follow up [35]. However, the role of anti-VEGF therapy in pituitary tumors is still controversial due to

Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) cascades is key signaling pathways in tumorigenesis of pituitary adenoma

upregulated and overactivated in pituitary adenomas, implicating an important role in tumor formation and progression of pituitary adenoma [37–39]. Inhibition of the PI3K/mTOR signaling pathway not only displays antitumor efficacy against pituitary tumor [40, 41] but also sensitizes pituitary adenoma cells to radiotherapy and chemotherapy [23, 42]. Donovan reported one patient with pituitary carcinoma, which is refractory to multiple surgery, radiation, and chemotherapy, after the treatment with mTOR inhibitor (everolimus) and radiation, and the clinical

[36]. The previous studies reported that the PI3K/AKT/mTOR pathway is

As a promising therapeutic approach, cancer immunotherapy has been attracting more and more attention recently. To date, immunotherapy has been applied for the treatment of many tumors including glioma, lung cancer, melanoma, prostate cancer, and B cell lymphoma [44]. In 2007, Hazrati and his colleagues have reported one case of a prolactinoma treated successfully with immunotherapy for the first time [45]. Lu has reported that CD68+ macrophage

improvement and stability >6 months were achieved [43].

—

tance of TMZ. Some molecular status of pituitary tumors, such as O<sup>6</sup>

enhance the TMZ-mediated cytotoxicity [23].

in animal model of prolactinomas [27].

the lack of large-scale clinical trial.

tory pituitary tumors.

Primary Intracranial Tumors

80

Although various treatment options are available to manage these refractory pituitary tumors, the efficacy is limited. Therefore, the new therapeutic approaches and such randomized clinical trials are needed. It is hoped that further research may clarify the tumorigenesis and pathogenesis of refractory PAs, and additional alternative treatments may be developed for these tumors in the near future.

#### Declaration of interest

None of the authors have potential financial conflicts of interests related to this article. The financial support for this study was provided by the National Natural Science Foundation of China (grant number: 81502639, 81501192), Scientific Research Project of Capital Health Development in 2018 (grant number: 2018-4-4018), and the Youth Scientific Research Fund in Peking Union Medical College Hospital (grant number: pumch-2016-2.20). The funding institutions had no role in the design of the study, data collection and analysis, the decision to publish, or the preparation of the manuscript.

#### Abbreviations


Primary Intracranial Tumors

#### Author details

Congxin Dai<sup>1</sup> , Xiaohai Liu<sup>1</sup> , Sihai Ma<sup>1</sup> , Ming Feng<sup>1</sup> , Xinjie Bao1 , Kan Deng<sup>1</sup> , Yong Yao<sup>1</sup> , Renzhi Wang<sup>1</sup> \*, DX. Feng<sup>2</sup> , E. Fonkem<sup>2</sup> , Frank Y. Shan2 and Jason H. Huang<sup>2</sup>

1 Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China

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2 Department of Neurosurgery, Ballor Scott and White Medical Center, College of Medicine, Texas A&M University, Temple, TX, USA

\*Address all correspondence to: wangrz@126.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Management of Refractory/Aggressive Pituitary Adenomas Review of Current Treatment Options DOI: http://dx.doi.org/10.5772/intechopen.81464

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[3] Chatzellis E, Alexandraki KI, Androulakis II, Kaltsas G. Aggressive pituitary tumors. Neuroendocrinology. 2015;101(2):87-104

[4] Heaney A. Management of aggressive pituitary adenomas and pituitary carcinomas. Journal of Neuro-Oncology. 2014;117(3):459-468

[5] Hirohata T, Ishii Y, Matsuno A. Treatment of pituitary carcinomas and atypical pituitary adenomas: A review. Neurologia Medico-Chirurgica. 2014; 54(12):966-973

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[7] Esquenazi Y, Essayed WI, Singh H, Mauer E, Ahmed M, Christos PJ, et al. Endoscopic endonasal versus microscopic transsphenoidal surgery for recurrent and/or residual pituitary adenomas. World Neurosurgery. 2017; 101:186-195

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[11] Rughani A, Schwalb JM, Sidiropoulos C, Pilitsis J, Ramirez-Zamora A, Sweet JA, et al. Congress of neurological surgeons systematic review and evidence-based guideline on subthalamic nucleus and globus pallidus internus deep brain stimulation for the treatment of patients with Parkinson's disease: Executive summary. Neurosurgery. 2018;82(6):753-756

[12] Tritos NA, Biller BMK. Update on radiation therapy in patients with Cushing's disease. Pituitary. 2015;18(2): 263-268

[13] Lee C, Sheehan JP. Advances in Gamma Knife radiosurgery for pituitary tumors. Current Opinion in Endocrinology, Diabetes, and Obesity. 2016;23(4):331-338

[14] Buchfelder M. Management of aggressive pituitary adenomas: Current treatment strategies. Pituitary. 2009; 12(3):256-260

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Author details

Primary Intracranial Tumors

Jason H. Huang<sup>2</sup>

, Xiaohai Liu<sup>1</sup>

, Renzhi Wang<sup>1</sup>

, Sihai Ma<sup>1</sup>

\*, DX. Feng<sup>2</sup>

Medicine, Texas A&M University, Temple, TX, USA

\*Address all correspondence to: wangrz@126.com

provided the original work is properly cited.

, Ming Feng<sup>1</sup>

1 Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing,

2 Department of Neurosurgery, Ballor Scott and White Medical Center, College of

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, E. Fonkem<sup>2</sup>

, Xinjie Bao1

, Frank Y. Shan2 and

, Kan Deng<sup>1</sup>

,

Congxin Dai<sup>1</sup>

Yong Yao<sup>1</sup>

P.R. China

82

adenomas. Cancer. 2007;110(4): 854-860

[16] Mehta GU, Ding D, Patibandla MR, Kano H, Sisterson N, Su YH, et al. Stereotactic radiosurgery for cushing disease: Results of an international, multicenter study. The Journal of Clinical Endocrinology and Metabolism. 2017;102(11):4284-4291

[17] Raverot G, Burman P, McCormack A, Heaney A, Petersenn S, Popovic V, et al. European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. European Journal of Endocrinology. 2018;178(1): G1-G24

[18] Fadul CE, Kominsky AL, Meyer LP, Kingman LS, Kinlaw WB, Rhodes CH, et al. Long-term response of pituitary carcinoma to temozolomide. Report of two cases. Journal of Neurosurgery. 2006;105(4):621-626

[19] Lim S, Shahinian H, Maya MM, Yong W, Heaney AP. Temozolomide: A novel treatment for pituitary carcinoma. The Lancet Oncology. 2006;7(6): 518-520

[20] Losa M, Bogazzi F, Cannavo S, Ceccato F, Curt L, De Marinis L, et al. Temozolomide therapy in patients with aggressive pituitary adenomas or carcinomas. Journal of Neuro-Oncology. 2016;126(3):519-525

[21] Lasolle H, Cortet C, Castinetti F, Cloix L, Caron P, Delemer B, et al. Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas. European Journal of Endocrinology. 2017;176(6):769-777

[22] Matsuno A, Murakami M, Hoya K, Yamada SM, Miyamoto S, Yamada S, et al. Molecular status of pituitary carcinoma and atypical adenoma that contributes the effectiveness of

temozolomide. Medical Molecular Morphology. 2014;47(1):1-7

[23] Dai C, Zhang B, Liu X, Ma S, Yang Y, Yao Y, et al. Inhibition of PI3K/AKT/ mTOR pathway enhances temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice. Endocrinology. 2013; 154(3):1247-1259

pituitary adenomas is associated with extrasellar growth and recurrence. Pituitary. 2013;16(3):370-377

DOI: http://dx.doi.org/10.5772/intechopen.81464

downstream effectors.

[37] Sajjad EA, Zielinski G,

Pathology. 2013;24(1):11-19

1329-1338

Management of Refractory/Aggressive Pituitary Adenomas Review of Current Treatment Options

979-988

Endocrine-Related Cancer. 2009;16(4):

Maksymowicz M, Hutnik L, Bednarczuk T, Wlodarski P. mTOR is frequently active in GH-secreting pituitary adenomas without influencing their morphopathological features. Endocrine

[38] Rubinfeld H, Shimon I. PI3K/Akt/ mTOR and Raf/MEK/ERK signaling pathways perturbations in nonfunctioning pituitary adenomas. Endocrine. 2012;42(2):285-291

[39] Chen R, Duan J, Li L, Ma Q, Sun Q, Ma J, et al. mTOR promotes pituitary tumor development through activation of PTTG1. Oncogene. 2017;36(7):

[40] Monsalves E, Juraschka K, Tateno T, Agnihotri S, Asa SL, Ezzat S, et al. The PI3K/AKT/mTOR pathway in the pathophysiology and treatment of pituitary adenomas. Endocrine-Related

Cancer. 2014;21(4):R331-R344

2015;21(14):3204-3215

International. 2011;2:22

2016;5(4):203-209

[41] Lee M, Wiedemann T, Gross C, Leinhauser I, Roncaroli F, Braren R, et al. Targeting PI3K/mTOR signaling displays potent antitumor efficacy against nonfunctioning pituitary adenomas. Clinical Cancer Research.

[42] Sukumari-Ramesh S, Singh N, Dhandapani KM, Vender JR. mTOR inhibition reduces cellular proliferation and sensitizes pituitary adenoma cells to ionizing radiation. Surgical Neurology

[43] Donovan LE, Arnal AV, Wang SH, Odia Y. Widely metastatic atypical pituitary adenoma with mTOR pathway STK11(F298L) mutation treated with everolimus therapy. CNS Oncology.

[30] Jia W, Sander AJ, Jia G, Ni M, Liu X, Lu R, et al. Vascular endothelial growth inhibitor (VEGI) is an independent indicator for invasion in human pituitary adenomas. Anticancer Research. 2013;33(9):3815-3822

[31] Lee KM, Park SH, Park KS, Hwang JH, Hwang SK. Analysis of circulating endostatin and vascular endothelial growth factor in patients with pituitary adenoma treated by stereotactic radiosurgery: A Preliminary Study. Brain Tumor Research and Treatment.

[32] Miyajima K, Takekoshi S, Itoh J, Kakimoto K, Miyakoshi T, Osamura RY.

[33] Cohen AB, Lessell S. Angiogenesis and pituitary tumors. Seminars in Ophthalmology. 2009;24(3):185-189

[34] Ortiz LD, Syro LV, Scheithauer BW, Ersen A, Uribe H, Fadul CE, et al. Anti-VEGF therapy in pituitary carcinoma.

[35] Touma W, Hoostal S, Peterson RA, Wiernik A, SantaCruz KS, Lou E. Successful treatment of pituitary carcinoma with concurrent radiation, temozolomide, and bevacizumab after

Pituitary. 2012;15(3):445-449

resection. Journal of Clinical Neuroscience. 2017;41:75-77

85

[36] Dworakowska D, Wlodek E,

Leontiou CA, Igreja S, Cakir M, Teng M, et al. Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on

Inhibitory effects of anti-VEGF antibody on the growth and angiogenesis of estrogen-induced pituitary prolactinoma in fischer 344 rats: Animal model of VEGF-targeted therapy for human endocrine tumors. Acta Histochemica et Cytochemica.

2015;3(2):89-94

2010;43(2):33-44

[24] Cooper O, Mamelak A, Bannykh S, Carmichael J, Bonert V, Lim S, et al. Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors. Endocrine. 2014;46(2):318-327

[25] Fukuoka H, Cooper O, Ben-Shlomo A, Mamelak A, Ren S, Bruyette D, et al. EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. The Journal of Clinical Investigation. 2011;121(12): 4712-4721

[26] Fukuoka H, Cooper O, Mizutani J, Tong Y, Ren SG, Bannykh S, et al. HER2/ErbB2 receptor signaling in rat and human prolactinoma cells: Strategy for targeted prolactinoma therapy. Molecular Endocrinology. 2011;25(1): 92-103

[27] Liu X, Kano M, Araki T, Cooper O, Fukuoka H, Tone Y, et al. ErbB receptor-driven prolactinomas respond to targeted lapatinib treatment in female transgenic mice. Endocrinology. 2015; 156(1):71-79

[28] Cristina C, Luque GM, Demarchi G, Lopez Vicchi F, Zubeldia-Brenner L, Perez Millan MI, et al. Angiogenesis in pituitary adenomas: human studies and new mutant mouse models. International Journal of Endocrinology. 2014;2014:608497

[29] Sánchez-Ortiga R, Sánchez-Tejada L, Moreno-Perez O, Riesgo P, Niveiro M, Picó Alfonso AM. Over-expression of vascular endothelial growth factor in

Management of Refractory/Aggressive Pituitary Adenomas Review of Current Treatment Options DOI: http://dx.doi.org/10.5772/intechopen.81464

pituitary adenomas is associated with extrasellar growth and recurrence. Pituitary. 2013;16(3):370-377

adenomas. Cancer. 2007;110(4):

Primary Intracranial Tumors

2017;102(11):4284-4291

2006;105(4):621-626

2016;126(3):519-525

2017;176(6):769-777

84

[16] Mehta GU, Ding D, Patibandla MR, Kano H, Sisterson N, Su YH, et al. Stereotactic radiosurgery for cushing disease: Results of an international, multicenter study. The Journal of Clinical Endocrinology and Metabolism. temozolomide. Medical Molecular Morphology. 2014;47(1):1-7

mTOR pathway enhances

154(3):1247-1259

4712-4721

92-103

156(1):71-79

[23] Dai C, Zhang B, Liu X, Ma S, Yang Y, Yao Y, et al. Inhibition of PI3K/AKT/

temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice. Endocrinology. 2013;

[24] Cooper O, Mamelak A, Bannykh S, Carmichael J, Bonert V, Lim S, et al. Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors. Endocrine. 2014;46(2):318-327

[25] Fukuoka H, Cooper O, Ben-Shlomo A, Mamelak A, Ren S, Bruyette D, et al. EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. The Journal of Clinical Investigation. 2011;121(12):

[26] Fukuoka H, Cooper O, Mizutani J, Tong Y, Ren SG, Bannykh S, et al. HER2/ErbB2 receptor signaling in rat and human prolactinoma cells: Strategy for targeted prolactinoma therapy. Molecular Endocrinology. 2011;25(1):

[27] Liu X, Kano M, Araki T, Cooper O,

receptor-driven prolactinomas respond to targeted lapatinib treatment in female transgenic mice. Endocrinology. 2015;

[28] Cristina C, Luque GM, Demarchi G, Lopez Vicchi F, Zubeldia-Brenner L, Perez Millan MI, et al. Angiogenesis in pituitary adenomas: human studies and

International Journal of Endocrinology.

[29] Sánchez-Ortiga R, Sánchez-Tejada L, Moreno-Perez O, Riesgo P, Niveiro M, Picó Alfonso AM. Over-expression of vascular endothelial growth factor in

Fukuoka H, Tone Y, et al. ErbB

new mutant mouse models.

2014;2014:608497

[17] Raverot G, Burman P, McCormack A, Heaney A, Petersenn S, Popovic V, et al. European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. European Journal of Endocrinology. 2018;178(1):

[18] Fadul CE, Kominsky AL, Meyer LP, Kingman LS, Kinlaw WB, Rhodes CH, et al. Long-term response of pituitary carcinoma to temozolomide. Report of two cases. Journal of Neurosurgery.

[19] Lim S, Shahinian H, Maya MM, Yong W, Heaney AP. Temozolomide: A novel treatment for pituitary carcinoma. The Lancet Oncology. 2006;7(6):

[20] Losa M, Bogazzi F, Cannavo S, Ceccato F, Curt L, De Marinis L, et al. Temozolomide therapy in patients with aggressive pituitary adenomas or carcinomas. Journal of Neuro-Oncology.

[21] Lasolle H, Cortet C, Castinetti F, Cloix L, Caron P, Delemer B, et al. Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas. European Journal of Endocrinology.

[22] Matsuno A, Murakami M, Hoya K, Yamada SM, Miyamoto S, Yamada S, et al. Molecular status of pituitary carcinoma and atypical adenoma that contributes the effectiveness of

854-860

G1-G24

518-520

[30] Jia W, Sander AJ, Jia G, Ni M, Liu X, Lu R, et al. Vascular endothelial growth inhibitor (VEGI) is an independent indicator for invasion in human pituitary adenomas. Anticancer Research. 2013;33(9):3815-3822

[31] Lee KM, Park SH, Park KS, Hwang JH, Hwang SK. Analysis of circulating endostatin and vascular endothelial growth factor in patients with pituitary adenoma treated by stereotactic radiosurgery: A Preliminary Study. Brain Tumor Research and Treatment. 2015;3(2):89-94

[32] Miyajima K, Takekoshi S, Itoh J, Kakimoto K, Miyakoshi T, Osamura RY. Inhibitory effects of anti-VEGF antibody on the growth and angiogenesis of estrogen-induced pituitary prolactinoma in fischer 344 rats: Animal model of VEGF-targeted therapy for human endocrine tumors. Acta Histochemica et Cytochemica. 2010;43(2):33-44

[33] Cohen AB, Lessell S. Angiogenesis and pituitary tumors. Seminars in Ophthalmology. 2009;24(3):185-189

[34] Ortiz LD, Syro LV, Scheithauer BW, Ersen A, Uribe H, Fadul CE, et al. Anti-VEGF therapy in pituitary carcinoma. Pituitary. 2012;15(3):445-449

[35] Touma W, Hoostal S, Peterson RA, Wiernik A, SantaCruz KS, Lou E. Successful treatment of pituitary carcinoma with concurrent radiation, temozolomide, and bevacizumab after resection. Journal of Clinical Neuroscience. 2017;41:75-77

[36] Dworakowska D, Wlodek E, Leontiou CA, Igreja S, Cakir M, Teng M, et al. Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on

downstream effectors. Endocrine-Related Cancer. 2009;16(4): 1329-1338

[37] Sajjad EA, Zielinski G, Maksymowicz M, Hutnik L, Bednarczuk T, Wlodarski P. mTOR is frequently active in GH-secreting pituitary adenomas without influencing their morphopathological features. Endocrine Pathology. 2013;24(1):11-19

[38] Rubinfeld H, Shimon I. PI3K/Akt/ mTOR and Raf/MEK/ERK signaling pathways perturbations in nonfunctioning pituitary adenomas. Endocrine. 2012;42(2):285-291

[39] Chen R, Duan J, Li L, Ma Q, Sun Q, Ma J, et al. mTOR promotes pituitary tumor development through activation of PTTG1. Oncogene. 2017;36(7): 979-988

[40] Monsalves E, Juraschka K, Tateno T, Agnihotri S, Asa SL, Ezzat S, et al. The PI3K/AKT/mTOR pathway in the pathophysiology and treatment of pituitary adenomas. Endocrine-Related Cancer. 2014;21(4):R331-R344

[41] Lee M, Wiedemann T, Gross C, Leinhauser I, Roncaroli F, Braren R, et al. Targeting PI3K/mTOR signaling displays potent antitumor efficacy against nonfunctioning pituitary adenomas. Clinical Cancer Research. 2015;21(14):3204-3215

[42] Sukumari-Ramesh S, Singh N, Dhandapani KM, Vender JR. mTOR inhibition reduces cellular proliferation and sensitizes pituitary adenoma cells to ionizing radiation. Surgical Neurology International. 2011;2:22

[43] Donovan LE, Arnal AV, Wang SH, Odia Y. Widely metastatic atypical pituitary adenoma with mTOR pathway STK11(F298L) mutation treated with everolimus therapy. CNS Oncology. 2016;5(4):203-209

[44] Grullich C. Immunotherapy as modern tumor treatment. Radiologe. 2017;57(10):822-825

[45] Hazrati SM, Aghazadeh J, Mohtarami F, Abouzari M, Rashidi A. Immunotherapy of prolactinoma with a T helper 1 activator adjuvant and autoantigens: A case report. Neuroimmunomodulation. 2007;13(4): 205-208

[46] Lu J, Adam B, Jack AS, Lam A, Broad RW, Chik CL. Immune cell infiltrates in pituitary adenomas: More macrophages in larger adenomas and more T cells in growth hormone adenomas. Endocrine Pathology. 2015; 26(3):263-272

[47] Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. The New England Journal of Medicine. 2012;366(26):2443-2454

[48] Mei Y, Bi WL, Greenwald NF, Du Z, Agar NY, Kaiser UB, et al. Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors. Oncotarget. 2016;7(47):76565-76576

**87**

**Chapter 6**

**Abstract**

residual tumors.

**1. Introduction**

are common.

**2. Natural history**

cerebellopontine angle

Vestibular Schwannomas:

*Gustavo Jung and Ricardo Ramina*

Diagnosis and Surgical Treatment

Over the last decades, significant advances in skull base surgery have enabled many neurosurgical centers around the world to perform surgical resection of vestibular schwannomas; otherwise, clinical observation and radiotherapy/radiosurgery can be possible management options. Auditory pattern, the presence of bilateral tumors, tumor size, and neurological symptoms are deeply considered in the decision-making process. In this chapter, we expanded the general discussion of vestibular schwannomas, discussing bases for an accurate diagnose and the technical aspects for the surgical approaches, drilling of internal auditory canal, and its reconstruction as well as the technical nuances when handling very small and large/

Vestibular schwannomas (VS) account for 6–8% of all intracranial neoplasms and around 90% of cerebellopontine angle tumors (CPA) [1]. It is usually a sporadic tumor but can be bilateral in cases of neurofibromatosis type 2, when larger tumors

Over the last decades, significant advances in skull base surgery have enabled many neurosurgical centers around the world to perform surgical resection of VS with good functional outcomes (facial nerve and hearing preservation). Deeper observation about the natural history of these lesions and the development of radiosurgery have increased the options to manage VS. The rates of surgical morbidity and mortality have also declined dramatically, and functional preservation of

The natural history of VS is highly unpredictable. Some tumors exhibit continuous growth, while others remain stable or even decrease in size, and its reason is not known. In the literature, a mean growth rate of 2.9 mm per year is reported, and a

growth rate of 2.5 mm/year is associated with worse hearing function.

**Keywords:** vestibular schwannoma, acoustic neuroma, acoustic tumor,

the facial nerve has been possible even in larger tumors.

#### **Chapter 6**

[44] Grullich C. Immunotherapy as modern tumor treatment. Radiologe.

Mohtarami F, Abouzari M, Rashidi A. Immunotherapy of prolactinoma with a T helper 1 activator adjuvant and autoantigens: A case report.

Neuroimmunomodulation. 2007;13(4):

[47] Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. The New England Journal of Medicine. 2012;366(26):2443-2454

[48] Mei Y, Bi WL, Greenwald NF, Du Z, Agar NY, Kaiser UB, et al. Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors. Oncotarget. 2016;7(47):76565-76576

[46] Lu J, Adam B, Jack AS, Lam A, Broad RW, Chik CL. Immune cell infiltrates in pituitary adenomas: More macrophages in larger adenomas and more T cells in growth hormone adenomas. Endocrine Pathology. 2015;

[45] Hazrati SM, Aghazadeh J,

2017;57(10):822-825

Primary Intracranial Tumors

205-208

26(3):263-272

86

## Vestibular Schwannomas: Diagnosis and Surgical Treatment

*Gustavo Jung and Ricardo Ramina*

#### **Abstract**

Over the last decades, significant advances in skull base surgery have enabled many neurosurgical centers around the world to perform surgical resection of vestibular schwannomas; otherwise, clinical observation and radiotherapy/radiosurgery can be possible management options. Auditory pattern, the presence of bilateral tumors, tumor size, and neurological symptoms are deeply considered in the decision-making process. In this chapter, we expanded the general discussion of vestibular schwannomas, discussing bases for an accurate diagnose and the technical aspects for the surgical approaches, drilling of internal auditory canal, and its reconstruction as well as the technical nuances when handling very small and large/ residual tumors.

**Keywords:** vestibular schwannoma, acoustic neuroma, acoustic tumor, cerebellopontine angle

#### **1. Introduction**

Vestibular schwannomas (VS) account for 6–8% of all intracranial neoplasms and around 90% of cerebellopontine angle tumors (CPA) [1]. It is usually a sporadic tumor but can be bilateral in cases of neurofibromatosis type 2, when larger tumors are common.

Over the last decades, significant advances in skull base surgery have enabled many neurosurgical centers around the world to perform surgical resection of VS with good functional outcomes (facial nerve and hearing preservation). Deeper observation about the natural history of these lesions and the development of radiosurgery have increased the options to manage VS. The rates of surgical morbidity and mortality have also declined dramatically, and functional preservation of the facial nerve has been possible even in larger tumors.

#### **2. Natural history**

The natural history of VS is highly unpredictable. Some tumors exhibit continuous growth, while others remain stable or even decrease in size, and its reason is not known. In the literature, a mean growth rate of 2.9 mm per year is reported, and a growth rate of 2.5 mm/year is associated with worse hearing function.

#### **3. Management options**

Clinical observation, microsurgical removal, and radiotherapy/radiosurgery are the management options. Different factors make treatment decision highly variable. Small tumors may be followed with regular MRI examinations and audiograms. Patients harboring small tumors and presenting progressive hearing loss, microsurgical removal, or radiosurgery should be considered. Preoperative hearing level is a prognostic factor for postoperative hearing preservation. Tumors up to 3 cm in diameter may be treated either by microsurgical removal or radiosurgery, and larger tumors will require surgical resection. Cystic VS may present sudden growth and surgical removal is the best option. The management of bilateral tumors in NF2 patients is complex, and the quality of hearing in both ears and size of the tumors will be the main factors to decide how to treat these patients.

#### **4. Diagnosis**

VS commonly arise from the vestibular division of the eighth cranial nerve. Dizziness, vertigo, and progressive hearing loss (earliest symptom) are the most frequent complaints. Dizziness is routinely transient and episodic, and the patient can neglect it for a variable period of time. Dizziness is a frequent complaint in daily ENT practice, and patients complaining of unilateral hearing loss associated or not to vestibular symptoms are frequently seen by ENT surgeons. Very often these symptoms are not adequately investigated, and it is a common cause to miss the diagnosis.

Facial nerve weakness is observed in only 6% of the patients [2]. In larger and mainly cystic tumors that present fast growth, facial numbness (due to trigeminal nerve compression) and gait ataxia (due to brain stem displacement) can appear [3, 4].

Hydrocephalus is relatively common in VS patients. In larger tumors it is caused by IV ventricle displacement, leading to obstructive hydrocephalus. In smaller tumors, degenerative changes on the tumor content can increase the protein rates on CSF, causing CSF malabsorption and consequent hydrocephalus [5]. When hydrocephalus is present, a preoperative external ventricular CSF drainage is required. Ventriculoperitoneal shunt is done especially in patients without major CSF obstruction when the tumor removal is less probable to relieve.

#### **5. Audiological evaluation**

Hearing function is evaluated with audiograms with sound discrimination. There are different classifications to preoperatively grade the hearing function. Brain stem evoked response audiometry (BERA) provides reliable information on the hearing function from the ear to the brain stem, and to determine the nerve of origin in vestibular schwannomas, the video Head Impulse Test (vHIT) is usually performed.

#### **6. Radiological diagnosis**

CT scan is useful to demonstrate the bony anatomy, the position of the jugular bulb, and the semicircular canals. Vestibular schwannomas often expand the internal auditory canal [10].

**89**

**Figure 2.**

*(blue arrow)*.

**Figure 1.**

*Vestibular Schwannomas: Diagnosis and Surgical Treatment*

provides best images to monitor tumor growth [8, 9].

suggests tumor recurrence [12].

Magnetic resonance imaging (MRI) is the eligible test to diagnose and evaluate patients with a vestibular schwannomas. T1, T2, FLAIR, and DWI images are usually sufficient for the diagnosis. Over 50% of vestibular schwannomas are isointense in T1-weighted images; hypointensities usually represent a cystic component (**Figure 1**). VS present usually intense homogeneous gadolinium enhancement on T1-weighted images, but cystic lesions can present a heterogenous pattern. A hyperintense signal inside of the IAC in FLAIR images and nodular hyperintense signal in the vestibular nuclei on the dorsal pons in T2-weighted images can additionally differentiate vestibular schwannomas from other cerebellopontine angle tumors (**Figure 2**). T2-weighted images and tractography may demonstrate the position of the facial nerve and its relation to the tumor capsule [5, 6]. When a watchful waiting is decided, MRI volumetric studies have an excellent accuracy to follow tumor growth [7]. 3D T2 CISS or post-contrast 3D T1 MPRAGE MRI (evidence class II)

After surgical resection, a thin not-nodular enhancement is often visualized in surgical resection field. It can persist for years but usually reduces over the time [11]. Fat grafts, fibrin glue, and muscle grafts, used to reconstruct the IAC, can generate a nodular enhancement which usually appear within the first 3 days after surgery. New nodular enhancement appearing in the postoperative follow-up highly

*Large vestibular schwannoma. (A) T2-weighted image showing a solid (red arrow) and cystic tumor (black arrow). (B) Post-contrast-weighted image exhibiting intense contrast enhancement in the solid portion* 

*T2-weighted image with a small vestibular schwannoma (green arrow) with hyperintensity in the dorsal pons* 

*(red arrow) and heterogeneous pattern in the cystic component (black arrow).*

*DOI: http://dx.doi.org/10.5772/intechopen.81352*

*Vestibular Schwannomas: Diagnosis and Surgical Treatment DOI: http://dx.doi.org/10.5772/intechopen.81352*

Magnetic resonance imaging (MRI) is the eligible test to diagnose and evaluate patients with a vestibular schwannomas. T1, T2, FLAIR, and DWI images are usually sufficient for the diagnosis. Over 50% of vestibular schwannomas are isointense in T1-weighted images; hypointensities usually represent a cystic component (**Figure 1**). VS present usually intense homogeneous gadolinium enhancement on T1-weighted images, but cystic lesions can present a heterogenous pattern. A hyperintense signal inside of the IAC in FLAIR images and nodular hyperintense signal in the vestibular nuclei on the dorsal pons in T2-weighted images can additionally differentiate vestibular schwannomas from other cerebellopontine angle tumors (**Figure 2**). T2-weighted images and tractography may demonstrate the position of the facial nerve and its relation to the tumor capsule [5, 6]. When a watchful waiting is decided, MRI volumetric studies have an excellent accuracy to follow tumor growth [7]. 3D T2 CISS or post-contrast 3D T1 MPRAGE MRI (evidence class II) provides best images to monitor tumor growth [8, 9].

After surgical resection, a thin not-nodular enhancement is often visualized in surgical resection field. It can persist for years but usually reduces over the time [11]. Fat grafts, fibrin glue, and muscle grafts, used to reconstruct the IAC, can generate a nodular enhancement which usually appear within the first 3 days after surgery. New nodular enhancement appearing in the postoperative follow-up highly suggests tumor recurrence [12].

#### **Figure 1.**

*Primary Intracranial Tumors*

**3. Management options**

**4. Diagnosis**

diagnosis.

appear [3, 4].

**5. Audiological evaluation**

**6. Radiological diagnosis**

internal auditory canal [10].

Clinical observation, microsurgical removal, and radiotherapy/radiosurgery are the management options. Different factors make treatment decision highly variable. Small tumors may be followed with regular MRI examinations and audiograms. Patients harboring small tumors and presenting progressive hearing loss, microsurgical removal, or radiosurgery should be considered. Preoperative hearing level is a prognostic factor for postoperative hearing preservation. Tumors up to 3 cm in diameter may be treated either by microsurgical removal or radiosurgery, and larger tumors will require surgical resection. Cystic VS may present sudden growth and surgical removal is the best option. The management of bilateral tumors in NF2 patients is complex, and the quality of hearing in both ears and size of the tumors

VS commonly arise from the vestibular division of the eighth cranial nerve. Dizziness, vertigo, and progressive hearing loss (earliest symptom) are the most frequent complaints. Dizziness is routinely transient and episodic, and the patient can neglect it for a variable period of time. Dizziness is a frequent complaint in daily ENT practice, and patients complaining of unilateral hearing loss associated or not to vestibular symptoms are frequently seen by ENT surgeons. Very often these symptoms are not adequately investigated, and it is a common cause to miss the

Facial nerve weakness is observed in only 6% of the patients [2]. In larger and mainly cystic tumors that present fast growth, facial numbness (due to trigeminal nerve compression) and gait ataxia (due to brain stem displacement) can

Hydrocephalus is relatively common in VS patients. In larger tumors it is caused

by IV ventricle displacement, leading to obstructive hydrocephalus. In smaller tumors, degenerative changes on the tumor content can increase the protein rates on CSF, causing CSF malabsorption and consequent hydrocephalus [5]. When hydrocephalus is present, a preoperative external ventricular CSF drainage is required. Ventriculoperitoneal shunt is done especially in patients without major

Hearing function is evaluated with audiograms with sound discrimination. There are different classifications to preoperatively grade the hearing function. Brain stem evoked response audiometry (BERA) provides reliable information on the hearing function from the ear to the brain stem, and to determine the nerve of origin in vestibular schwannomas, the video Head Impulse Test (vHIT) is usually

CT scan is useful to demonstrate the bony anatomy, the position of the jugular

bulb, and the semicircular canals. Vestibular schwannomas often expand the

CSF obstruction when the tumor removal is less probable to relieve.

will be the main factors to decide how to treat these patients.

**88**

performed.

*Large vestibular schwannoma. (A) T2-weighted image showing a solid (red arrow) and cystic tumor (black arrow). (B) Post-contrast-weighted image exhibiting intense contrast enhancement in the solid portion (red arrow) and heterogeneous pattern in the cystic component (black arrow).*

#### **Figure 2.**

*T2-weighted image with a small vestibular schwannoma (green arrow) with hyperintensity in the dorsal pons (blue arrow)*.

#### **Figure 3.**

*(A) Expansion of IAC caused by vestibular schwannoma (green arrow). (B) Normal width of IAC in a patient with CPA meningioma and IAC involvement (white arrow). Dural enhancement (blue arrow) strongly suggests its diagnosis.*

Meningiomas are the most frequent differential diagnosis between non-schwannomatous lesions that arise or protrude into the IAC. Meningiomas usually present a dural enhancement and display calcification, and hyperostosis in the adjacent bone is usually seen (**Figure 3**).

#### **7. Treatment**

Vestibular schwannoma is a benign intracranial nerve sheath tumor, usually sporadic but that may be bilateral in the context of neurofibromatosis type 2. Wait and scan strategy, microsurgical resection, and radiotherapy/radiosurgery are the options. Presenting symptoms, hearing status, growth rate, size and characteristic of tumor, and surgeon preference will interfere in these treatment decisions [13].

#### **8. Microsurgical resection**

The goals of the treatment are radical resection with zero mortality and complete anatomical and functional preservation of the involved cranial nerves. Some authors propose partial resection followed, or not, by radiotherapy/radiosurgery to preserve cranial nerve function [14]. However, the only treatment that offers cure is radical microsurgical removal.

VS might be approached through translabyrinthine, retrosigmoid, or middle fossa craniotomy. The main advantage of the translabyrinthine approach is to minimize brain retraction. The difficulty to resect larger tumor damage to hearing structures is the limitation of this surgical approach. Fat grafts are needed to close the dura and avoid CSF fistula. In small tumors, best suited to tranlabyrinthine approach, commonly serviceable hearing is present, which ultimately turns this surgical option unfeasible.

The middle fossa approach (MFA) is a lateral access to the IAC and was popularized by House in 1961. The exposition of the IAC through its superior wall makes it a good option for small lateral tumors restricted to the internal auditory canal and brings the lowest risk to the labyrinth structures.

The retrosigmoid (RS) approach is the most used access by the majority of neurosurgeons offering an excellent exposition of all anatomical structures of the posterior fossa. The IAC is opened through the RS, and injury to the inner ear structures (labyrinth) and jugular bulb are avoidable complications [15]. This is the approach of choice to VS, regardless of its size, in our department. The dorsal

**91**

*Vestibular Schwannomas: Diagnosis and Surgical Treatment*

provide a more comfortable work position for the surgeon.

decubitus is preferred by the authors due to the lower risk of air embolism and to

A 4 cm diameter craniotomy is cut laterally bordering the sigmoid sinus to avoid cerebellar retraction. In most cases, in the dorsal position, a cerebellar retractor is only used to protect the cerebellum during the drilling of internal auditory canal. After the dura opening, CSF is released from the cerebellomedullary cisterna to relax the pressure in the posterior fossa. The inspection of the bridging veins over the tentorial surface of the cerebellum is highly recommended as it can be a poten-

The IAC is drilled as the first step in most cases. It reduces the pressure over the cochlear and the facial nerves. Piecemeal resection with ultrasound aspirator is useful to debulk the cisternal component and reduces the traction over the tumor capsule. The facial nerve is usually very attached to the tumor capsule at its entrance in the IAC, and careful microsurgical dissection should be performed under continuous electrophysiologic monitoring. Preservation of the cochlear nerve is also attempted under continuous BERA monitoring. If an alteration of the waves is observed, the surgical field is irrigated with papaverine solution awaiting until recovery is recorded. Cystic and larger tumors usually present more difficulty to dissect the facial nerve from tumor capsule. Hearing preservation is a challenge in tumors larger than 3 cm in diameter. In NF2 patients with bilateral tumor, preservation of hearing should be attempted even if residual tumor must be left. Brain stem decompression with hearing preservation is the goal of treat-

Reconstruction of the IAC is extremely important to avoid CSF fistula and infection. To identify the mastoid air cells inside the IAC, the use of the endoscope can be opportune, and small pieces of muscle or fat graft should be used to seal these cells.

In our series of 541 VS surgically resected between 1987 and 2016, 31 patients had residual/recurrent tumors. Twenty-seven patients had been operated elsewhere. From the 4 patients in our own casuistry, two cases were recurrences and two were residual lesions. One of the residual cases was a patient with neurofibromatosis type 2 and showing large bilateral VS who underwent radical resection in one side and subtotal removal of the contralateral tumor for hearing preservation. The other case was a 75-year-old patient with large cystic VS who underwent stereotactic aspiration of the cyst to alleviate mass effect, since surgical resection was not advised for

The causes for subtotal removal, as reported by the patient, were extensive intraoperative bleeding, adherence to the brain stem or facial nerve, and intraoperative cerebellar edema. All patients were reoperated at our institution through the retrosigmoid/transmeatal approach. The surgical procedure proved to be significantly more difficult than in non-operated cases. Fibrosis from previous procedure(s) altered the anatomical location of the transverse and sigmoid sinus, as well as the dissection and opening of the dura mater. Intracranially, the arachnoid plane usually found between the tumor and the brain stem and cranial nerves was lost; thus, dissection of the tumor required more manipulation of those structures. This was especially significant in irradiated patients. We observed that in cases in which the IAC had not been previously opened, identification and dissection of the facial nerve and subsequent dissection were less difficult. Postoperative anatomical preservation of the facial nerve was possible in 13 (76%) of 17 patients with preoperative facial nerve function. There was no permanent morbidity or mortality. All

cases were histologically confirmed as WHO grade I schwannomas [16].

*DOI: http://dx.doi.org/10.5772/intechopen.81352*

tial source of bleeding.

ment in these cases.

**9. Residual tumor**

medical reasons.

#### *Vestibular Schwannomas: Diagnosis and Surgical Treatment DOI: http://dx.doi.org/10.5772/intechopen.81352*

*Primary Intracranial Tumors*

is usually seen (**Figure 3**).

*strongly suggests its diagnosis.*

**8. Microsurgical resection**

radical microsurgical removal.

surgical option unfeasible.

brings the lowest risk to the labyrinth structures.

**7. Treatment**

**Figure 3.**

Meningiomas are the most frequent differential diagnosis between non-schwannomatous lesions that arise or protrude into the IAC. Meningiomas usually present a dural enhancement and display calcification, and hyperostosis in the adjacent bone

*(A) Expansion of IAC caused by vestibular schwannoma (green arrow). (B) Normal width of IAC in a patient with CPA meningioma and IAC involvement (white arrow). Dural enhancement (blue arrow)* 

Vestibular schwannoma is a benign intracranial nerve sheath tumor, usually sporadic but that may be bilateral in the context of neurofibromatosis type 2. Wait and scan strategy, microsurgical resection, and radiotherapy/radiosurgery are the options. Presenting symptoms, hearing status, growth rate, size and characteristic of tumor, and surgeon preference will interfere in these treatment decisions [13].

The goals of the treatment are radical resection with zero mortality and complete anatomical and functional preservation of the involved cranial nerves. Some authors propose partial resection followed, or not, by radiotherapy/radiosurgery to preserve cranial nerve function [14]. However, the only treatment that offers cure is

VS might be approached through translabyrinthine, retrosigmoid, or middle fossa craniotomy. The main advantage of the translabyrinthine approach is to minimize brain retraction. The difficulty to resect larger tumor damage to hearing structures is the limitation of this surgical approach. Fat grafts are needed to close the dura and avoid CSF fistula. In small tumors, best suited to tranlabyrinthine approach, commonly serviceable hearing is present, which ultimately turns this

The middle fossa approach (MFA) is a lateral access to the IAC and was popularized by House in 1961. The exposition of the IAC through its superior wall makes it a good option for small lateral tumors restricted to the internal auditory canal and

The retrosigmoid (RS) approach is the most used access by the majority of neurosurgeons offering an excellent exposition of all anatomical structures of the posterior fossa. The IAC is opened through the RS, and injury to the inner ear structures (labyrinth) and jugular bulb are avoidable complications [15]. This is the approach of choice to VS, regardless of its size, in our department. The dorsal

**90**

decubitus is preferred by the authors due to the lower risk of air embolism and to provide a more comfortable work position for the surgeon.

A 4 cm diameter craniotomy is cut laterally bordering the sigmoid sinus to avoid cerebellar retraction. In most cases, in the dorsal position, a cerebellar retractor is only used to protect the cerebellum during the drilling of internal auditory canal.

After the dura opening, CSF is released from the cerebellomedullary cisterna to relax the pressure in the posterior fossa. The inspection of the bridging veins over the tentorial surface of the cerebellum is highly recommended as it can be a potential source of bleeding.

The IAC is drilled as the first step in most cases. It reduces the pressure over the cochlear and the facial nerves. Piecemeal resection with ultrasound aspirator is useful to debulk the cisternal component and reduces the traction over the tumor capsule. The facial nerve is usually very attached to the tumor capsule at its entrance in the IAC, and careful microsurgical dissection should be performed under continuous electrophysiologic monitoring. Preservation of the cochlear nerve is also attempted under continuous BERA monitoring. If an alteration of the waves is observed, the surgical field is irrigated with papaverine solution awaiting until recovery is recorded. Cystic and larger tumors usually present more difficulty to dissect the facial nerve from tumor capsule. Hearing preservation is a challenge in tumors larger than 3 cm in diameter. In NF2 patients with bilateral tumor, preservation of hearing should be attempted even if residual tumor must be left. Brain stem decompression with hearing preservation is the goal of treatment in these cases.

Reconstruction of the IAC is extremely important to avoid CSF fistula and infection. To identify the mastoid air cells inside the IAC, the use of the endoscope can be opportune, and small pieces of muscle or fat graft should be used to seal these cells.

#### **9. Residual tumor**

In our series of 541 VS surgically resected between 1987 and 2016, 31 patients had residual/recurrent tumors. Twenty-seven patients had been operated elsewhere. From the 4 patients in our own casuistry, two cases were recurrences and two were residual lesions. One of the residual cases was a patient with neurofibromatosis type 2 and showing large bilateral VS who underwent radical resection in one side and subtotal removal of the contralateral tumor for hearing preservation. The other case was a 75-year-old patient with large cystic VS who underwent stereotactic aspiration of the cyst to alleviate mass effect, since surgical resection was not advised for medical reasons.

The causes for subtotal removal, as reported by the patient, were extensive intraoperative bleeding, adherence to the brain stem or facial nerve, and intraoperative cerebellar edema. All patients were reoperated at our institution through the retrosigmoid/transmeatal approach. The surgical procedure proved to be significantly more difficult than in non-operated cases. Fibrosis from previous procedure(s) altered the anatomical location of the transverse and sigmoid sinus, as well as the dissection and opening of the dura mater. Intracranially, the arachnoid plane usually found between the tumor and the brain stem and cranial nerves was lost; thus, dissection of the tumor required more manipulation of those structures. This was especially significant in irradiated patients. We observed that in cases in which the IAC had not been previously opened, identification and dissection of the facial nerve and subsequent dissection were less difficult. Postoperative anatomical preservation of the facial nerve was possible in 13 (76%) of 17 patients with preoperative facial nerve function. There was no permanent morbidity or mortality. All cases were histologically confirmed as WHO grade I schwannomas [16].

### **10. Intralabyrinthine tumors**

Intralabyrinthine VS are by definition tumors arising at the terminal end of the eighth cranial nerve within the vestibule, cochlea, or semicircular canal [17]. According to its location, intralabyrinthine schwannomas may be anatomically divided in six major types: intravestibular, vestibulocochlear, modiolar, transotic, intracochlear, and transmacular schwannomas (**Figures 4**–**7**).

#### **Figure 4.**

*(A) Intravestibular schwannoma. (B) Vestibulocochlear schwannoma. Intravestibular schwannomas are located in the labyrinth. Vestibulocochlear schwannomas grow in the labyrinth and cochlea.*

**Figure 5.** *(A) Modiolar schwannoma. (B) Transotic schwannoma.*

**93**

**Author details**

macula cribrosa.

**Figure 7.**

provided the original work is properly cited.

Gustavo Jung\* and Ricardo Ramina

surgical removal of the lesion [20, 21].

Curitiba, Curitiba, Brazil

*Vestibular Schwannomas: Diagnosis and Surgical Treatment*

*DOI: http://dx.doi.org/10.5772/intechopen.81352*

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Skull Base Division, Department of Neurosurgery, Neurological Institute of

Modiolar schwannomas arise at the cochlea and extend in the modiolus and the IAC. Transotic schwannomas grow from the labyrinth into the IAC and middle ear. Intracochlear schwannomas are located in the cochlea. Transmacular schwannomas arise in the vestibule and extend into the internal auditory canal through the

*Post-contrast T1-weighted image demonstrating a transmacular schwannoma (white arrow)*.

These tumors have been frequently observed on MRI examinations, but their

Labyrinthitis and otitis may also cause gadolinium enhancement of the vestibular nerves and mimic intralabyrinthine tumors. However, in these pathologies the enhancement is less sharp, and the cochlea, as well as the entire vestibular system,

Clinical observation is recommended in patients already deaf and if the vestibular symptoms are slight and treatable. Microsurgical removal is curative, but hearing preservation is very challenging since these tumors often affect the cochlea and the semicircular canals. The retrosigmoid-transmeatal endoscopic-assisted approach is very useful and provides an excellent view of the lateral portion of IAC. A wide and deep opening of the IAC (about 1 cm in length) is required to resect those lesions. Symptoms of intractable vertigo usually disappear after micro-

\*Address all correspondence to: gustavosjung@gmail.com

management was rarely reported in the literature [18].

may exhibit contrast enhancement [19].

**Figure 6.** *(A) Intracochlear schwannoma. (B) Transmacular schwannoma.*

*Vestibular Schwannomas: Diagnosis and Surgical Treatment DOI: http://dx.doi.org/10.5772/intechopen.81352*

*Primary Intracranial Tumors*

**10. Intralabyrinthine tumors**

Intralabyrinthine VS are by definition tumors arising at the terminal end of the eighth cranial nerve within the vestibule, cochlea, or semicircular canal [17]. According to its location, intralabyrinthine schwannomas may be anatomically divided in six major types: intravestibular, vestibulocochlear, modiolar, transotic,

*(A) Intravestibular schwannoma. (B) Vestibulocochlear schwannoma. Intravestibular schwannomas are* 

*located in the labyrinth. Vestibulocochlear schwannomas grow in the labyrinth and cochlea.*

intracochlear, and transmacular schwannomas (**Figures 4**–**7**).

**92**

**Figure 6.**

**Figure 5.**

**Figure 4.**

*(A) Modiolar schwannoma. (B) Transotic schwannoma.*

*(A) Intracochlear schwannoma. (B) Transmacular schwannoma.*

**Figure 7.** *Post-contrast T1-weighted image demonstrating a transmacular schwannoma (white arrow)*.

Modiolar schwannomas arise at the cochlea and extend in the modiolus and the IAC. Transotic schwannomas grow from the labyrinth into the IAC and middle ear.

Intracochlear schwannomas are located in the cochlea. Transmacular schwannomas arise in the vestibule and extend into the internal auditory canal through the macula cribrosa.

These tumors have been frequently observed on MRI examinations, but their management was rarely reported in the literature [18].

Labyrinthitis and otitis may also cause gadolinium enhancement of the vestibular nerves and mimic intralabyrinthine tumors. However, in these pathologies the enhancement is less sharp, and the cochlea, as well as the entire vestibular system, may exhibit contrast enhancement [19].

Clinical observation is recommended in patients already deaf and if the vestibular symptoms are slight and treatable. Microsurgical removal is curative, but hearing preservation is very challenging since these tumors often affect the cochlea and the semicircular canals. The retrosigmoid-transmeatal endoscopic-assisted approach is very useful and provides an excellent view of the lateral portion of IAC. A wide and deep opening of the IAC (about 1 cm in length) is required to resect those lesions. Symptoms of intractable vertigo usually disappear after microsurgical removal of the lesion [20, 21].

#### **Author details**

Gustavo Jung\* and Ricardo Ramina Skull Base Division, Department of Neurosurgery, Neurological Institute of Curitiba, Curitiba, Brazil

\*Address all correspondence to: gustavosjung@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Machinis TG, Fountas KN, Dimomopolos V, Robinson JS. History of acoustic neurinoma surgery. Neurosurgical Focus. 2005;**18**(4):1-4

[2] Matthies C, Samii M. Management of 1000 vestibular schwannomas (acoustic neuromas): Clinical presentation. Neurosurgery. 1997;**40**(1):1-10

[3] Piccirillo E, Wiet MR, Flanagan S, Dispenza F, Giannuzzi A, Mancini F, et al. Cystic vestibular schwannoma: Classification, management, and facial nerve outcomes. Otology & Neurotology. 2009;**30**(6):826-834

[4] Thakur JD, Khan IS, Shorter CD, Sonig A, Gardner GL, Guthikonda B, et al. Do cystic vestibular schwannomas have worse surgical outcomes: Systematic analysis of the literature. Neurosurgical Focus. 2012;**33**(3):E12

[5] Taniguchi M, Nakai T, Kohta M, Kimura H, Kohmura E. Communicating hydrocephalus associated with small- to medium-sized vestibular schwannomas: Clinical significance of the tumor apparent diffusion coefficient map. World Neurosurgery. 2016;**94**:261-267

[6] Liang C, Zhang B, Wu L, Du Y, Wang X, Liu C, et al. The superiority of 3D-CISS sequence in displaying the cisternal segment of facial, vestibulocochlear nerves and their abnormal changes. European Journal of Radiology. 2010;**74**(3):437-440

[7] Choi KS, Kim MS, Kwon HG, Jang SH, Kim OL. Preoperative identification of facial nerve in vestibular schwannomas surgery using diffusion tensor tractography. Journal of Korean Neurosurgical Association. 2014;**56**(1):11-15

[8] Tan TY. Non-contrast high resolution fast spin echo magnetic resonance

imaging of acoustic schwannoma. Singapore Medical Journal. 1999;**40**(1):27-31

[9] Held P, Fellner C, Seitz J, Graf S, Fellner F, Strutz J. The value of T2(\*) weighted MR images for the diagnosis of acoustic neuromas. European Journal of Radiology. 1999;**30**(3):237-244

[10] Held P, Fellner C, Fellner F, Seitz J, Graf S, Hilbert M, et al. MRI of inner ear and facial nerve pathology using 3D MP-RAGE and 3D CISS sequences. The British Journal of Radiology. 1997;**70**(834):558-566

[11] Tomogane Y, Mori K, Izumoto S, Kaba K, Ishikura R, Ando K, et al. Usefulness of PRESTO magnetic resonance imaging for the differentiation of schwannoma and meningioma in the cerebellopontine angle. Neurologia Medico-Chirurgica (Tokyo). 2013;**53**(7):482-489

[12] Carlson ML, Van Abel KM, Driscoll CL, Neff BA, Beatty CW, Lane JI, et al. Magnetic resonance imaging surveillance following vestibular schwannoma resection. Laryngoscope. 2012;**122**(2):378-388

[13] Bennett ML, Jackson CG, Kaufmann R, Warren F. Postoperative imaging of vestibular schwannomas. Otolaryngology and Head and Neck Surgery. 2008;**138**(5):667-671

[14] Taylor RL, Kong J, Flanagan S, Pogson J, Croxson G, Pohl D, et al. Prevalence of vestibular dysfunction in patients with vestibular schwannoma using video head-impulses and vestibular-evoked potentials. Journal of Neurology. 2015;**262**(5):1228-1237

[15] Samii M, Gerganov VM, Samii A. Functional outcome after complete surgical removal of giant vestibular

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*Vestibular Schwannomas: Diagnosis and Surgical Treatment*

*DOI: http://dx.doi.org/10.5772/intechopen.81352*

schwannomas. Journal of Neurosurgery.

[16] Tatagiba M, Samii M, Matthies C, El Azm M, Schönmayr R. The significance for postoperative heating of preserving the labyrinth in acoustic neurinoma surgery. Journal of Neurosurgery.

[17] Kennedy RJ, Shelton C, Salzman KL,

Davidson HC, Harnsberger HR. Intralabyrinthine schwannomas: Diagnosis, management, and a new classification system. Otology & Neurotology. 2004;**25**(2):160-167

[18] Magliulo G, Colicchio G,

Michel MA, Harnsberger HR, Glastonbury CM, Michel MA, et al. Diagnostic Imaging: Head and Neck. 2nd ed. Baltimore: Lippincott, Williams & Wilkins; 2010. https://www.amazon. co.uk/s/ref=dp\_byline\_sr\_book\_4?ie= UTF8&text=Bernadette+L.+Koch&sea rch-alias=books-uk&field-author=Bern adette+L.+Koch&sort=relevancerank

schwannoma. Skull Base. 2010;**20**(2):115-118

Romana AF, Stasolla A. Intracochlear

[19] Harnsberger R, Glastonbury CM,

[20] Samii M, Matthies C, Tatagiba M. Intracanalicular acoustic neurinomas. Neurosurgery.

[21] Samii M, Metwali H, Gerganov V. Eficacy of microsurgical tumor removal for treatment of patients with intracanalicular vestibular schwannoma presenting with disabling vestibular symptoms. Journal of Neurosurgery.

1991;**29**(2):189-199

2017;**126**(5):1514-1519

2010;**112**(4):860-867

1992;**77**(5):677-684

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schwannomas. Journal of Neurosurgery. 2010;**112**(4):860-867

[16] Tatagiba M, Samii M, Matthies C, El Azm M, Schönmayr R. The significance for postoperative heating of preserving the labyrinth in acoustic neurinoma surgery. Journal of Neurosurgery. 1992;**77**(5):677-684

[17] Kennedy RJ, Shelton C, Salzman KL, Davidson HC, Harnsberger HR. Intralabyrinthine schwannomas: Diagnosis, management, and a new classification system. Otology & Neurotology. 2004;**25**(2):160-167

[18] Magliulo G, Colicchio G, Romana AF, Stasolla A. Intracochlear schwannoma. Skull Base. 2010;**20**(2):115-118

[19] Harnsberger R, Glastonbury CM, Michel MA, Harnsberger HR, Glastonbury CM, Michel MA, et al. Diagnostic Imaging: Head and Neck. 2nd ed. Baltimore: Lippincott, Williams & Wilkins; 2010. https://www.amazon. co.uk/s/ref=dp\_byline\_sr\_book\_4?ie= UTF8&text=Bernadette+L.+Koch&sea rch-alias=books-uk&field-author=Bern adette+L.+Koch&sort=relevancerank

[20] Samii M, Matthies C, Tatagiba M. Intracanalicular acoustic neurinomas. Neurosurgery. 1991;**29**(2):189-199

[21] Samii M, Metwali H, Gerganov V. Eficacy of microsurgical tumor removal for treatment of patients with intracanalicular vestibular schwannoma presenting with disabling vestibular symptoms. Journal of Neurosurgery. 2017;**126**(5):1514-1519

**94**

2014;**56**(1):11-15

*Primary Intracranial Tumors*

**References**

[1] Machinis TG, Fountas KN,

Dimomopolos V, Robinson JS. History of acoustic neurinoma surgery. Neurosurgical Focus. 2005;**18**(4):1-4

imaging of acoustic schwannoma. Singapore Medical Journal.

[9] Held P, Fellner C, Seitz J, Graf S, Fellner F, Strutz J. The value of T2(\*) weighted MR images for the diagnosis of acoustic neuromas. European Journal of

[10] Held P, Fellner C, Fellner F, Seitz J, Graf S, Hilbert M, et al. MRI of inner ear and facial nerve pathology using 3D MP-RAGE and 3D CISS sequences. The British Journal of Radiology.

[11] Tomogane Y, Mori K, Izumoto S, Kaba K, Ishikura R, Ando K, et al. Usefulness of PRESTO magnetic resonance imaging for the

differentiation of schwannoma and meningioma in the cerebellopontine angle. Neurologia Medico-Chirurgica

[12] Carlson ML, Van Abel KM, Driscoll CL, Neff BA, Beatty CW, Lane JI, et al. Magnetic resonance imaging surveillance following vestibular schwannoma resection. Laryngoscope.

(Tokyo). 2013;**53**(7):482-489

[13] Bennett ML, Jackson CG,

Kaufmann R, Warren F. Postoperative imaging of vestibular schwannomas. Otolaryngology and Head and Neck Surgery. 2008;**138**(5):667-671

[14] Taylor RL, Kong J, Flanagan S, Pogson J, Croxson G, Pohl D, et al. Prevalence of vestibular dysfunction in patients with vestibular schwannoma using video head-impulses and

vestibular-evoked potentials. Journal of Neurology. 2015;**262**(5):1228-1237

[15] Samii M, Gerganov VM, Samii A. Functional outcome after complete surgical removal of giant vestibular

2012;**122**(2):378-388

Radiology. 1999;**30**(3):237-244

1997;**70**(834):558-566

1999;**40**(1):27-31

[2] Matthies C, Samii M. Management of 1000 vestibular schwannomas (acoustic neuromas): Clinical presentation. Neurosurgery. 1997;**40**(1):1-10

[3] Piccirillo E, Wiet MR, Flanagan S, Dispenza F, Giannuzzi A, Mancini F, et al. Cystic vestibular schwannoma: Classification, management, and facial nerve outcomes. Otology & Neurotology. 2009;**30**(6):826-834

[4] Thakur JD, Khan IS, Shorter CD, Sonig A, Gardner GL, Guthikonda B, et al. Do cystic vestibular schwannomas

[5] Taniguchi M, Nakai T, Kohta M, Kimura H, Kohmura E. Communicating hydrocephalus associated with small- to medium-sized vestibular schwannomas: Clinical significance of the tumor apparent diffusion coefficient map. World Neurosurgery. 2016;**94**:261-267

[6] Liang C, Zhang B, Wu L, Du Y, Wang X, Liu C, et al. The superiority of 3D-CISS sequence in displaying the cisternal segment of facial, vestibulocochlear nerves and their abnormal changes. European Journal of

Radiology. 2010;**74**(3):437-440

[7] Choi KS, Kim MS, Kwon HG, Jang SH, Kim OL. Preoperative identification of facial nerve in

vestibular schwannomas surgery using diffusion tensor tractography. Journal of Korean Neurosurgical Association.

[8] Tan TY. Non-contrast high resolution fast spin echo magnetic resonance

have worse surgical outcomes: Systematic analysis of the literature. Neurosurgical Focus. 2012;**33**(3):E12

**97**

**Chapter 7**

**Abstract**

**1. Introduction**

*Johnny Camargo*

The Systemic Treatment of Glioma

Gliomas have been treated by a specialized team including neurosurgery, radiation therapy, and neuro-oncology, as well as depending on integrated sophisticated facilities and multi-professional team. Despite these huge efforts to glioma treatment, glioblastoma, one of the most frequent gliomas, has median life expectance for just 15 months, so these results are still an unmet need. Related to the systemic treatment, some cancer approaches have been revolutionized with new strategies, such as immunotherapy, although in neuro-oncology, this alternative still has challenges to overcome. Throughout this chapter, relevant information and key points will be discussed to the best way to manage systemic treatment and improve glioma overall survival.

Gliomas are the most common primary brain tumors [1]; their origin is from glial cells, i.e., from astrocytes, oligodendrocytes, and ependymal cells. Usually, it has diffused appearance, and depending on their molecular features, they may have different behaviors. The worst evolution is related to glioblastoma, in which the best treatment might provide the dismal evolution in 15 months of overall survival (OS) [2]. On the other hand, even with diffuse infiltration, when there are astrocytic features, the OS might be up to 7 years, and with oligodendroglial features [3, 4], the OS is around more than 10 years. So, these diseases are very heterogeneous in regard to pathogenesis, histopathology, and molecular and clinical features.

Related to glioma treatment, for the optimization of results [5], it is necessary to be aware of clinical variables, such as age, sex, Karnofsky Performance Status on admission, isocitrate dehydrogenase 1/2 mutation ratio, or resection rate. Besides, there is a necessity of engaged and specialized staff of neurosurgeons, radiation therapist, neuro-oncologist, anesthetist, radiologist, and a supportive staff, in an

The systemic approaches make part of glioma treatment, using drugs with direct

The preferred treatment for brain tumors has been attempting to maximize the degree of surgical resection. But irrespective of the relevance of this approach, it

action in tumor cells [6, 7], in association with radiation therapy [2] aiming to potentialize it, as an adjuvant therapy [8], and currently for action in the vascular

equipped and organized structure with facilities for brain tumor care.

formation [9, 10] and to modulate immune system.

**2. Challenges for drug efficacy in CNS tumors**

**Keywords:** gliomas, glioblastoma, astrocytoma, oligodendroglioma,

immunotherapy, systemic treatment, chemotherapy

## **Chapter 7** The Systemic Treatment of Glioma

*Johnny Camargo*

#### **Abstract**

Gliomas have been treated by a specialized team including neurosurgery, radiation therapy, and neuro-oncology, as well as depending on integrated sophisticated facilities and multi-professional team. Despite these huge efforts to glioma treatment, glioblastoma, one of the most frequent gliomas, has median life expectance for just 15 months, so these results are still an unmet need. Related to the systemic treatment, some cancer approaches have been revolutionized with new strategies, such as immunotherapy, although in neuro-oncology, this alternative still has challenges to overcome. Throughout this chapter, relevant information and key points will be discussed to the best way to manage systemic treatment and improve glioma overall survival.

**Keywords:** gliomas, glioblastoma, astrocytoma, oligodendroglioma, immunotherapy, systemic treatment, chemotherapy

#### **1. Introduction**

Gliomas are the most common primary brain tumors [1]; their origin is from glial cells, i.e., from astrocytes, oligodendrocytes, and ependymal cells. Usually, it has diffused appearance, and depending on their molecular features, they may have different behaviors. The worst evolution is related to glioblastoma, in which the best treatment might provide the dismal evolution in 15 months of overall survival (OS) [2]. On the other hand, even with diffuse infiltration, when there are astrocytic features, the OS might be up to 7 years, and with oligodendroglial features [3, 4], the OS is around more than 10 years. So, these diseases are very heterogeneous in regard to pathogenesis, histopathology, and molecular and clinical features.

Related to glioma treatment, for the optimization of results [5], it is necessary to be aware of clinical variables, such as age, sex, Karnofsky Performance Status on admission, isocitrate dehydrogenase 1/2 mutation ratio, or resection rate. Besides, there is a necessity of engaged and specialized staff of neurosurgeons, radiation therapist, neuro-oncologist, anesthetist, radiologist, and a supportive staff, in an equipped and organized structure with facilities for brain tumor care.

The systemic approaches make part of glioma treatment, using drugs with direct action in tumor cells [6, 7], in association with radiation therapy [2] aiming to potentialize it, as an adjuvant therapy [8], and currently for action in the vascular formation [9, 10] and to modulate immune system.

#### **2. Challenges for drug efficacy in CNS tumors**

The preferred treatment for brain tumors has been attempting to maximize the degree of surgical resection. But irrespective of the relevance of this approach, it

#### *Primary Intracranial Tumors*

has limitations with respect to gliomas due to the invasiveness of these tumors and their tendency to reside in or near important brain areas. Traditional postsurgical therapy for gliomas involved standard radiation therapy and chemotherapy. There are some issues which might be considered as a challenge to improve glioma treatment.

#### **2.1 Blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (blood-CSFB), and blood-tumor barrier**

Anatomically, CNS can be subdivided into the parenchyma, meninges, special sense organs, cranial nerves, spinal nerves, and the ventricular system with its contents. All these structures are limited by boundaries under normal conditions, such as blood-brain barrier, blood-CSFB, and, in pathologic scenario, blood-tumor barrier. Under normal physiology, the BBB's unique anatomic structure and the tightly regulated interplay of its cellular and acellular components allow for maintenance of brain homeostasis, regulation of influx and efflux, and protection from harm; these characteristics ensure an optimal environment for the neural network to function properly. It is not really a barrier but rather a communication "center," responding to and passing signals between the CNS and blood [11]. It is constituted by cells that surround the vessels, the endothelium cells, which have been considered the central unit, and there is a growing understanding in the interactions of this central cell with other cells and systems, such as pericytes [12], astrocytes [13], and microglia. The integration among them results in maintenance of BBB permeability. There is a vast research to study the relation between this complex system and pathologies. Under pathologic conditions, these barriers might lose their permeability allowing easy traffic between the compartments.

Charge, lipophilicity, and molecular size are key issues for drugs to pass through BBB. Drugs currently in use for CNS tumors, for example, temozolomide and lomustine, can reach, despite BBB permeability, in areas with neoplastic enhancement in imaging studies, which might have dysfunctional BBB and permit some drugs to get in easily.

For instance, BBB is part of complex environment that supports the balance and homeostasis of CNS, and it is as well a barrier both to drugs and chemotherapeutic agents and to immunotherapeutic agents.

#### **2.2 Drug development**

The best quality preclinical testing model would select appropriate molecular targets, determine the effectiveness of drugs directed against those targets and the ideal genetic and cellular context for their use, evaluate the toxicity of selected drugs, and identify relevant biomarkers demonstrating drug efficacy and specificity to assist in subsequent clinical trials [14].

At the laboratory level, there are limitations of drug development for gliomas. Preclinical tests might be performed in in vitro tests or in animal model tests. In in vitro tests, there are limitations owing to cellular homogeneity that could not reproduce the real tumor environment and cellular heterogeneity; moreover, the systemic influences affect drug metabolism and distribution, and what's more, in an animal model in which are based on xenografts inserts in flank or directly into the animal brain. But these models, despite working in preclinical models, usually fail to reproduce the same result at the clinical level. Another strategy that has been developed by using genetically engineered mouse models (GEMMs) [15] has shown that glial tumors spontaneously develop, mostly of high grade, after a variable

**99**

*The Systemic Treatment of Glioma*

evasion, and brain invasion.

**2.3 Tumor heterogeneity**

and strategies to overcome it.

immunotherapy [23].

**3. Glioma classification**

relevance, were deleted.

tic issues.

**2.4 Immunosuppressive environment of brain tissue**

drugs [18, 19].

*DOI: http://dx.doi.org/10.5772/intechopen.80047*

the biology of CNS neoplasms in humans.

latent period. Such GEMMs are the best current models we have for approximating

Tumor heterogeneity may keep tumor evolution and adaptation, which prevent personalized medicine agents to work [17]. It has been described in various tumor models, and this feature in gliomas allowed them to be resistant to several known

There is a growing knowledge in the molecular and cellular basis of glioblastoma; Diane J. Aum [18], in her paper, introduced emerging concepts on the molecular and cellular heterogeneity of glioblastoma and laid emphasis that we should begin to consider each individual glioblastoma to be an ensemble of distinct subclones that reflect a spectrum of dynamic cell states. And this knowledge partially explains this entity's resistance to treatment, as well as allows new researches

A detailed understanding of the supportive role that the microenvironment plays in glioblastoma (GBM) is critical to the design of effective immunotherapeutic strategies. Glioma histology shows that >30% of GBM tumors are composed of infiltrating microglia [20] with active recruitment of peripheral macrophages [21]. The secretion of immunomodulatory cytokines from GBM cells, including interleukins 10 (IL-10), 4 (IL-4), and 6 (IL-6), and, particularly, tumor growth factor-beta

Tumor-associated macrophages (TAM) [22] are often considered to be facilitators of tumor growth because of their proangiogenic and immunosuppressive properties. Besides it, the glioma tumor cells are between the least immunogenic in the spectrum of the human tumors, which confer then to be less responsive to

Therefore, a complex system allows tumor cells to grow without immune system control, and this knowledge opens new avenues to exploration of immunotherapeu-

The new version of the World Health Organization Classification of Tumors of the Central Nervous System (WHO 2016) [24] introduced the concept of an integrated diagnosis, based on a union of both phenotypic (microscopic) and genotypic parameters. Major changes are seen in glioma and medulloblastoma groups. Fewer entities are included and some, related to their no longer diagnostic and therapeutic

(TGF-β) in addition to prostaglandin E2 can suppress microglia activation.

Other efforts have been made in order to better understand the overlap of various models and human brain tumor behavior; in recent published paper [16], the authors have studied the differences and similarities in glioma biology as conveyed by transcriptomic patterns across four mammalian hosts: rats, mice, dogs, and humans. And they have found notable differences that were observed in gene expression patterns as well as related biological pathways and cell populations known to mediate key elements of glioma biology, including angiogenesis, immune *Primary Intracranial Tumors*

treatment.

drugs to get in easily.

**2.2 Drug development**

agents and to immunotherapeutic agents.

ity to assist in subsequent clinical trials [14].

has limitations with respect to gliomas due to the invasiveness of these tumors and their tendency to reside in or near important brain areas. Traditional postsurgical therapy for gliomas involved standard radiation therapy and chemotherapy. There are some issues which might be considered as a challenge to improve glioma

Anatomically, CNS can be subdivided into the parenchyma, meninges, special sense organs, cranial nerves, spinal nerves, and the ventricular system with its contents. All these structures are limited by boundaries under normal conditions, such as blood-brain barrier, blood-CSFB, and, in pathologic scenario, blood-tumor barrier. Under normal physiology, the BBB's unique anatomic structure and the tightly regulated interplay of its cellular and acellular components allow for maintenance of brain homeostasis, regulation of influx and efflux, and protection from harm; these characteristics ensure an optimal environment for the neural network to function properly. It is not really a barrier but rather a communication "center," responding to and passing signals between the CNS and blood [11]. It is constituted by cells that surround the vessels, the endothelium cells, which have been considered the central unit, and there is a growing understanding in the interactions of this central cell with other cells and systems, such as pericytes [12], astrocytes [13], and microglia. The integration among them results in maintenance of BBB permeability. There is a vast research to study the relation between this complex system and pathologies. Under pathologic conditions, these barriers might lose their

Charge, lipophilicity, and molecular size are key issues for drugs to pass through

For instance, BBB is part of complex environment that supports the balance and homeostasis of CNS, and it is as well a barrier both to drugs and chemotherapeutic

The best quality preclinical testing model would select appropriate molecular targets, determine the effectiveness of drugs directed against those targets and the ideal genetic and cellular context for their use, evaluate the toxicity of selected drugs, and identify relevant biomarkers demonstrating drug efficacy and specific-

At the laboratory level, there are limitations of drug development for gliomas. Preclinical tests might be performed in in vitro tests or in animal model tests. In in vitro tests, there are limitations owing to cellular homogeneity that could not reproduce the real tumor environment and cellular heterogeneity; moreover, the systemic influences affect drug metabolism and distribution, and what's more, in an animal model in which are based on xenografts inserts in flank or directly into the animal brain. But these models, despite working in preclinical models, usually fail to reproduce the same result at the clinical level. Another strategy that has been developed by using genetically engineered mouse models (GEMMs) [15] has shown that glial tumors spontaneously develop, mostly of high grade, after a variable

BBB. Drugs currently in use for CNS tumors, for example, temozolomide and lomustine, can reach, despite BBB permeability, in areas with neoplastic enhancement in imaging studies, which might have dysfunctional BBB and permit some

**2.1 Blood-brain barrier (BBB), blood-cerebrospinal fluid barrier** 

permeability allowing easy traffic between the compartments.

**(blood-CSFB), and blood-tumor barrier**

**98**

latent period. Such GEMMs are the best current models we have for approximating the biology of CNS neoplasms in humans.

Other efforts have been made in order to better understand the overlap of various models and human brain tumor behavior; in recent published paper [16], the authors have studied the differences and similarities in glioma biology as conveyed by transcriptomic patterns across four mammalian hosts: rats, mice, dogs, and humans. And they have found notable differences that were observed in gene expression patterns as well as related biological pathways and cell populations known to mediate key elements of glioma biology, including angiogenesis, immune evasion, and brain invasion.

#### **2.3 Tumor heterogeneity**

Tumor heterogeneity may keep tumor evolution and adaptation, which prevent personalized medicine agents to work [17]. It has been described in various tumor models, and this feature in gliomas allowed them to be resistant to several known drugs [18, 19].

There is a growing knowledge in the molecular and cellular basis of glioblastoma; Diane J. Aum [18], in her paper, introduced emerging concepts on the molecular and cellular heterogeneity of glioblastoma and laid emphasis that we should begin to consider each individual glioblastoma to be an ensemble of distinct subclones that reflect a spectrum of dynamic cell states. And this knowledge partially explains this entity's resistance to treatment, as well as allows new researches and strategies to overcome it.

#### **2.4 Immunosuppressive environment of brain tissue**

A detailed understanding of the supportive role that the microenvironment plays in glioblastoma (GBM) is critical to the design of effective immunotherapeutic strategies. Glioma histology shows that >30% of GBM tumors are composed of infiltrating microglia [20] with active recruitment of peripheral macrophages [21]. The secretion of immunomodulatory cytokines from GBM cells, including interleukins 10 (IL-10), 4 (IL-4), and 6 (IL-6), and, particularly, tumor growth factor-beta (TGF-β) in addition to prostaglandin E2 can suppress microglia activation.

Tumor-associated macrophages (TAM) [22] are often considered to be facilitators of tumor growth because of their proangiogenic and immunosuppressive properties. Besides it, the glioma tumor cells are between the least immunogenic in the spectrum of the human tumors, which confer then to be less responsive to immunotherapy [23].

Therefore, a complex system allows tumor cells to grow without immune system control, and this knowledge opens new avenues to exploration of immunotherapeutic issues.

#### **3. Glioma classification**

The new version of the World Health Organization Classification of Tumors of the Central Nervous System (WHO 2016) [24] introduced the concept of an integrated diagnosis, based on a union of both phenotypic (microscopic) and genotypic parameters. Major changes are seen in glioma and medulloblastoma groups. Fewer entities are included and some, related to their no longer diagnostic and therapeutic relevance, were deleted.

In the previous version, WHO 2007, all astrocytic tumors had been grouped together, but now in new 2016 classification, all diffuse gliomas whether they are astrocytic or oligodendroglial are grouped under one heading, mainly based on their growth pattern, behavior, as well as a mutation in IDH.

Regarding the histological classification at the WHO 2016, there were few modifications; tumors are still being classified as grade I, II, III, and IV; and just a new category "grade unknown" is added for diffuse leptomeningeal glioneuronal tumor [25].

#### **3.1 Nomenclature**

The nomenclature of the combination of histopathological and molecular features must be standardized to simplify its use; CNS tumor diagnoses should consist of a histopathological name followed by the genetic features, with the genetic features following a comma and as adjectives, as in *diffuse astrocytoma*, IDH *mutant*, and *medulloblastoma*, wingless (WNT) *activated*. If there are more than one genetic features, it must be included in the description, for example, *oligodendroglioma,* IDH *mutant* and *1p/19q co-deleted.* When the tumor has no genetic alteration, the term "wild type" might be used if an official entity already exists, for example, *glioblastoma* IDH *wild type.*

For situations which there are no access to molecular tests, or it was not done, by whatever reason, the term not otherwise specified (NOS) must be used, for example, *diffuse astrocytoma, NOS.* For instance, the NOS terminology refers to an incomplete or unavailable information related to molecular tests.

#### **3.2 Gliomas**

Despite having astrocytic or oligodendroglial features, in the WHO 2016, they are grouped together as diffuse gliomas, and for pathologic point of view, it is useful, so they are grouped together; for prognostic issues and patient management, the therapeutic orientation might be driven biologically and genetically.

Astrocytic gliomas include diffuse lesions, which may be grade II, grade III (anaplastic), and grade IV (glioblastoma), and main molecular features are IDH and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) gene. IDH-mutated lesions may have better evolution. Grades II and III are mainly IDH mutated, whereas grade IV (glioblastoma) is predominately IDH wild type.

Oligodendroglial tumors have their histological features; although astrocytic ones might have its feature as well, and its molecular features are IDH mutated and 1p/19q co-deleted, these classes of tumors have better prognosis. It may have grade II and grade III (anaplastic). When the genetic tests are not available, it will be classified as diffuse astrocytoma, NOS; oligodendroglioma, NOS; or glioblastoma, NOS.

#### **4. Glioma molecular markers**

#### **4.1 IDH1 and IDH2**

IDH is the most important diagnostic marker as it can differentiate glioma from gliosis. These mutations have affected amino acid 132 of isocitrate dehydrogenase 1 gene (IDH1) in more than 70% of the WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that have developed from these lowergrade lesions [26].

**101**

same.

in neuro-oncology [32].

clinical courses [30, 33].

*The Systemic Treatment of Glioma*

metabolism [28].

**4.2 1p/19q co-deletion**

*DOI: http://dx.doi.org/10.5772/intechopen.80047*

Two IDH variants have been used, IDH1 and IDH2, which are enzymes in Krebs cycle that catalyzes the conversion of isocitrate to alpha-ketoglutarate. IDH1 mutations are heterozygous, and these are involving an amino acid substitution (glycine to arginine) in the active site of the enzyme in codon 132 (R132H). This mutation results in the abnormal production of 2-hydroxyglutarate, which causes histone and deoxyribonucleic acid (DNA) methylation, hence promoting tumorigenesis [27], while IDH2 variants are reported to influence angiogenesis, apoptosis, and glucose

IDH can be demonstrated by IDH1 or IDH2 mutation by immunohistochemistry using mutation-specific antibody against R132H-mutant IDH1; if immunostaining is negative, then it should be followed by IDH1/IDH2 DNA genotyping. Mutation in both IDH1 and IDH2 entities is known as IDH mutant. When both are negative, then it is known as IDH wild type. If IDH testing is not available or cannot be fully

In 1p/19q co-deletion, there is a complete deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q). 1p/19q co-deletion can be demonstrated by fluorescent *in situ* hybridization (FISH), polymerase chain reaction, chromogenic *in situ* hybridization, or molecular genetic testing. It is definitive for the diagnosis of grade II and grade III (anaplastic) oligodendrogliomas. It is a strong prognostic factor associated with improved survival and also a predictive factor for response to chemotherapy as well as radiotherapy [29, 30].

**4.3 O6-methylguanine-DNA methyltransferase methylation (MGMT)**

The MGMT gene encodes a DNA repair enzyme that can nullify the effects of alkylating chemotherapy such as temozolomide [31]. The alkylating chemotherapy damages DNA by adding methyl groups. Therefore, a tumor with a high degree of MGMT activity will be resistant to chemotherapies which target DNA at this location. If the promoter region of the MGMT gene is unmethylated, the gene will be active, whereas if the promoter region of MGMT is hypermethylated, the gene will be silenced. However, if the MGMT gene is active, the damage is rapidly repaired. Methylation of the MGMT gene promoter is a favorable prognostic and predictive factor in glioblastoma patients, but it is not a diagnostic marker for the

The correlation with other biomarkers is mandatory to have oriented treatment

TERT mutations often involve C228T and C250T mutations of the promoter region. TERT promoter mutations and long telomere length predict poor survival and radiotherapy resistance in gliomas. It occurs mainly in glioblastoma and oligodendroglioma. TERTp and IDH mutations are routinely used clinically to facilitate diagnosis by classifying 80% of GBMs into molecular subgroups with distinct

It is a chromatin-remodeling protein important in DNA replication, telomere stability, gene transcription, chromosome congression, and cohesion during cell

**4.5 Alpha-thalassemia/mental retardation syndrome X-linked (ATRX)**

**4.4 TERT (telomerase reverse transcriptase) promoter mutations**

performed or is inconclusive, then it is labeled as IDH NOS.

#### *The Systemic Treatment of Glioma DOI: http://dx.doi.org/10.5772/intechopen.80047*

*Primary Intracranial Tumors*

tumor [25].

**3.1 Nomenclature**

*toma* IDH *wild type.*

**3.2 Gliomas**

In the previous version, WHO 2007, all astrocytic tumors had been grouped together, but now in new 2016 classification, all diffuse gliomas whether they are astrocytic or oligodendroglial are grouped under one heading, mainly based on

Regarding the histological classification at the WHO 2016, there were few modifications; tumors are still being classified as grade I, II, III, and IV; and just a new category "grade unknown" is added for diffuse leptomeningeal glioneuronal

The nomenclature of the combination of histopathological and molecular features must be standardized to simplify its use; CNS tumor diagnoses should consist of a histopathological name followed by the genetic features, with the genetic features following a comma and as adjectives, as in *diffuse astrocytoma*, IDH *mutant*, and *medulloblastoma*, wingless (WNT) *activated*. If there are more than one genetic features, it must be included in the description, for example, *oligodendroglioma,* IDH *mutant* and *1p/19q co-deleted.* When the tumor has no genetic alteration, the term "wild type" might be used if an official entity already exists, for example, *glioblas-*

For situations which there are no access to molecular tests, or it was not done, by whatever reason, the term not otherwise specified (NOS) must be used, for example, *diffuse astrocytoma, NOS.* For instance, the NOS terminology refers to an

Despite having astrocytic or oligodendroglial features, in the WHO 2016, they are grouped together as diffuse gliomas, and for pathologic point of view, it is useful, so they are grouped together; for prognostic issues and patient management,

Astrocytic gliomas include diffuse lesions, which may be grade II, grade III (anaplastic), and grade IV (glioblastoma), and main molecular features are IDH and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) gene. IDH-mutated lesions may have better evolution. Grades II and III are mainly IDH mutated, whereas grade IV (glioblastoma) is predominately IDH wild type.

Oligodendroglial tumors have their histological features; although astrocytic ones might have its feature as well, and its molecular features are IDH mutated and 1p/19q co-deleted, these classes of tumors have better prognosis. It may have grade II and grade III (anaplastic). When the genetic tests are not available, it will be classified as diffuse astrocytoma, NOS; oligodendroglioma, NOS; or glioblastoma,

IDH is the most important diagnostic marker as it can differentiate glioma from gliosis. These mutations have affected amino acid 132 of isocitrate dehydrogenase 1 gene (IDH1) in more than 70% of the WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that have developed from these lower-

incomplete or unavailable information related to molecular tests.

the therapeutic orientation might be driven biologically and genetically.

their growth pattern, behavior, as well as a mutation in IDH.

**100**

NOS.

**4. Glioma molecular markers**

**4.1 IDH1 and IDH2**

grade lesions [26].

Two IDH variants have been used, IDH1 and IDH2, which are enzymes in Krebs cycle that catalyzes the conversion of isocitrate to alpha-ketoglutarate. IDH1 mutations are heterozygous, and these are involving an amino acid substitution (glycine to arginine) in the active site of the enzyme in codon 132 (R132H). This mutation results in the abnormal production of 2-hydroxyglutarate, which causes histone and deoxyribonucleic acid (DNA) methylation, hence promoting tumorigenesis [27], while IDH2 variants are reported to influence angiogenesis, apoptosis, and glucose metabolism [28].

IDH can be demonstrated by IDH1 or IDH2 mutation by immunohistochemistry using mutation-specific antibody against R132H-mutant IDH1; if immunostaining is negative, then it should be followed by IDH1/IDH2 DNA genotyping. Mutation in both IDH1 and IDH2 entities is known as IDH mutant. When both are negative, then it is known as IDH wild type. If IDH testing is not available or cannot be fully performed or is inconclusive, then it is labeled as IDH NOS.

#### **4.2 1p/19q co-deletion**

In 1p/19q co-deletion, there is a complete deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q). 1p/19q co-deletion can be demonstrated by fluorescent *in situ* hybridization (FISH), polymerase chain reaction, chromogenic *in situ* hybridization, or molecular genetic testing. It is definitive for the diagnosis of grade II and grade III (anaplastic) oligodendrogliomas. It is a strong prognostic factor associated with improved survival and also a predictive factor for response to chemotherapy as well as radiotherapy [29, 30].

#### **4.3 O6-methylguanine-DNA methyltransferase methylation (MGMT)**

The MGMT gene encodes a DNA repair enzyme that can nullify the effects of alkylating chemotherapy such as temozolomide [31]. The alkylating chemotherapy damages DNA by adding methyl groups. Therefore, a tumor with a high degree of MGMT activity will be resistant to chemotherapies which target DNA at this location. If the promoter region of the MGMT gene is unmethylated, the gene will be active, whereas if the promoter region of MGMT is hypermethylated, the gene will be silenced. However, if the MGMT gene is active, the damage is rapidly repaired. Methylation of the MGMT gene promoter is a favorable prognostic and predictive factor in glioblastoma patients, but it is not a diagnostic marker for the same.

The correlation with other biomarkers is mandatory to have oriented treatment in neuro-oncology [32].

#### **4.4 TERT (telomerase reverse transcriptase) promoter mutations**

TERT mutations often involve C228T and C250T mutations of the promoter region. TERT promoter mutations and long telomere length predict poor survival and radiotherapy resistance in gliomas. It occurs mainly in glioblastoma and oligodendroglioma. TERTp and IDH mutations are routinely used clinically to facilitate diagnosis by classifying 80% of GBMs into molecular subgroups with distinct clinical courses [30, 33].

#### **4.5 Alpha-thalassemia/mental retardation syndrome X-linked (ATRX)**

It is a chromatin-remodeling protein important in DNA replication, telomere stability, gene transcription, chromosome congression, and cohesion during cell division. ATRX mutation results in lengthening of telomerase which helps in chromatin maintenance and remodeling. All cells are ATRX positive. If ATRX mutation is present, then there will be a loss of staining in the cells [34].

ATRX mutations are almost always accompanied by other mutations in the histone regulation (IDH, H33 K27M, tumor protein p53 [TP53], etc.) [35]. Loss of ATRX expression is seen in 45% of anaplastic astrocytoma, 27% of anaplastic oligoastrocytoma, and 10% of anaplastic oligodendroglioma and also in pediatric and adult high-grade astrocytoma [36].

#### **4.6 Tumor protein p53**

p53 is a tumor suppressor gene located on the short arm of chromosome 17. Loss of p53 leads to DNA damage, hypoxia, oncogene activation, microtubule disruption, and oxidative damage which in turn contributes to the CNS tumor pathogenesis mainly medulloblastoma, glioblastoma, and in 56–58% of IDH-mutant astrocytoma [37]. Copy number neutral loss of heterozygosity of chromosome 17p (CNLOH 17p) was nearly exclusively associated with IDH1-mutant astrocytoma with TP53 mutations. "CNLOH" means that one copy of the chromosome has been deleted, whereas the remaining copy has been duplicated. The net result is that the cell still has a total of two copies of the gene or chromosomal segment, but instead of having two different copies, a single copy has been duplicated. CNLOH 17p was found to be a significant prognostic factor, with better survival outcomes for those with the CNLOH 17p alteration [38].

#### **5. Low-grade gliomas**

Usually, the term "low-grade glioma" refers to the glioma class, which has an indolent evolution and an incurable disease, and during their evolution transform into a high grade. It has a specific molecular and genetic profile. In the WHO 2016, they are represented by diffuse astrocytic glioma grade II, IDH mutant and IDH wild type, and diffuse oligodendroglioma, IDH mutant with 1p/19q co-deletion or not [39].

Surgery is a key point on its management, getting tissue for biopsy and molecular analysis, and the timing depends on some variables, such as tumor size, localization, age of patient, and symptoms. Patients with small tumors might be followed regularly; despite not having randomized studies, early intervention has been showing OS advantages, as well the extension of resection and maximum safe resection rather than partial resection or biopsy [40–42].

Radiation therapy is an important part of the low-grade glioma treatment, and the optimal timing is controversial; by the way, for those ones with high risk of relapse, the immediate delivery of radiation is of the standard approaches [43].

Regarding the systemic treatment, chemotherapy is part of its treatment in the adjuvant and at relapse setting of the low-grade glioma spectrum.

In RTOG 9802, patients were randomly assigned to radiation therapy (RT) alone or RT followed by six cycles of procarbazine, lomustine, and vincristine (PCV). The primary endpoint was OS, and the secondary endpoint was PFS and grade III toxicity. At the time of the first publication [44] with a median follow-up of 5.9 years in surviving patients, there was a trend toward longer survival in the RT plus chemotherapy group (5-year overall survival 72 vs. 63%, hazard ratio [HR] 0.72, 95% CI 0.47–1.10), but with a median follow-up of 11.9 years showed at second publication [45], the significance of OS and progression-free survival (PFS) was reached, with median overall survival 13.3 vs. 7.8 years for patients treated with RT followed by

**103**

*The Systemic Treatment of Glioma*

OS advantage.

demands.

ing in account the updated WHO 2016.

tumor must have IDH mutation and 1p/19q co-deletion.

**6.1 Grade III diffuse gliomas**

*6.1.1 Anaplastic oligodendroglioma*

**6. High-grade gliomas**

*DOI: http://dx.doi.org/10.5772/intechopen.80047*

PCV, HR 0.59, p = 0.03, and the median progression-free survival was also pro-

These results bring level 1 evidence to treat high-risk patients with low-grade gliomas with RT and PCV. As PCV is toxic and there are further evidences of equivalences with temozolomide [46], despite not being randomized by studies comparing it in this population, this drug can be used with the 2B level of evidence. At CATNON trial, there was a comparison in patients with anaplastic oligodendrogliomas with no co-deletion, between RT and RT followed by temozolomide, with

In the subgroup of patients who had had 1p/19q co-deletion, the significance of benefit from PCV was greater in patients with oligodendroglioma (n = 101; HR 0.43, 95% CI 0.23–0.82) and oligoastrocytoma (n = 77; HR 0.56, 95% CI 0.32–1.0)

This category is composed by grade III diffuse gliomas (anaplastic astrocytoma, anaplastic oligodendroglioma) and grade IV (glioblastoma). Typically, the symptom evolution occurs in few weeks or months. Among them, there are different prognoses, so as anaplastic oligodendroglioma has OS of 9 years, anaplastic astrocytoma has OS of 3–5 years, and glioblastoma has OS of just 15 months. The prognosis will be dependent on age, performance status, localization of the lesion, grade of resection [47, 48], and molecular profile for grade III diffuse gliomas (IDH and 1p/19q co-deletion) and for glioblastoma (IDH status, MGMT, TERT, p53, epider-

Surgery for high-grade gliomas has the goal of maximum safe resection [49], with prognosis improvement, or at least partial resection or stereotactic biopsy to define histology, as well as molecular markers to drive treatment. Many strategies have been tested to reach maximum safe resection, such as awake surgery, intraoperative magnetic resonance [50], 5-aminolevulinic acid (5-ALA) guide surgery [48], and other techniques that require expertise and facilities to deal with these

Further adjuvant treatment, considering gold standard, using radiation therapy and systemic treatment is required. To revisit this issue, it might be considered that previous trials took data from a mix of histologic and molecular subtypes, not tak-

In this subtype, the knowledge of the role of 1p/19q co-deletion as better prognostic marker as far has been demonstrated [51]. According to the WHO 2016, this

One of the evidences to treat this class of patient with combination of radiation therapy and chemotherapy was demonstrated in EORTC brain tumor group study 26951 [29], where 368 adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either RT or the same RT followed by six cycles of adjuvant PCV, and with a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 vs. 30.6 months in the RT arm, hazard ratio [HR], 0.75; 95% CI, 0.60–0.95). In an exploratory analysis of 80 patients with a 1p/19q co-deletion, OS was increased, with a trend toward more benefits

longed in patients who received PCV (10.4 vs. 4.0 years, p = 0.002).

than in those with astrocytoma (n = 46; HR 0.73, 95% CI 0.40–1.34).

mal growth factor receptor variant III (EGFRvIII), and others).

#### *The Systemic Treatment of Glioma DOI: http://dx.doi.org/10.5772/intechopen.80047*

*Primary Intracranial Tumors*

**4.6 Tumor protein p53**

and adult high-grade astrocytoma [36].

with the CNLOH 17p alteration [38].

tion rather than partial resection or biopsy [40–42].

adjuvant and at relapse setting of the low-grade glioma spectrum.

**5. Low-grade gliomas**

not [39].

division. ATRX mutation results in lengthening of telomerase which helps in chromatin maintenance and remodeling. All cells are ATRX positive. If ATRX mutation

ATRX mutations are almost always accompanied by other mutations in the histone regulation (IDH, H33 K27M, tumor protein p53 [TP53], etc.) [35]. Loss of ATRX expression is seen in 45% of anaplastic astrocytoma, 27% of anaplastic oligoastrocytoma, and 10% of anaplastic oligodendroglioma and also in pediatric

p53 is a tumor suppressor gene located on the short arm of chromosome 17. Loss of p53 leads to DNA damage, hypoxia, oncogene activation, microtubule disruption, and oxidative damage which in turn contributes to the CNS tumor pathogenesis mainly medulloblastoma, glioblastoma, and in 56–58% of IDH-mutant astrocytoma [37]. Copy number neutral loss of heterozygosity of chromosome 17p (CNLOH 17p) was nearly exclusively associated with IDH1-mutant astrocytoma with TP53 mutations. "CNLOH" means that one copy of the chromosome has been deleted, whereas the remaining copy has been duplicated. The net result is that the cell still has a total of two copies of the gene or chromosomal segment, but instead of having two different copies, a single copy has been duplicated. CNLOH 17p was found to be a significant prognostic factor, with better survival outcomes for those

Usually, the term "low-grade glioma" refers to the glioma class, which has an indolent evolution and an incurable disease, and during their evolution transform into a high grade. It has a specific molecular and genetic profile. In the WHO 2016, they are represented by diffuse astrocytic glioma grade II, IDH mutant and IDH wild type, and diffuse oligodendroglioma, IDH mutant with 1p/19q co-deletion or

Surgery is a key point on its management, getting tissue for biopsy and molecular analysis, and the timing depends on some variables, such as tumor size, localization, age of patient, and symptoms. Patients with small tumors might be followed regularly; despite not having randomized studies, early intervention has been showing OS advantages, as well the extension of resection and maximum safe resec-

Radiation therapy is an important part of the low-grade glioma treatment, and the optimal timing is controversial; by the way, for those ones with high risk of relapse, the immediate delivery of radiation is of the standard approaches [43]. Regarding the systemic treatment, chemotherapy is part of its treatment in the

In RTOG 9802, patients were randomly assigned to radiation therapy (RT) alone or RT followed by six cycles of procarbazine, lomustine, and vincristine (PCV). The primary endpoint was OS, and the secondary endpoint was PFS and grade III toxicity. At the time of the first publication [44] with a median follow-up of 5.9 years in surviving patients, there was a trend toward longer survival in the RT plus chemotherapy group (5-year overall survival 72 vs. 63%, hazard ratio [HR] 0.72, 95% CI 0.47–1.10), but with a median follow-up of 11.9 years showed at second publication [45], the significance of OS and progression-free survival (PFS) was reached, with median overall survival 13.3 vs. 7.8 years for patients treated with RT followed by

is present, then there will be a loss of staining in the cells [34].

**102**

PCV, HR 0.59, p = 0.03, and the median progression-free survival was also prolonged in patients who received PCV (10.4 vs. 4.0 years, p = 0.002).

These results bring level 1 evidence to treat high-risk patients with low-grade gliomas with RT and PCV. As PCV is toxic and there are further evidences of equivalences with temozolomide [46], despite not being randomized by studies comparing it in this population, this drug can be used with the 2B level of evidence. At CATNON trial, there was a comparison in patients with anaplastic oligodendrogliomas with no co-deletion, between RT and RT followed by temozolomide, with OS advantage.

In the subgroup of patients who had had 1p/19q co-deletion, the significance of benefit from PCV was greater in patients with oligodendroglioma (n = 101; HR 0.43, 95% CI 0.23–0.82) and oligoastrocytoma (n = 77; HR 0.56, 95% CI 0.32–1.0) than in those with astrocytoma (n = 46; HR 0.73, 95% CI 0.40–1.34).

#### **6. High-grade gliomas**

This category is composed by grade III diffuse gliomas (anaplastic astrocytoma, anaplastic oligodendroglioma) and grade IV (glioblastoma). Typically, the symptom evolution occurs in few weeks or months. Among them, there are different prognoses, so as anaplastic oligodendroglioma has OS of 9 years, anaplastic astrocytoma has OS of 3–5 years, and glioblastoma has OS of just 15 months. The prognosis will be dependent on age, performance status, localization of the lesion, grade of resection [47, 48], and molecular profile for grade III diffuse gliomas (IDH and 1p/19q co-deletion) and for glioblastoma (IDH status, MGMT, TERT, p53, epidermal growth factor receptor variant III (EGFRvIII), and others).

Surgery for high-grade gliomas has the goal of maximum safe resection [49], with prognosis improvement, or at least partial resection or stereotactic biopsy to define histology, as well as molecular markers to drive treatment. Many strategies have been tested to reach maximum safe resection, such as awake surgery, intraoperative magnetic resonance [50], 5-aminolevulinic acid (5-ALA) guide surgery [48], and other techniques that require expertise and facilities to deal with these demands.

Further adjuvant treatment, considering gold standard, using radiation therapy and systemic treatment is required. To revisit this issue, it might be considered that previous trials took data from a mix of histologic and molecular subtypes, not taking in account the updated WHO 2016.

#### **6.1 Grade III diffuse gliomas**

#### *6.1.1 Anaplastic oligodendroglioma*

In this subtype, the knowledge of the role of 1p/19q co-deletion as better prognostic marker as far has been demonstrated [51]. According to the WHO 2016, this tumor must have IDH mutation and 1p/19q co-deletion.

One of the evidences to treat this class of patient with combination of radiation therapy and chemotherapy was demonstrated in EORTC brain tumor group study 26951 [29], where 368 adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either RT or the same RT followed by six cycles of adjuvant PCV, and with a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 vs. 30.6 months in the RT arm, hazard ratio [HR], 0.75; 95% CI, 0.60–0.95). In an exploratory analysis of 80 patients with a 1p/19q co-deletion, OS was increased, with a trend toward more benefits

from adjuvant PCV (OS not reached in the RT/PCV group vs. 112 months in the RT group; HR, 0.56; 95% CI, 0.31–1.03). IDH mutational status was also of prognostic significance.

At RTOG 9402 in an updated publication [52], 291 patients with anaplastic oligodendrogliomas and pure (AO) and mixed (anaplastic oligoastrocytoma (AOA) were randomized to four cycles of PCV followed by radiation therapy (RT). For the entire cohort, there was no difference in median survival by treatment (4.6 years for PCV plus RT vs. 4.7 years for RT), but for 1p/19q co-deleted patients as in EORTC 26951, there was survival benefit, although this analysis was not preplanned.

#### *6.1.2 Anaplastic astrocytoma*

In the WHO 2016, anaplastic astrocytoma molecular feature is IDH1/IDH2 mutated and IDH1/IDH2 wild type, with no 1p/19q co-deletion. Anaplastic astrocytoma IDH1/IDH2 wild type has worse prognosis than the IDH1/IDH-2 mutated [25].

At CATNON trial (EORTC study 26053-22054) [8], 745 patients (99%) of the planned 748 patients, with anaplastic astrocytoma with no 1p/19q co-deletion, had been enrolled in a four-arm study comparing RT alone, RT with concurrent daily temozolomide, RT followed by 12 cycles of adjuvant temozolomide, and RT with both concurrent and 12 cycles of adjuvant temozolomide. At the interim analysis of RT × RT followed by 12 cycles of adjuvant temozolomide, the temozolomide addition had a significant improvement in both progression-free survival (HR 0.62, 95% CI 0.50–0.76) and overall survival (median 44.1 months vs. not yet reached; HR 0.65, 95% CI 0.45–0.93).

So, based upon CATNON trial and other observations [53, 54], patients with anaplastic astrocytoma must be treated with adjuvant RT and chemotherapy, and if IDH is wild type, it must be treated as glioblastoma. To IDH-mutated lesions, until final analysis of CATNON trial, there is no evidence-based data supporting concomitant adjuvant treatment for this subgroup.

#### **6.2 Grade IV gliomas: glioblastoma**

Glioblastoma has been a daily challenge for those who attend these patients, as well for those who are involved in research area. Glioblastoma is the most common glioma and usually has dismal evolution in few months or years, so it has OS of just 15 months. At the Stupp trial [2], in the current standard of care of postoperative therapy for glioblastoma, 573 newly diagnosed patients with histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone or radiotherapy plus continuous daily temozolomide, followed by six cycles of adjuvant temozolomide. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy plus temozolomide group was 0.63 (95% confidence interval, 0.52–0.75; P < 0.001 by the log-rank test).

At this trial and others [55, 56], MGMT-methylated patients are doing better, and this biomarker became a strong predictor of temozolomide response.

Low-intensity alternating electric field therapy (TTFields) is a novel treatment to glioblastoma, in which locoregionally delivered antimitotic treatment interferes with cell division and organelle assembly. This stimulus is delivered continuously by transducers applied to a shaved scalp. In an open-label randomized trial of 695 adults with newly diagnosed glioblastoma, median survival was improved in patients assigned to wear the device during the adjuvant temozolomide phase of

**105**

[63, 64].

**7.1 Vaccines**

*The Systemic Treatment of Glioma*

*DOI: http://dx.doi.org/10.5772/intechopen.80047*

that is not acceptable to all patients [59].

hematologic toxicity was frequent.

**7. New strategies to treat gliomas**

lenging results, waiting for publication for further details.

improve OS, immunotherapy has demonstrated hopeful results.

having synergistic effect [67], but this hypothesis must be proven.

limited for better use of this strategy in glioma field.

standard chemoradiation compared with those assigned to standard chemoradiation alone (21 vs. 16 months) [57, 58]. The requirement to carry a device and maintain a shaved scalp for the duration of treatment presents a potential burden

On a phase II study [60], 39 glioblastoma patients are offered with radiotherapy of tumor site only and CCNU/TMZ (carmustine/temozolomide) chemotherapy for up to six courses. It results in a longer survival when compared to historical controls, mainly in MGMT-methylated patients; in the whole cohort, the median overall survival (mOS) was 23.1 months, and comparing MGMT methylated or not, the mOS was significantly longer with 34.3 vs. 12.5 months. The WHO grade IV

CeTeG/NOA-09 trial was designed to prove that MGMT-methylated glioblastoma patients might have better survival using CCNU/TMZ. In this trial, there was randomization between MGMT-methylated glioblastoma patients to treat with a standard Stupp protocol vs. six cycles of CCNU/TMZ, its results were presented at plenary section of 22nd SNO (Society of Neuro-oncology meeting) [61], and it results in mOS for TMZ of 30.4 and 46.9 months for CCNU/TMZ. These are chal-

In the last 30 years, there have been huge investments in glioma research for better outcomes; despite being fruitful, it is far from being solved. There are studies in anti-angiogenic drugs, inhibition of integrins, inhibition of growth factor receptors and intracellular signaling pathways, and immunotherapy, and despite failing to

Immunotherapy has been extensively studied, with better understanding of relationship between tumors and immune system [62], and it is totally clear that immune system plays a key role in the tumor evolution as well as its control. Currently, immunotherapy has been standard in a growing spectrum of tumors

Immunotherapy challenges in glioblastoma, owing to low mutational load (TML) and therefore potential immunogenicity, and tight immune regulation within the CNS result in limited T-cell effector responses, which means that immunosuppressive microenvironment and blockade of some cells to CNS have been

As an active immunotherapy (vaccine), rindopepimut (Rintega) consists of an EGFRvIII peptide conjugated to keyhole limpet hemocyanin, which is expressed in 30% of cells from glioblastoma patients and was previously tested in a phase II trial (ACT III) [65], and it had been the first immunotherapeutic to demonstrate increased survival. The hypothesis had been tested in a phase III trial, ACT IV [66], in which patients with newly diagnosed GBM with EGFRvIII expressed treated with standard chemoradiation with or without rindopepimut. Its publication showed that there was no difference at primary endpoint, with OS of 20.4 vs. 21.1 months. There are some evidences of association between bevacizumab and rindopepimut

Another provocative strategy has just been published [68] in a phase III trial which evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma.

#### *The Systemic Treatment of Glioma DOI: http://dx.doi.org/10.5772/intechopen.80047*

*Primary Intracranial Tumors*

*6.1.2 Anaplastic astrocytoma*

HR 0.65, 95% CI 0.45–0.93).

**6.2 Grade IV gliomas: glioblastoma**

concomitant adjuvant treatment for this subgroup.

significance.

mutated [25].

from adjuvant PCV (OS not reached in the RT/PCV group vs. 112 months in the RT group; HR, 0.56; 95% CI, 0.31–1.03). IDH mutational status was also of prognostic

At RTOG 9402 in an updated publication [52], 291 patients with anaplastic oligodendrogliomas and pure (AO) and mixed (anaplastic oligoastrocytoma (AOA) were randomized to four cycles of PCV followed by radiation therapy (RT). For the entire cohort, there was no difference in median survival by treatment (4.6 years for PCV plus RT vs. 4.7 years for RT), but for 1p/19q co-deleted patients as in EORTC 26951, there was survival benefit, although this analysis was not preplanned.

In the WHO 2016, anaplastic astrocytoma molecular feature is IDH1/IDH2 mutated and IDH1/IDH2 wild type, with no 1p/19q co-deletion. Anaplastic astrocytoma IDH1/IDH2 wild type has worse prognosis than the IDH1/IDH-2

At CATNON trial (EORTC study 26053-22054) [8], 745 patients (99%) of the planned 748 patients, with anaplastic astrocytoma with no 1p/19q co-deletion, had been enrolled in a four-arm study comparing RT alone, RT with concurrent daily temozolomide, RT followed by 12 cycles of adjuvant temozolomide, and RT with both concurrent and 12 cycles of adjuvant temozolomide. At the interim analysis of RT × RT followed by 12 cycles of adjuvant temozolomide, the temozolomide addition had a significant improvement in both progression-free survival (HR 0.62, 95% CI 0.50–0.76) and overall survival (median 44.1 months vs. not yet reached;

So, based upon CATNON trial and other observations [53, 54], patients with anaplastic astrocytoma must be treated with adjuvant RT and chemotherapy, and if IDH is wild type, it must be treated as glioblastoma. To IDH-mutated lesions, until final analysis of CATNON trial, there is no evidence-based data supporting

Glioblastoma has been a daily challenge for those who attend these patients, as well for those who are involved in research area. Glioblastoma is the most common glioma and usually has dismal evolution in few months or years, so it has OS of just 15 months. At the Stupp trial [2], in the current standard of care of postoperative therapy for glioblastoma, 573 newly diagnosed patients with histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone or radiotherapy plus continuous daily temozolomide, followed by six cycles of adjuvant temozolomide. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy plus temozolomide group was 0.63 (95% confidence interval, 0.52–0.75; P < 0.001 by

At this trial and others [55, 56], MGMT-methylated patients are doing better,

Low-intensity alternating electric field therapy (TTFields) is a novel treatment to glioblastoma, in which locoregionally delivered antimitotic treatment interferes with cell division and organelle assembly. This stimulus is delivered continuously by transducers applied to a shaved scalp. In an open-label randomized trial of 695 adults with newly diagnosed glioblastoma, median survival was improved in patients assigned to wear the device during the adjuvant temozolomide phase of

and this biomarker became a strong predictor of temozolomide response.

**104**

the log-rank test).

standard chemoradiation compared with those assigned to standard chemoradiation alone (21 vs. 16 months) [57, 58]. The requirement to carry a device and maintain a shaved scalp for the duration of treatment presents a potential burden that is not acceptable to all patients [59].

On a phase II study [60], 39 glioblastoma patients are offered with radiotherapy of tumor site only and CCNU/TMZ (carmustine/temozolomide) chemotherapy for up to six courses. It results in a longer survival when compared to historical controls, mainly in MGMT-methylated patients; in the whole cohort, the median overall survival (mOS) was 23.1 months, and comparing MGMT methylated or not, the mOS was significantly longer with 34.3 vs. 12.5 months. The WHO grade IV hematologic toxicity was frequent.

CeTeG/NOA-09 trial was designed to prove that MGMT-methylated glioblastoma patients might have better survival using CCNU/TMZ. In this trial, there was randomization between MGMT-methylated glioblastoma patients to treat with a standard Stupp protocol vs. six cycles of CCNU/TMZ, its results were presented at plenary section of 22nd SNO (Society of Neuro-oncology meeting) [61], and it results in mOS for TMZ of 30.4 and 46.9 months for CCNU/TMZ. These are challenging results, waiting for publication for further details.

#### **7. New strategies to treat gliomas**

In the last 30 years, there have been huge investments in glioma research for better outcomes; despite being fruitful, it is far from being solved. There are studies in anti-angiogenic drugs, inhibition of integrins, inhibition of growth factor receptors and intracellular signaling pathways, and immunotherapy, and despite failing to improve OS, immunotherapy has demonstrated hopeful results.

Immunotherapy has been extensively studied, with better understanding of relationship between tumors and immune system [62], and it is totally clear that immune system plays a key role in the tumor evolution as well as its control. Currently, immunotherapy has been standard in a growing spectrum of tumors [63, 64].

Immunotherapy challenges in glioblastoma, owing to low mutational load (TML) and therefore potential immunogenicity, and tight immune regulation within the CNS result in limited T-cell effector responses, which means that immunosuppressive microenvironment and blockade of some cells to CNS have been limited for better use of this strategy in glioma field.

#### **7.1 Vaccines**

As an active immunotherapy (vaccine), rindopepimut (Rintega) consists of an EGFRvIII peptide conjugated to keyhole limpet hemocyanin, which is expressed in 30% of cells from glioblastoma patients and was previously tested in a phase II trial (ACT III) [65], and it had been the first immunotherapeutic to demonstrate increased survival. The hypothesis had been tested in a phase III trial, ACT IV [66], in which patients with newly diagnosed GBM with EGFRvIII expressed treated with standard chemoradiation with or without rindopepimut. Its publication showed that there was no difference at primary endpoint, with OS of 20.4 vs. 21.1 months. There are some evidences of association between bevacizumab and rindopepimut having synergistic effect [67], but this hypothesis must be proven.

Another provocative strategy has just been published [68] in a phase III trial which evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma.

The final results are not yet available, because they are still unblinded, until the sufficient events have occurred to elucidate the final curves. Despite being an interim analysis, it has been shown 23.4 months of medium OS (mOS), as the intention-totreat (ITT) population is similar, and it was allowed to crossover. So, we have to wait for the final data.

#### **7.2 Checkpoint inhibitors**

Another promising area is immunotherapy with checkpoint inhibitors, although a recent trial failed to demonstrate survival benefit. The CheckMate 143 was the first randomized phase III clinical trial in GBM with a PD-1 checkpoint inhibitor. In nivolumab alone vs. bevacizumab alone in recurrent GBM, 369 patients were randomized to the nivolumab (n = 184) or bevacizumab (n = 185), resulting in a median OS of 9.8 months with nivolumab and 10 months with bevacizumab, and the 12-month OS rate was 42% in both arms. Despite having failed to demonstrate advantage, in a specific scenario, in patients with biallelic mismatch repair deficiency (bMMRD), it can benefit from checkpoint inhibitor treatment [69]. This might be explained by a high mutational burden in bMMRD. In other considerations, CheckMate 143 failure involves an inability of nivolumab to reach tumor-infiltrating lymphocytes (TILs) already sequestered in the recurrent tumor microenvironment; it may be expected to function better in patients with newly diagnosed GBM, where newly activated circulating T cells would be available for interaction with nivolumab prior to their migration to tumor sites. So, further investigation is required to set PD-1 checkpoint in glioma treatment [70, 71].

#### **7.3 CAR T cells**

Tumor immunotherapy with T lymphocytes, which can recognize and destroy malignant cells, has been limited by the ability to isolate and expand T cells restricted to tumor-associated antigens. Chimeric antigen receptors (CARs) composed of antibody-binding domains connected to domains that activate T cells could overcome tolerance by allowing T cells to respond to cell surface antigens; however, to date, lymphocytes engineered to express CARs have demonstrated minimal in vivo expansion and antitumor effects in clinical trials [72]. The very begging publications related to CAR T-cell therapy were related to a relapsed and refractory acute lymphoblastic leukemia, which made this technology known.

At glioma setting, CAR T-cell therapy has been tested, in recurrent GBM utilizing CAR T-cell GBM-associated antigen IL13Ra2 that utilizes CD62L-enriched central memory T cells (Tcm) engineered by lentiviral transduction to express [73]. Second-generation 4-1BB-containing CAR (IL13BBZ) signaling domain was utilized by both intratumoral and intraventricular deliveries, with multiple doses via reservoir. Safely and well tolerated, some dramatic responses were observed, both in brain and meninx lesions.

Further efforts have been made to improve results of this therapy [74–76].

#### **7.4 Cancer-targeting oncolytic viruses**

Cancer virotherapy mediated by oncolytic viruses (OV) has emerged as a novel and effective strategy in cancer therapeutics [77]. Desjardins [78] in a dose-finding and toxicity phase I study evaluated an intratumoral delivery of the recombinant nonpathogenic poliovirus-rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment. Overall survival

**107**

**Author details**

Brazil

Brazil

Johnny Camargo1,2\*

provided the original work is properly cited.

\*Address all correspondence to: jfccamargo@gmail.com

*The Systemic Treatment of Glioma*

setting is ongoing NCT02986178.

**8. Conclusions**

**Conflict of interest**

*DOI: http://dx.doi.org/10.5772/intechopen.80047*

among the patients who received PVSRIPO reached a plateau of 21% (95% confidence interval, 11–33) at 24 months that was sustained at 36 months. For glioma grade IV with standard treatment, there is no plateau. A phase II study in this

Glioma treatment is still a challenge, and its quality is related to integrated team,

in which the systemic treatment must be based on awareness of drug limitation

Thanks for those colleagues who based on their professionalism, dedication, future vision, engagement, and commitment have been an example to be followed and have made this task easier, as well as to brain tumor patients and their families,

usage and keeping in mind strategies to overcome these issues.

The author declares no conflict of interests.

**Notes/thanks/other declarations**

for whom all the efforts are being made.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Curitiba's Neurologic Institute (INC), Parana's Oncology Institute (IOP), Curitiba,

2 Brazilian Society of Clinical Oncology, American Society of Clinical Oncology,

among the patients who received PVSRIPO reached a plateau of 21% (95% confidence interval, 11–33) at 24 months that was sustained at 36 months. For glioma grade IV with standard treatment, there is no plateau. A phase II study in this setting is ongoing NCT02986178.

### **8. Conclusions**

*Primary Intracranial Tumors*

for the final data.

**7.3 CAR T cells**

both in brain and meninx lesions.

**7.4 Cancer-targeting oncolytic viruses**

**7.2 Checkpoint inhibitors**

The final results are not yet available, because they are still unblinded, until the sufficient events have occurred to elucidate the final curves. Despite being an interim analysis, it has been shown 23.4 months of medium OS (mOS), as the intention-totreat (ITT) population is similar, and it was allowed to crossover. So, we have to wait

Another promising area is immunotherapy with checkpoint inhibitors, although a recent trial failed to demonstrate survival benefit. The CheckMate 143 was the first randomized phase III clinical trial in GBM with a PD-1 checkpoint inhibitor. In nivolumab alone vs. bevacizumab alone in recurrent GBM, 369 patients were randomized to the nivolumab (n = 184) or bevacizumab (n = 185), resulting in a median OS of 9.8 months with nivolumab and 10 months with bevacizumab, and the 12-month OS rate was 42% in both arms. Despite having failed to demonstrate advantage, in a specific scenario, in patients with biallelic mismatch repair deficiency (bMMRD), it can benefit from checkpoint inhibitor treatment [69]. This might be explained by a high mutational burden in bMMRD. In other considerations, CheckMate 143 failure involves an inability of nivolumab to reach tumor-infiltrating lymphocytes (TILs) already sequestered in the recurrent tumor microenvironment; it may be expected to function better in patients with newly diagnosed GBM, where newly activated circulating T cells would be available for interaction with nivolumab prior to their migration to tumor sites. So, further investigation is required to set PD-1 checkpoint in glioma treatment [70, 71].

Tumor immunotherapy with T lymphocytes, which can recognize and destroy

At glioma setting, CAR T-cell therapy has been tested, in recurrent GBM utilizing CAR T-cell GBM-associated antigen IL13Ra2 that utilizes CD62L-enriched central memory T cells (Tcm) engineered by lentiviral transduction to express [73]. Second-generation 4-1BB-containing CAR (IL13BBZ) signaling domain was utilized by both intratumoral and intraventricular deliveries, with multiple doses via reservoir. Safely and well tolerated, some dramatic responses were observed,

Further efforts have been made to improve results of this therapy [74–76].

Cancer virotherapy mediated by oncolytic viruses (OV) has emerged as a novel and effective strategy in cancer therapeutics [77]. Desjardins [78] in a dose-finding and toxicity phase I study evaluated an intratumoral delivery of the recombinant nonpathogenic poliovirus-rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment. Overall survival

malignant cells, has been limited by the ability to isolate and expand T cells restricted to tumor-associated antigens. Chimeric antigen receptors (CARs) composed of antibody-binding domains connected to domains that activate T cells could overcome tolerance by allowing T cells to respond to cell surface antigens; however, to date, lymphocytes engineered to express CARs have demonstrated minimal in vivo expansion and antitumor effects in clinical trials [72]. The very begging publications related to CAR T-cell therapy were related to a relapsed and refractory acute lymphoblastic leukemia, which made this technology known.

**106**

Glioma treatment is still a challenge, and its quality is related to integrated team, in which the systemic treatment must be based on awareness of drug limitation usage and keeping in mind strategies to overcome these issues.

### **Conflict of interest**

The author declares no conflict of interests.

#### **Notes/thanks/other declarations**

Thanks for those colleagues who based on their professionalism, dedication, future vision, engagement, and commitment have been an example to be followed and have made this task easier, as well as to brain tumor patients and their families, for whom all the efforts are being made.

### **Author details**

Johnny Camargo1,2\*

1 Curitiba's Neurologic Institute (INC), Parana's Oncology Institute (IOP), Curitiba, Brazil

2 Brazilian Society of Clinical Oncology, American Society of Clinical Oncology, Brazil

\*Address all correspondence to: jfccamargo@gmail.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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2011;**132**(1):39-48

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[21] Atai AN et al. Osteopontin is up-regulated and associated with neutrophil and macrophage infiltration

in glioblastoma. Immunology.

[22] Chen Z, Hambardzumyan D. Immune microenvironment in glioblastoma subtypes. Frontiers in

[23] Reardon DA, Wen PY. Unravelling tumour heterogeneity—Implications for therapy. Nature Reviews. Clinical

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[25] Komori T. The 2016 WHO

classification of tumours of the central nervous system: The major points of revision. Neurologia Medico-Chirurgica (Tokyo). 2017;**57**(7):

[26] Hai Yan D et al. IDH1 and IDH2 mutations in gliomas. The New England Journal of Medicine. 2009;**360**:765-773

dehydrogenase mutations in gliomas:

therapeutic target. Current Opinion in

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Mechanisms, biomarkers and

Neurology. 2011;**24**(6):648-652

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[18] Aum DJ et al. Molecular and cellular heterogeneity: The hallmark of glioblastoma. Neurosurgical Focus. 2014;**37**(6):E11

[19] Patel AP et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;**344**(6190):1396-1401

[20] Watters JJ, Schartner JM, Behnam B. Microglia function in brain tumors. Journal of Neuroscience Research. 2005;**81**(3):447-455

[21] Atai AN et al. Osteopontin is up-regulated and associated with neutrophil and macrophage infiltration in glioblastoma. Immunology. 2011;**132**(1):39-48

[22] Chen Z, Hambardzumyan D. Immune microenvironment in glioblastoma subtypes. Frontiers in Immunology. 2018;**9**:1004

[23] Reardon DA, Wen PY. Unravelling tumour heterogeneity—Implications for therapy. Nature Reviews. Clinical Oncology. 2015;**12**:69

[24] Louis DN et al. The 2016 world health organization classification of tumors of the central nervous system: A summary. Acta Neuropathologica. 2016;**131**(6):803-820

[25] Komori T. The 2016 WHO classification of tumours of the central nervous system: The major points of revision. Neurologia Medico-Chirurgica (Tokyo). 2017;**57**(7): 301-311

[26] Hai Yan D et al. IDH1 and IDH2 mutations in gliomas. The New England Journal of Medicine. 2009;**360**:765-773

[27] Guo C et al. Isocitrate dehydrogenase mutations in gliomas: Mechanisms, biomarkers and therapeutic target. Current Opinion in Neurology. 2011;**24**(6):648-652

[28] van Thuijl HF et al. Genetics and pharmacogenomics of diffuse gliomas. Pharmacology & Therapeutics. 2013;**137**(1):78-88

[29] van den Bent MJ et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: Long-term follow-up of EORTC brain tumor group study 26951. Journal of Clinical Oncology. 2013;**31**(3):344-350

[30] Eckel-Passow JE et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. The New England Journal of Medicine. 2015;**372**(26):2499-2508

[31] Cankovic M et al. The role of *MGMT* testing in clinical practice. The Journal of Molecular Diagnostics. 2013;**15**(5):539-555

[32] Wick W et al. Prognostic or predictive value of *MGMT* promoter methylation in gliomas depends on *IDH1* mutation. Neurology. 2013;**81**(17):1515-1522

[33] Killela PJ et al. Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas. Öncotarget. 2014;**5**(6):1515-1565

[34] The Cancer Genome Atlas Research, N. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. The New England Journal of Medicine. 2015;**372**(26):2481-2498

[35] Diplas BH et al. The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma. Nature Communications. 2018;**9**(1):2087

[36] Haase S et al. Mutant ATRX: Uncovering a new therapeutic target for glioma. Expert Opinion on Therapeutic Targets. 2018;**22**(7):599-613

**108**

*Primary Intracranial Tumors*

**References**

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bevacizumab plus daily temozolomide

as the salvage therapy. Clinical Neurology and Neurosurgery.

[10] Winkler F, Osswald M, Wick W. Anti-angiogenics: Their role in the treatment of glioblastoma. Oncology Research and Treatment.

[11] Keaney J, Campbell M. The dynamic blood-brain barrier. The FEBS Journal.

[12] Nakagawa S et al. Pericytes from brain microvessels strengthen the barrier integrity in primary cultures of rat brain endothelial cells. Cellular

[13] Placone AL et al. Human astrocytes develop physiological morphology and remain quiescent in a novel 3D matrix.

and Molecular Neurobiology.

Biomaterials. 2015;**42**:134-143

mouse models in cancer drug development. Nature Reviews. Drug

Discovery. 2006;**5**(9):741-754

[16] Connolly NP et al. Crossspecies transcriptional analysis reveals conserved and hostspecific neoplastic processes in

2018;**8**:1180

[14] Sharpless NE, Depinho RA. The mighty mouse: Genetically engineered

[15] Huse JT, Holland EC. Genetically engineered mouse models of brain cancer and the promise of preclinical testing. Brain Pathology (Zurich, Switzerland). 2009;**19**(1):132-143

mammalian glioma. Scientific Reports.

[17] Gerlinger M et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. New England Journal of Medicine.

2012;**366**(10):883-892

2007;**27**:687-694

2018;**169**:64-70

2018;**41**(4):181-186

2015;**282**(21):4067-4079

[2] Stupp R et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England Journal of Medicine.

[3] Olson JD, Riedel E, DeAngelis LM. Long-term outcome of low-grade oligodendroglioma and mixed glioma. Neurology. 2000;**54**(7):1442-1448

Physics. 2009;**75**(5):1401-1407

factors correlate with delay in radiotherapy initiation and worse overall survival. Journal of Radiation Research. 2018;**59**(suppl\_1):i11-i18

[6] Yung WK. Temozolomide in malignant gliomas. Seminars in Oncology. 2000;**27**(3 Suppl 6):27-34

[7] Friedman HS, Kerby T, Calvert H. Temozolomide and treatment of malignant glioma. Clinical Cancer Research. 2000;**6**(7):2585-2597

2017;**390**(10103):1645-1653

[9] Liu Y et al. Improvement of health related quality of life in patients with recurrent glioma treated with

[8] van den Bent MJ et al. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: A phase 3, randomised, openlabel intergroup study. The Lancet.

[5] Pollom EL et al. Newly diagnosed glioblastoma: Adverse socioeconomic

[4] Bauman G et al. Adult supratentorial low-grade glioma: Long-term experience at a single institution. International Journal of Radiation Oncology, Biology,

2005;**352**(10):987-996

[37] Kondo T. Molecular mechanisms involved in gliomagenesis. Brain Tumor Pathology. 2017;**34**(1):1-7

[38] Lin T et al. The expression of p53, mgmt and egfr in brain glioma and clinical significance. Journal of Biological Regulators and Homeostatic Agents. 2015;**29**(1):143-149

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[49] Trifiletti DM et al. Prognostic implications of extent of resection in glioblastoma: Analysis from a large database. World Neurosurgery. 2017;**103**:330-340

[50] Ramina R et al. Optimizing costs of intraoperative magnetic resonance imaging. A series of 29 glioma cases. Acta Neurochirurgica. 2010;**152**(1):27-33

[51] Dubbink HJ et al. Molecular classification of anaplastic oligodendroglioma using nextgeneration sequencing: A report of the prospective randomized EORTC brain tumor group 26951 phase III trial. Neuro-Oncology. 2016;**18**(3):388-400

[52] Cairncross G et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: Long-term results of RTOG 9402. Journal of Clinical Oncology. 2013;**31**(3):337-343

[53] Shin JY, Diaz AZ. Anaplastic astrocytoma: Prognostic factors and survival in 4807 patients with emphasis

**111**

*The Systemic Treatment of Glioma*

2016;**129**(3):557-565

2015;**124**(2):197-205

2009;**10**(5):459-466

2013;(4):Cd007415

[56] Hart MG et al. Temozolomide for high grade glioma. Cochrane Database of Systematic Reviews.

[57] Stupp R et al. Maintenance therapy

temozolomide vs. temozolomide alone for glioblastoma: A randomized clinical trial. JAMA. 2015;**314**(23):2535-2543

with tumor-treating fields plus

[58] Magouliotis DE et al. Tumortreating fields as a fourth treating modality for glioblastoma: A metaanalysis. Acta Neurochirurgica.

[59] Onken J et al. Acceptance and compliance of TTFields treatment among high grade glioma patients. Journal of Neuro-Oncology.

[60] Glas M et al. Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. Journal of Clinical Oncology. 2009;**27**(8):1257-1261

[61] Herrlinger U et al. Phase III trial of CCNU/temozolomide (TMZ) combination therapy vs. standard TMZ therapy for newly diagnosed MGMTmethylated glioblastoma patients: The

2018;**160**(6):1167-1174

2018;**139**(1):177-184

[54] Juratli TA et al. Radio-

[55] Stupp R et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet Oncology.

on receipt and impact of adjuvant therapy. Journal of Neuro-Oncology.

chemotherapy improves survival in IDH-mutant, 1p/19q non-codeleted secondary high-grade astrocytoma patients. Journal of Neuro-Oncology.

*DOI: http://dx.doi.org/10.5772/intechopen.80047*

CeTeg/NOA-09 trial. Neuro-Oncology.

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[63] Drake CG, Lipson EJ, Brahmer

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2017;**19**(suppl\_6):vi13-vi14

JR. Breathing new life into

2016;**372**(4):320-330

2017;**18**(10):1373-1385

Oncology. 2016;**5**(1):11-26

2001;**40**(2):105-123

*The Systemic Treatment of Glioma DOI: http://dx.doi.org/10.5772/intechopen.80047*

on receipt and impact of adjuvant therapy. Journal of Neuro-Oncology. 2016;**129**(3):557-565

*Primary Intracranial Tumors*

Pathology. 2017;**34**(1):1-7

Agents. 2015;**29**(1):143-149

2015;**125**(3):503-530

[41] McGirt MJ et al. Extent of surgical resection is independently associated with survival in patients with hemispheric infiltrating low-grade gliomas. Neurosurgery. 2008;**63**(4):700-707; author reply 707-8

[42] Zetterling M et al. Prognostic markers for survival in patients with oligodendroglial tumors; a singleinstitution review of 214 cases. PLoS

One. 2017;**12**(11):e0188419

2015;**125**(3):551-583

lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: Initial results of RTOG 9802. Journal of Clinical Oncology. 2012;**30**(25):3065-3070

[45] Buckner JC et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. The

[43] Ryken TC et al. The role of radiotherapy in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline. Journal of Neuro-Oncology.

[44] Shaw EG et al. Randomized trial of radiation therapy plus procarbazine,

[37] Kondo T. Molecular mechanisms involved in gliomagenesis. Brain Tumor New England Journal of Medicine.

[46] Fisher BJ et al. Phase 2 study of temozolomide-based chemoradiation therapy for high-risk low-grade gliomas: Preliminary results of radiation therapy oncology group 0424. International Journal of Radiation Oncology, Biology,

2016;**374**(14):1344-1355

Physics. 2015;**91**(3):497-504

2016;**2**(11):1460-1469

2006;**7**(5):392-401

2017;**103**:330-340

2010;**152**(1):27-33

[47] Brown TJ et al. Association of the extent of resection with survival in glioblastoma: A systematic review and meta-analysis. JAMA Oncology.

[48] Stummer W et al. Fluorescenceguided surgery with 5-aminolevulinic acid for resection of malignant glioma: A randomised controlled multicentre phase III trial. The Lancet Oncology.

[49] Trifiletti DM et al. Prognostic implications of extent of resection in glioblastoma: Analysis from a large database. World Neurosurgery.

[50] Ramina R et al. Optimizing costs of intraoperative magnetic resonance imaging. A series of 29 glioma cases. Acta Neurochirurgica.

[51] Dubbink HJ et al. Molecular classification of anaplastic oligodendroglioma using nextgeneration sequencing: A report of the prospective randomized EORTC brain tumor group 26951 phase III trial. Neuro-Oncology. 2016;**18**(3):388-400

[52] Cairncross G et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: Long-term results of RTOG 9402. Journal of Clinical Oncology. 2013;**31**(3):337-343

[53] Shin JY, Diaz AZ. Anaplastic astrocytoma: Prognostic factors and survival in 4807 patients with emphasis

[38] Lin T et al. The expression of p53, mgmt and egfr in brain glioma and clinical significance. Journal of Biological Regulators and Homeostatic

[39] Louis DN et al. WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon: IARC; 2016

[40] Aghi MK et al. The role of surgery in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline. Journal of Neuro-Oncology.

**110**

[54] Juratli TA et al. Radiochemotherapy improves survival in IDH-mutant, 1p/19q non-codeleted secondary high-grade astrocytoma patients. Journal of Neuro-Oncology. 2015;**124**(2):197-205

[55] Stupp R et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet Oncology. 2009;**10**(5):459-466

[56] Hart MG et al. Temozolomide for high grade glioma. Cochrane Database of Systematic Reviews. 2013;(4):Cd007415

[57] Stupp R et al. Maintenance therapy with tumor-treating fields plus temozolomide vs. temozolomide alone for glioblastoma: A randomized clinical trial. JAMA. 2015;**314**(23):2535-2543

[58] Magouliotis DE et al. Tumortreating fields as a fourth treating modality for glioblastoma: A metaanalysis. Acta Neurochirurgica. 2018;**160**(6):1167-1174

[59] Onken J et al. Acceptance and compliance of TTFields treatment among high grade glioma patients. Journal of Neuro-Oncology. 2018;**139**(1):177-184

[60] Glas M et al. Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. Journal of Clinical Oncology. 2009;**27**(8):1257-1261

[61] Herrlinger U et al. Phase III trial of CCNU/temozolomide (TMZ) combination therapy vs. standard TMZ therapy for newly diagnosed MGMTmethylated glioblastoma patients: The

CeTeg/NOA-09 trial. Neuro-Oncology. 2017;**19**(suppl\_6):vi13-vi14

[62] Escors D. Tumour immunogenicity, antigen presentation and immunological barriers in cancer immunotherapy. New Journal of Science. 2014;**2014**:1-25

[63] Drake CG, Lipson EJ, Brahmer JR. Breathing new life into immunotherapy: Review of melanoma, lung and kidney cancer. Nature Reviews. Clinical Oncology. 2013;**11**(1):24-37

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[65] Zussman BM, Engh JA. Outcomes of the ACT III study: Rindopepimut (CDX-110) therapy for glioblastoma. Neurosurgery. 2015;**76**(6):N17

[66] Weller M et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIIIexpressing glioblastoma (ACT IV): A randomised, double-blind, international phase 3 trial. The Lancet Oncology. 2017;**18**(10):1373-1385

[67] Gatson NT, Weathers SP, de Groot JF. ReACT phase II trial: A critical evaluation of the use of rindopepimut plus bevacizumab to treat EGFRvIIIpositive recurrent glioblastoma. CNS Oncology. 2016;**5**(1):11-26

[68] Emerich DF, Rl D, Osborn C, Bartus RT. The development of the bradykinin agonist labradimil as a means to increase the permeability of the blood-brain barrier: From concept to clinical evaluation. Clinical Pharmacokinetics. 2001;**40**(2):105-123

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**113**

**Chapter 8**

**Abstract**

radiosurgery

**1. Introduction**

temozolomide and radiation.

over the delineations of tumor volume.

radiation in the salvage scenario.

Grade Glioma

*Henrique Balloni*

Role of Radiotherapy in High

improved outcomes while at the same time limiting toxicity.

**Keywords:** glioblastoma, radiotherapy, target volume, hypofractionated,

The benefit of radiation therapy in patients with newly diagnosed glioblastoma has been demonstrated in many randomized trials and has been the basis of treatment for decades. To make an effort to achieve and improve the very poor outcomes associated with this disease, numerous therapeutics have been added to radiation though with lack of success until the landmark study by Stupp et al. [1] established a standard of care of treatment, gross surgical excision followed by concurrent

The use of radiation in glioblastoma is constantly evolving as a result of advances in imaging methods and personalized medicine leading to continuous controversies

Multiple recent studies on personalized medicine, especially in elderly patients with glioblastoma suggest that the role and dose/fractionation of radiation delivery to this increasing population will continue to develop. This chapter will highlight the major historical studies that have resulted in radiation being the current standard of care; discuss the continuing controversies of volume delineation in radiation delivery planning; discuss dose evolution and fractionation of radiotherapy in the management of patients; and review studies and ongoing trials on the use of

The aim of this review is to explore the changing utility of radiotherapy in the treatment of patients with glioblastoma over the past decades. Surgery and radiotherapy has always been the cornerstone of treatment of glioblastoma, but techniques have significantly advanced over this time. We selected the main studies that support the advances of radiotherapy in the present day as well as controversies in several aspects of the treatment will be approached; definition of the target volume in the magnetic resonance imaging (MRI) planning, size of the margins around the target volume; prescribed dose (satnadard vs. hypofactionated); management of glioblastoma in elderly; review role of radiosurgery past and new potential use in recurrence and the evidence of reirradiation in patients with local recurrence. Finally, continued development on many fronts have allowed for modestly

#### **Chapter 8**

*Primary Intracranial Tumors*

[70] Filley AC, Henriquez M, Dey M. Recurrent glioma clinical trial, CheckMate-143: The game is not over yet. Oncotarget. 2017;**8**(53):91779-91794

[71] Mirzaei R, Sarkar S, Yong VW. T cell exhaustion in glioblastoma: Intricacies of immune checkpoints. Trends in Immunology. 2017;**38**(2):104-115

[72] Maude SL et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. The New England Journal of Medicine. 2014;**371**(16):1507-1517

[73] Brown CE et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. The New England Journal of Medicine. 2016;**375**(26):2561-2569

[74] Harris M et al. Emerging patents in the therapeutic areas of glioma and glioblastoma. Expert Opinion on Therapeutic Patents. 2018;**28**(7):573-590

[75] Sahin A et al. Development of third generation anti-EGFRvIII chimeric T cells and EGFRvIII-expressing artificial antigen presenting cells for adoptive cell therapy for glioma. PLoS One.

2018;**13**(7):e0199414

2018;**3**(10)

[76] Wang D et al. Glioblastomatargeted CD4+ CAR T cells mediate superior antitumor activity. JCI Insight.

[77] Lin CZ et al. Advances in the mechanisms of action of cancertargeting oncolytic viruses. Oncology

Letters. 2018;**15**(4):4053-4060

Medicine. 2018;**379**:150-161

[78] Desjardins A et al. Recurrent glioblastoma treated with recombinant poliovirus. The New England Journal of

**112**

## Role of Radiotherapy in High Grade Glioma

*Henrique Balloni*

#### **Abstract**

The aim of this review is to explore the changing utility of radiotherapy in the treatment of patients with glioblastoma over the past decades. Surgery and radiotherapy has always been the cornerstone of treatment of glioblastoma, but techniques have significantly advanced over this time. We selected the main studies that support the advances of radiotherapy in the present day as well as controversies in several aspects of the treatment will be approached; definition of the target volume in the magnetic resonance imaging (MRI) planning, size of the margins around the target volume; prescribed dose (satnadard vs. hypofactionated); management of glioblastoma in elderly; review role of radiosurgery past and new potential use in recurrence and the evidence of reirradiation in patients with local recurrence. Finally, continued development on many fronts have allowed for modestly improved outcomes while at the same time limiting toxicity.

**Keywords:** glioblastoma, radiotherapy, target volume, hypofractionated, radiosurgery

#### **1. Introduction**

The benefit of radiation therapy in patients with newly diagnosed glioblastoma has been demonstrated in many randomized trials and has been the basis of treatment for decades. To make an effort to achieve and improve the very poor outcomes associated with this disease, numerous therapeutics have been added to radiation though with lack of success until the landmark study by Stupp et al. [1] established a standard of care of treatment, gross surgical excision followed by concurrent temozolomide and radiation.

The use of radiation in glioblastoma is constantly evolving as a result of advances in imaging methods and personalized medicine leading to continuous controversies over the delineations of tumor volume.

Multiple recent studies on personalized medicine, especially in elderly patients with glioblastoma suggest that the role and dose/fractionation of radiation delivery to this increasing population will continue to develop. This chapter will highlight the major historical studies that have resulted in radiation being the current standard of care; discuss the continuing controversies of volume delineation in radiation delivery planning; discuss dose evolution and fractionation of radiotherapy in the management of patients; and review studies and ongoing trials on the use of radiation in the salvage scenario.

#### **2. Radiotherapy target volume definitions**

In the 1970s, a randomized trial showed that 60 Gy of postoperative whole-brain RT (WBRT) could improve the survival for patients with high-grade glioma (HGG). Since then, postoperative RT was a standard treatment for newly diagnosed HGG. [2] However, other studies started to compare WBRT with partial-brain irradiation and concluded that there was no advantage of WBRT [3]. Tomography (CT) and magnetic resonance imaging (MRI) has contributed largely to improve the accuracy of tumor delineation and establish that partial-brain irradiation standard to treat HGG [4]. The three-dimensional (3D) conformal radiation technique makes partial-brain irradiation for glioma possible and reduces neurotoxicity [5]. The image fusion pre- and postoperative MRI with planning CT images is normally used to determine the RT treatment volume for GBM. However, the optimal treatment volume for GBM remains a controversial issue and varies among different institutions. The Radiation Therapy Oncology Group (RTOG) refers to a two-phase treatment at 60 Gy, where the initial clinical target volume (CTV) typically includes postoperative peritumoral edema plus a 2 cm margin, followed by a boost field defined as the residual tumor plus a 2 cm margin (as per RTOG 0525 and RTOG 0825 trials) [6]. Inversely, the European Organization for Research and Treatment of Cancer (EORTC) defines a single-phase treatment with 2–3 cm dosimetric margins around the tumor (as evaluated by MRI), because 80–90% of treatment failures occur within this margin [1]. The University of Texas MD Anderson Cancer Center uses a 2 cm margin around the gross tumor volume (GTV), which consists of the resection cavity and any residual contrast-enhancing tumor without regard to edema [7]. However, several studies have raised the hypothesis that the results are similar when using reduced margins as small as 5 mm to delineate the CTV in the treatment of GBM [8].

In daily clinical practice between different institutions, the margins of the planned target volume vary significantly. A survey of radiation oncologists in Canada showed that 32 and 14% followed the RTOG and EORTC guidelines, respectively, while 54% followed the center's specific guidelines. Biphasic treatments were reported by 37% and single-phase by 60% of clinicians. For clinicians treating in single phase, 61% treat the surgical cavity and enhancing tumor with a margin, and 33% treat an area that includes tumor edema in addition to the surgical cavity and enhancing tumor. The GTV margins to generate the planning treatment volume (PTV) also varied widely and included 0.5 cm (6%), 1 cm (6%), 1.5 cm (25%), 2 cm (56%), 2.5 cm (25%), and 3 cm (12.5%). For clinicians treating in multiple phases, 90% include peritumoral edema in Phase I of the treatment. In Phase II, respondents reported using total margins (from GTV to PTV) of 1 cm (10%), 2 cm (40%), 2.5 cm (30%), and 3 cm (20%) [9]. Examples of differences in guidelines are shown (**Table 1** and **Figures 1** and **2**).

#### **2.1 Peritumoral edema**

It is discussed regarding the inclusion of edema in the treatment plan. The rationale for including peritumoral edema is that such areas are believed to contain high concentrations of tumor cells. A study compared the histopathologic distributions of neoplastic cells in GBM with the corresponding CT images and found that the vast majority of the neoplastic tissue was contained within the contrastenhancing and low-density peritumoral areas; however, the CT low-density area was not always identical to the area infiltrated by tumor cells. No tumor cells were found in some areas of low density, whereas, in some instances, normal appearing brain tissue beyond the CT low-density area was also found to contain tumor cells [10]. Furthermore, Halperin et al. [11] compared preoperative CT scans with the postmortem topography of recurrent tumors and found that 9/11 (81.8%) tumor cells were found beyond the enhancement area plus a 1 cm margin on CT. Indeed,

**115**

**Figure 1.**

*colors lines different protocol volumes.*

**Table 1.**

only treatment plans that covered the contrast-enhancing tumor, the "edema" volume, plus an additional 3 cm margin would cover the entire histologically identified tumor. Kelly et al. [12] also reported on the correlation between histopathologic and MRI findings for 177 biopsy specimens from 39 patients with glial neoplasms. Pathologic evaluation of biopsy specimens obtained from various locations in the volumes defined by CT and MRI showed that contrast enhancement most

*Example planning treatment volumes (PTV) delineation of high grade. MRI T1 contrast enhanced showing in* 

*The definition of radiation treatment volumes during the delineation of high-grade gliomas.*

*Role of Radiotherapy in High Grade Glioma DOI: http://dx.doi.org/10.5772/intechopen.80923*


**Table 1.**

*Primary Intracranial Tumors*

**2. Radiotherapy target volume definitions**

In the 1970s, a randomized trial showed that 60 Gy of postoperative whole-brain RT (WBRT) could improve the survival for patients with high-grade glioma (HGG). Since then, postoperative RT was a standard treatment for newly diagnosed HGG. [2] However, other studies started to compare WBRT with partial-brain irradiation and concluded that there was no advantage of WBRT [3]. Tomography (CT) and magnetic resonance imaging (MRI) has contributed largely to improve the accuracy of tumor delineation and establish that partial-brain irradiation standard to treat HGG [4]. The three-dimensional (3D) conformal radiation technique makes partial-brain irradiation for glioma possible and reduces neurotoxicity [5]. The image fusion pre- and postoperative MRI with planning CT images is normally used to determine the RT treatment volume for GBM. However, the optimal treatment volume for GBM remains a controversial issue and varies among different institutions. The Radiation Therapy Oncology Group (RTOG) refers to a two-phase treatment at 60 Gy, where the initial clinical target volume (CTV) typically includes postoperative peritumoral edema plus a 2 cm margin, followed by a boost field defined as the residual tumor plus a 2 cm margin (as per RTOG 0525 and RTOG 0825 trials) [6]. Inversely, the European Organization for Research and Treatment of Cancer (EORTC) defines a single-phase treatment with 2–3 cm dosimetric margins around the tumor (as evaluated by MRI), because 80–90% of treatment failures occur within this margin [1]. The University of Texas MD Anderson Cancer Center uses a 2 cm margin around the gross tumor volume (GTV), which consists of the resection cavity and any residual contrast-enhancing tumor without regard to edema [7]. However, several studies have raised the hypothesis that the results are similar when using reduced

margins as small as 5 mm to delineate the CTV in the treatment of GBM [8].

In daily clinical practice between different institutions, the margins of the planned target volume vary significantly. A survey of radiation oncologists in Canada showed that 32 and 14% followed the RTOG and EORTC guidelines, respectively, while 54% followed the center's specific guidelines. Biphasic treatments were reported by 37% and single-phase by 60% of clinicians. For clinicians treating in single phase, 61% treat the surgical cavity and enhancing tumor with a margin, and 33% treat an area that includes tumor edema in addition to the surgical cavity and enhancing tumor. The GTV margins to generate the planning treatment volume (PTV) also varied widely and included 0.5 cm (6%), 1 cm (6%), 1.5 cm (25%), 2 cm (56%), 2.5 cm (25%), and 3 cm (12.5%). For clinicians treating in multiple phases, 90% include peritumoral edema in Phase I of the treatment. In Phase II, respondents reported using total margins (from GTV to PTV) of 1 cm (10%), 2 cm (40%), 2.5 cm (30%), and 3 cm (20%) [9]. Examples of differences in guidelines are shown (**Table 1** and **Figures 1** and **2**).

It is discussed regarding the inclusion of edema in the treatment plan. The rationale for including peritumoral edema is that such areas are believed to contain high concentrations of tumor cells. A study compared the histopathologic distributions of neoplastic cells in GBM with the corresponding CT images and found that the vast majority of the neoplastic tissue was contained within the contrastenhancing and low-density peritumoral areas; however, the CT low-density area was not always identical to the area infiltrated by tumor cells. No tumor cells were found in some areas of low density, whereas, in some instances, normal appearing brain tissue beyond the CT low-density area was also found to contain tumor cells [10]. Furthermore, Halperin et al. [11] compared preoperative CT scans with the postmortem topography of recurrent tumors and found that 9/11 (81.8%) tumor cells were found beyond the enhancement area plus a 1 cm margin on CT. Indeed,

**114**

**2.1 Peritumoral edema**

*The definition of radiation treatment volumes during the delineation of high-grade gliomas.*

#### **Figure 1.**

*Example planning treatment volumes (PTV) delineation of high grade. MRI T1 contrast enhanced showing in colors lines different protocol volumes.*

only treatment plans that covered the contrast-enhancing tumor, the "edema" volume, plus an additional 3 cm margin would cover the entire histologically identified tumor. Kelly et al. [12] also reported on the correlation between histopathologic and MRI findings for 177 biopsy specimens from 39 patients with glial neoplasms. Pathologic evaluation of biopsy specimens obtained from various locations in the volumes defined by CT and MRI showed that contrast enhancement most

#### **Figure 2.**

*Example planning treatment volumes (PTV) delineation of high grade. MRI T2 showing in colors lines different protocols volumes*

often corresponded to tumor tissue without intervening parenchyma, whereas hypodensity corresponded to parenchyma infiltrated by isolated tumor cells or, in some instances, in low-HGGs, to tumor tissue or to edema. For the normal T1- and T2-weighted MRI regions that were biopsied, there was a false-negative rate of 69 and 40%, respectively [13]. A study conducted by Lu et al. [13] analyzed peritumoral edema using diffusion tensor MR imaging. This group divided gliomas associated with peritumoral edema into tumor-infiltrated edema and purely vasogenic edema.

It is controversial the prognostic of peritumoral edema. Some authors considered peritumoral edema on a preoperative MRI to be an independent prognostic factor, in addition to the postoperative Karnofsky performance score (KPS), age, and type of tumor resection [14]. Patients with major edema (>1 cm) had a significant shorter overall survival (OS) time, compared to patients with minor edema (<1 cm). Another study established that peritumoral edema, noncontrast-enhancing tumor, satellites, and multifocality were independent prognostic factors for survival in GBM, whereas preoperative tumor size, tumor location, and extent of necrosis had no significant impact on survival [15]. Conversely, there was no correlation between peritumoral edema, patient age, and tumor volume, but there was an association between edema, tumor location, and necrosis [16]. Similarly, Ramakrishna et al. [17] analyzed the predictive value of abnormal MRI features for the survival of patients with GBM. The result demonstrated that tumor burden and invasion characteristics indicated by the T1-weighted gadolinium-enhanced MRI were significant predictors of patient survival, but the total area of signal intensity abnormalities on the T2-weighted images and the T2/T1 ratio did not correlate with patient outcome.

In summary, for patients with GBM, the significance of peritumoral edema for the survival of a patient with GBM is not clear. A majority of tumor tissues are contained

**117**

*Role of Radiotherapy in High Grade Glioma DOI: http://dx.doi.org/10.5772/intechopen.80923*

**2.2 Recurrent patterns of postoperative GBM**

within the contrast enhancement areas in T1-weighted MRI, but not always, and infiltrate into the peritumoral edema area. We believe that GTV in HGG for RT should be focus in T1-weighted MRI and surgical bed, regarding the peritumoral edema area. In addition, the ability to accurately distinguish tumor-infiltrated edema from vasogenic edema composed purely of extracellular water could be helpful for target delineation.

Several studies have studied the pattern of relapse in patients with glioblastoma. One of them [18] retrospectively analyzed the patterns of radiographic presentation of 80 adult patients with supratentorial GBM at four clinically relevant time points: presentation, first recurrence, second recurrence, and third recurrence. At diagnosis, 87.5% (70/80), 6.25% (5/80), 3.75%, and 2.5% of patients presented with unifocal disease and distant, multifocal, and diffuse MRI-defined radiographic patterns, respectively. After RT and temozolamide treatment local recurrence occurs in 80%, distant in 7,5% and multifocal in 6,25% (including one with cerebrospinal fluid dissemination), and 6.25% was diffuse. In the same way, Wallner et al. [19] found that 78% of unifocal anaplastic astrocytoma and GBM recurrences occurred within 2 cm of the presurgical original tumor extent, which is defined as the enhancing edge of the tumor on preoperative CT, and 56% (18/32) of tumors recurred within 1 cm of the initial tumor margin. Liang et al. [20] published the pattern of failure for 42 patients with grade III or IV astrocytoma treated with chemoradiotherapy to a total of 60 Gy. In all 42 patients, recurrence occurred within a 2 cm margin of the original CT-enhancing lesion, and 10% of the patients suffered from multifocal recurrence. In a retrospective series of 34 patients treated either with WBRT and conformal boost or entirely with 3D conformal RT, Oppitz et al. [21] revealed that all GBM recurrences occurred within the 90% isodose line when targets were contoured around the original preoperative contrast-enhancing tumor plus a 2 cm margin. More than 80% of the recurrences occur in 2 cm of the surgical bed doseescalation studies analyzed 36 patients with HGGs treated with radiation alone to 70–80 Gy using the 3D conformal techniques [22]. In this study, recurrences were divided into several categories: (1) "central," in which 95% or more of the recurrent tumor volume (Vrecur) was within D95, the region treated to a high dose (95% of the prescription dose); (2) "infield," in which 80% or more of V recur was within the D95 isodose surface; (3) "marginal," when between 20 and 80% of Vrecur was inside the D95 surface; and (4) "outwith," in which <20% of Vrecur was inside the D95 surface. This study found that 89% of the recurrences were central or infield, 3/36 (8%) had a marginal recurrence pattern, and only one patient (3%) clearly failed outside of the high-dose region. Another trial [7] reported similar patterns of failure in a series of 48 patients with GBM, comparing treatment guidelines based on residual tumor and cavity plus 2 cm margin, as used at the MD Anderson Cancer Center, with RTOG guidelines that specified the inclusion of preoperative peritumoral edema. They showed that 90% (43/48) of patients failed in central and infield locations. The five remaining marginal and distal recurrences failed to be covered by the 46 Gy isodose line, even when overlaid by the RTOG plan incorporating edema volume, confirming them to be true marginal recurrences. Additionally, Minniti et al. [23] compared recurrence patterns in 105 patients whose surgical resections were delineated by the EORTC contouring technique, wherein the CTV includes the resection cavity, and any residual tumor seen on postoperative T1-weighted MRI, plus a 2 cm margin, and the PTV includes the CTV plus an additional 3 mm margin. After recurrence was confirmed, a theoretical plan, based on the addition of postoperative edema plus 2 cm margins, according to the current

It is hoped that advances in image techniques will enable this in the future.

*Primary Intracranial Tumors*

often corresponded to tumor tissue without intervening parenchyma, whereas hypodensity corresponded to parenchyma infiltrated by isolated tumor cells or, in some instances, in low-HGGs, to tumor tissue or to edema. For the normal T1- and T2-weighted MRI regions that were biopsied, there was a false-negative rate of 69 and 40%, respectively [13]. A study conducted by Lu et al. [13] analyzed peritumoral edema using diffusion tensor MR imaging. This group divided gliomas associated with peritumoral edema into tumor-infiltrated edema and purely vasogenic edema. It is controversial the prognostic of peritumoral edema. Some authors considered

*Example planning treatment volumes (PTV) delineation of high grade. MRI T2 showing in colors lines* 

peritumoral edema on a preoperative MRI to be an independent prognostic factor, in addition to the postoperative Karnofsky performance score (KPS), age, and type of tumor resection [14]. Patients with major edema (>1 cm) had a significant shorter overall survival (OS) time, compared to patients with minor edema (<1 cm). Another study established that peritumoral edema, noncontrast-enhancing tumor, satellites, and multifocality were independent prognostic factors for survival in GBM, whereas preoperative tumor size, tumor location, and extent of necrosis had no significant impact on survival [15]. Conversely, there was no correlation between peritumoral edema, patient age, and tumor volume, but there was an association between edema, tumor location, and necrosis [16]. Similarly, Ramakrishna et al. [17] analyzed the predictive value of abnormal MRI features for the survival of patients with GBM. The result demonstrated that tumor burden and invasion characteristics indicated by the T1-weighted gadolinium-enhanced MRI were significant predictors of patient survival, but the total area of signal intensity abnormalities on the T2-weighted images and the T2/T1 ratio did not correlate with patient outcome. In summary, for patients with GBM, the significance of peritumoral edema for the survival of a patient with GBM is not clear. A majority of tumor tissues are contained

**116**

**Figure 2.**

*different protocols volumes*

within the contrast enhancement areas in T1-weighted MRI, but not always, and infiltrate into the peritumoral edema area. We believe that GTV in HGG for RT should be focus in T1-weighted MRI and surgical bed, regarding the peritumoral edema area. In addition, the ability to accurately distinguish tumor-infiltrated edema from vasogenic edema composed purely of extracellular water could be helpful for target delineation. It is hoped that advances in image techniques will enable this in the future.

#### **2.2 Recurrent patterns of postoperative GBM**

Several studies have studied the pattern of relapse in patients with glioblastoma. One of them [18] retrospectively analyzed the patterns of radiographic presentation of 80 adult patients with supratentorial GBM at four clinically relevant time points: presentation, first recurrence, second recurrence, and third recurrence. At diagnosis, 87.5% (70/80), 6.25% (5/80), 3.75%, and 2.5% of patients presented with unifocal disease and distant, multifocal, and diffuse MRI-defined radiographic patterns, respectively. After RT and temozolamide treatment local recurrence occurs in 80%, distant in 7,5% and multifocal in 6,25% (including one with cerebrospinal fluid dissemination), and 6.25% was diffuse. In the same way, Wallner et al. [19] found that 78% of unifocal anaplastic astrocytoma and GBM recurrences occurred within 2 cm of the presurgical original tumor extent, which is defined as the enhancing edge of the tumor on preoperative CT, and 56% (18/32) of tumors recurred within 1 cm of the initial tumor margin. Liang et al. [20] published the pattern of failure for 42 patients with grade III or IV astrocytoma treated with chemoradiotherapy to a total of 60 Gy. In all 42 patients, recurrence occurred within a 2 cm margin of the original CT-enhancing lesion, and 10% of the patients suffered from multifocal recurrence. In a retrospective series of 34 patients treated either with WBRT and conformal boost or entirely with 3D conformal RT, Oppitz et al. [21] revealed that all GBM recurrences occurred within the 90% isodose line when targets were contoured around the original preoperative contrast-enhancing tumor plus a 2 cm margin. More than 80% of the recurrences occur in 2 cm of the surgical bed doseescalation studies analyzed 36 patients with HGGs treated with radiation alone to 70–80 Gy using the 3D conformal techniques [22]. In this study, recurrences were divided into several categories: (1) "central," in which 95% or more of the recurrent tumor volume (Vrecur) was within D95, the region treated to a high dose (95% of the prescription dose); (2) "infield," in which 80% or more of V recur was within the D95 isodose surface; (3) "marginal," when between 20 and 80% of Vrecur was inside the D95 surface; and (4) "outwith," in which <20% of Vrecur was inside the D95 surface. This study found that 89% of the recurrences were central or infield, 3/36 (8%) had a marginal recurrence pattern, and only one patient (3%) clearly failed outside of the high-dose region. Another trial [7] reported similar patterns of failure in a series of 48 patients with GBM, comparing treatment guidelines based on residual tumor and cavity plus 2 cm margin, as used at the MD Anderson Cancer Center, with RTOG guidelines that specified the inclusion of preoperative peritumoral edema. They showed that 90% (43/48) of patients failed in central and infield locations. The five remaining marginal and distal recurrences failed to be covered by the 46 Gy isodose line, even when overlaid by the RTOG plan incorporating edema volume, confirming them to be true marginal recurrences. Additionally, Minniti et al. [23] compared recurrence patterns in 105 patients whose surgical resections were delineated by the EORTC contouring technique, wherein the CTV includes the resection cavity, and any residual tumor seen on postoperative T1-weighted MRI, plus a 2 cm margin, and the PTV includes the CTV plus an additional 3 mm margin. After recurrence was confirmed, a theoretical plan, based on the addition of postoperative edema plus 2 cm margins, according to the current

RTOG guidelines, was created for each patient. The radiation coverage of the site of subsequent recurrences was compared for the different contouring techniques. The results revealed no significant differences in relapse patterns between the two target delineation techniques. Although, the median percent volume of normal brain irradiated to high doses was significantly smaller using the EORTC guideline. In our opinion, these data provide some evidence and reassurance to support treatment plans based on resection cavity and any residual tumor seen on postoperative T1-weighted MRI with a 2 cm margin, rather than specified inclusion of preoperative peritumoral edema plus a 2 cm margin. The use of this limited-margin RT can significantly decrease the volume of normal brain tissue that is irradiated, without a significant increase in the risk of marginal recurrences. A number of studies have been conducted to explore the feasibility of limited-margin RT in the context of a treatment paradigm involving RT with concurrent chemotherapy. Trying to reduce treatment volume, McDonald et al. [8] report the pattern of tumor failure in a series of 62 patients with GBM treated with postoperative limited-margin RT and concurrent chemotherapy. The initial CTV included the postoperative T2 abnormality, with a median margin of 0.7 cm. The boost CTV included the residual T1-enhancing tumor and resection cavity, with a median margin of 0.5 cm. The PTV margin varied from an additional 0.3 cm–0.5 cm. The initial dose was 46–54 Gy, followed by a boost to 60 Gy. In this study, the total boost PTV (PTVboost) margin was 1 cm or less in 92% of the patients. Results showed that 38/41 patients (93%) had a central or infield failure, two (5%) had a marginal failure, and one (2%) had a distant failure, relative to the 60 Gy isodose line. The author concluded that a PTVboost margin of 1 cm or less did not appear to increase the risk of marginal and/or distant tumor failure, compared with other published series. In the same direction, Dobelbower et al. [24] analyzed the patterns of failure in patients with GBM treated with concurrent radiation and TMZ. Patients generally received 46 Gy to the primary tumor, surrounding edema, plus a 1 cm margin and 60 Gy to the enhancing tumor plus a 1 cm margin. The result revealed that 18 patients (90%) had infield failures, 2 patients (10%) had marginal failures, and no regional failures were reported. Four patients (20%) suffered from distant failure, in which an independent satellite lesion was located completely outwith the 95% isodose curve. These studies also suggested that by delineating the GTV based on peritumoral edema, it is feasible to reduce the margin to 1 cm or less. Clinical studies showed that the volume of irradiated brain is important factor in the development of neurotoxicity and for the development of radiographic and pathologic surrogates for neurotoxicity [25–28].

Smaller RT fields may be more appropriate than larger RT fields, possibly reducing the risk of late neurological deterioration especially in patients with large peritumoral edema. The neurocognitive function would be likely to be affected by radiation therapy especially in long-term survivors [29].

The pattern of failure for GBM after radiation therapy has been studied previously; almost all tumors fail within a 2 cm margin of the resection cavity or residual tumor. The primary failure location was infield, but some patients had marginal failures, and few had a distant failure or an independent satellite lesion. Taking these data into consideration, we conclude that it is preferable to contour the GTV based on the T1-enhanced MRI, and regard the peritumoral edema as a subclinical lesion. We suggest that the CTV should be identified based on the residual T1-enhancing tumor and resection cavity (GTV) with a 2 cm margin or the postoperative T2 or FLAIR (fluid-attenuated inversion recovery) abnormality; however, in the case of a cone-down boost phase, the CTV should include the GTV with a 1 cm margin.

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*Role of Radiotherapy in High Grade Glioma DOI: http://dx.doi.org/10.5772/intechopen.80923*

Standard therapy for HGG patients is a total dose of 60 Gy in 30–33 fractions [30]. Adequate doses of RT are required to maximize the survival benefit [31–33]. One important study conducted by Walker et al. evaluated the relationship between survival and increasing doses of RT in malign gliomas [33]. Doses ranged from <45 Gy to 60 Gy. They showed that there was a significant improvement in median survival from 28 to 42 weeks in the groups treated with doses of 50–60 Gy. There is no benefit for dose escalation of >60 Gy. In two randomized trials, there were no significant differences in tumor control or survival in patients treated with 60 Gy cranial radiation or 60 Gy followed by a 10 Gy tumor boost [34, 35]. Two series [35, 36] analyzed failure patterns for patients with HGG dose escalation levels 70, 80, and 90 Gy. The GTV was defined based on postoperative gadolinium-enhanced T1-weighted images. They defined three separate PTVs in three dimensions by 0.5 cm to make PTV1, 1.5 cm to make PTV2, and 2.5 cm to make PTV3 from GTV. At median follow-up of 11.7 months, median survival was found to be 11.7 months, and 1- and 2-year survivals were 47.1% and 12.9%, respectively. The authors concluded that despite dose escalation to 90 Gy, the predominant failure pattern in HGG remained local. This suggested that close margins used in highly conformal treatments did not increase the risk of marginal or distant recurrences. Since the majority of tumor recurrences were seen within the previous radiation therapy fields and the poor outcomes associated with standard regimen, the new therapy strategies were evaluated to deliver higher doses to the tumor bed. Higher doses for HGG have been attempted with a variety of methods, including altered fractionation [37, 38], stereotactic radio surgery [39], and brachytherapy [40]. The term "conventional RT" refers to giving daily radiation of 180–200 cGy per day. "Hypofractionated RT" refers to the use of a higher daily dose of radiation (> 200 cGy per day) which typically reduces the overall number of fractions and therefore the overall treatment time. "Hyperfractionated RT" defined as the use of a lower daily dose of radiation (< 180 cGy per day), a greater number of fractions and multiple fractions delivered per day in order to deliver a total dose at least equivalent to external beam daily conventionally fractionated RT in the same time frame. The aim of this approach is to reduce the potential for late toxicity [41, 42]. In this study, the authors compared hyperfractionated RT (with or without chemotherapy) vs. conventionally fractionated RT (without chemotherapy). The trial included 81 HGG patients randomized to conventional fractionation (5800 cGy in 30 daily fractions) or hyperfractionation (6141 cGy in 89 cGy fractions given 3 times a day every 2–4 hours for 4.5 weeks). Median survival in two groups was 39 and 27 weeks, respectively, and the 1-year survival rates were 41 and 20%, respectively. Others have failed to confirm these results. Therefore, there is insufficient data regarding hyperfractionation vs. conventionally fractionated radiation (without chemotherapy) and insufficient data regarding accelerated radiation vs. conventionally fractionated radiation (without chemotherapy) [43]. "Hypofractionated RT" refers to the delivery of higher daily dose to reduce the

overall treatment time. Five studies that randomized participants to hypofractionated radiation therapy vs. conventionally fractionated RT [43]. Their results suggested that hypofractionated RT has similar efficacy for survival as compared to conventional radiotherapy, especially for individuals aged 60 and older with HGG. A randomized controlled trial (RCT) and several retrospective studies conducted in the elderly suggest that short course-radiation therapy (SCRT) of 34–40 Gy in 2.6–3.4 Gy fractions, with or without TMZ, may have similar results to LCRT [44–46]. Results from the Nordic trial suggested that SCRT may be superior to LCRT in patients aged ≥70 years [47]. An International Atomic Energy Agency Randomized Phase III Study of Radiation Therapy in Elderly and/or Frail Patients

**3. Dose**

#### **3. Dose**

*Primary Intracranial Tumors*

RTOG guidelines, was created for each patient. The radiation coverage of the site of subsequent recurrences was compared for the different contouring techniques. The results revealed no significant differences in relapse patterns between the two target delineation techniques. Although, the median percent volume of normal brain irradiated to high doses was significantly smaller using the EORTC guideline. In our opinion, these data provide some evidence and reassurance to support treatment plans based on resection cavity and any residual tumor seen on postoperative T1-weighted MRI with a 2 cm margin, rather than specified inclusion of preoperative peritumoral edema plus a 2 cm margin. The use of this limited-margin RT can significantly decrease the volume of normal brain tissue that is irradiated, without a significant increase in the risk of marginal recurrences. A number of studies have been conducted to explore the feasibility of limited-margin RT in the context of a treatment paradigm involving RT with concurrent chemotherapy. Trying to reduce treatment volume, McDonald et al. [8] report the pattern of tumor failure in a series of 62 patients with GBM treated with postoperative limited-margin RT and concurrent chemotherapy. The initial CTV included the postoperative T2 abnormality, with a median margin of 0.7 cm. The boost CTV included the residual T1-enhancing tumor and resection cavity, with a median margin of 0.5 cm. The PTV margin varied from an additional 0.3 cm–0.5 cm. The initial dose was 46–54 Gy, followed by a boost to 60 Gy. In this study, the total boost PTV (PTVboost) margin was 1 cm or less in 92% of the patients. Results showed that 38/41 patients (93%) had a central or infield failure, two (5%) had a marginal failure, and one (2%) had a distant failure, relative to the 60 Gy isodose line. The author concluded that a PTVboost margin of 1 cm or less did not appear to increase the risk of marginal and/or distant tumor failure, compared with other published series. In the same direction, Dobelbower et al. [24] analyzed the patterns of failure in patients with GBM treated with concurrent radiation and TMZ. Patients generally received 46 Gy to the primary tumor, surrounding edema, plus a 1 cm margin and 60 Gy to the enhancing tumor plus a 1 cm margin. The result revealed that 18 patients (90%) had infield failures, 2 patients (10%) had marginal failures, and no regional failures were reported. Four patients (20%) suffered from distant failure, in which an independent satellite lesion was located completely outwith the 95% isodose curve. These studies also suggested that by delineating the GTV based on peritumoral edema, it is feasible to reduce the margin to 1 cm or less. Clinical studies showed that the volume of irradiated brain is important factor in the development of neurotoxicity and for the development of radiographic and pathologic surrogates

Smaller RT fields may be more appropriate than larger RT fields, possibly reducing the risk of late neurological deterioration especially in patients with large peritumoral edema. The neurocognitive function would be likely to be affected by

The pattern of failure for GBM after radiation therapy has been studied previously; almost all tumors fail within a 2 cm margin of the resection cavity or residual tumor. The primary failure location was infield, but some patients had marginal failures, and few had a distant failure or an independent satellite lesion. Taking these data into consideration, we conclude that it is preferable to contour the GTV based on the T1-enhanced MRI, and regard the peritumoral edema as a subclinical lesion. We suggest that the CTV should be identified based on the residual T1-enhancing tumor and resection cavity (GTV) with a 2 cm margin or the postoperative T2 or FLAIR (fluid-attenuated inversion recovery) abnormality; however, in the case of a cone-down boost phase, the CTV should include the GTV with a 1 cm

radiation therapy especially in long-term survivors [29].

**118**

margin.

for neurotoxicity [25–28].

Standard therapy for HGG patients is a total dose of 60 Gy in 30–33 fractions [30]. Adequate doses of RT are required to maximize the survival benefit [31–33]. One important study conducted by Walker et al. evaluated the relationship between survival and increasing doses of RT in malign gliomas [33]. Doses ranged from <45 Gy to 60 Gy. They showed that there was a significant improvement in median survival from 28 to 42 weeks in the groups treated with doses of 50–60 Gy. There is no benefit for dose escalation of >60 Gy. In two randomized trials, there were no significant differences in tumor control or survival in patients treated with 60 Gy cranial radiation or 60 Gy followed by a 10 Gy tumor boost [34, 35]. Two series [35, 36] analyzed failure patterns for patients with HGG dose escalation levels 70, 80, and 90 Gy. The GTV was defined based on postoperative gadolinium-enhanced T1-weighted images. They defined three separate PTVs in three dimensions by 0.5 cm to make PTV1, 1.5 cm to make PTV2, and 2.5 cm to make PTV3 from GTV. At median follow-up of 11.7 months, median survival was found to be 11.7 months, and 1- and 2-year survivals were 47.1% and 12.9%, respectively. The authors concluded that despite dose escalation to 90 Gy, the predominant failure pattern in HGG remained local. This suggested that close margins used in highly conformal treatments did not increase the risk of marginal or distant recurrences. Since the majority of tumor recurrences were seen within the previous radiation therapy fields and the poor outcomes associated with standard regimen, the new therapy strategies were evaluated to deliver higher doses to the tumor bed. Higher doses for HGG have been attempted with a variety of methods, including altered fractionation [37, 38], stereotactic radio surgery [39], and brachytherapy [40].

The term "conventional RT" refers to giving daily radiation of 180–200 cGy per day. "Hypofractionated RT" refers to the use of a higher daily dose of radiation (> 200 cGy per day) which typically reduces the overall number of fractions and therefore the overall treatment time. "Hyperfractionated RT" defined as the use of a lower daily dose of radiation (< 180 cGy per day), a greater number of fractions and multiple fractions delivered per day in order to deliver a total dose at least equivalent to external beam daily conventionally fractionated RT in the same time frame. The aim of this approach is to reduce the potential for late toxicity [41, 42]. In this study, the authors compared hyperfractionated RT (with or without chemotherapy) vs. conventionally fractionated RT (without chemotherapy). The trial included 81 HGG patients randomized to conventional fractionation (5800 cGy in 30 daily fractions) or hyperfractionation (6141 cGy in 89 cGy fractions given 3 times a day every 2–4 hours for 4.5 weeks). Median survival in two groups was 39 and 27 weeks, respectively, and the 1-year survival rates were 41 and 20%, respectively. Others have failed to confirm these results. Therefore, there is insufficient data regarding hyperfractionation vs. conventionally fractionated radiation (without chemotherapy) and insufficient data regarding accelerated radiation vs. conventionally fractionated radiation (without chemotherapy) [43].

"Hypofractionated RT" refers to the delivery of higher daily dose to reduce the overall treatment time. Five studies that randomized participants to hypofractionated radiation therapy vs. conventionally fractionated RT [43]. Their results suggested that hypofractionated RT has similar efficacy for survival as compared to conventional radiotherapy, especially for individuals aged 60 and older with HGG. A randomized controlled trial (RCT) and several retrospective studies conducted in the elderly suggest that short course-radiation therapy (SCRT) of 34–40 Gy in 2.6–3.4 Gy fractions, with or without TMZ, may have similar results to LCRT [44–46]. Results from the Nordic trial suggested that SCRT may be superior to LCRT in patients aged ≥70 years [47]. An International Atomic Energy Agency Randomized Phase III Study of Radiation Therapy in Elderly and/or Frail Patients

with Newly Diagnosed Glioblastoma Multiforme showed no differences in overall survival time, progression-free survival time, and quality of life between patients receiving the two radiotherapy regimens (25 Gy in five daily fractions over 1 week vs. 40 Gy in 15 daily fractions over 3 weeks) [48].

There are no data comparing optimal dose and schedule in grade III gliomas vs. GBM. However, many radiation oncologists use a dose of 59.4 Gy in 1.8 Gy fractions for grade III tumors vs. 60 Gy in 2 Gy fractions for grade IV tumors with the expectation that dose reduction per fraction may lead to reduced late normal tissue effects for patients with probability longer-term survival [49].

#### **4. Stereotactic radiotherapy and radiosurgery (SRS)**

Stereotactic radiotherapy or radiosurgery (SRS) uses three-dimensional planning techniques to precisely deliver narrowly collimated beams of ionizing radiation in a single high-dose fraction to small lesions [50, 51]. This technique in primary treatment of HGG was used in some trials a boost (additional dose). The treatment was composed of 50 Gy conventional RT and four SRT boost fractions of either 5 or 7 Gy. SRT was administered once weekly during the final 4 weeks of therapy. The results suggested that while the regimen was safe, there was no survival benefit compared to the standard of care. Some retrospective studies suggest that it may be used in patients with recurrent HGG previously irradiated. A number of small prospective and retrospective series suggest that SRS may prolong survival in this setting, either alone or in combination with chemotherapy [52]. It is important to know the bias of these studies including the initial radiation dose, extent of initial and second surgical resections, tumor volume at the time of SRS, and timing and use of chemotherapy and the time between initial radiation therapy and retreatment have clear implications on patient outcomes but are variably reported [52, 53]. Patients newly diagnosed with progressive/recurrent gliomas, there is insufficient evidence in terms of the benefits/harms of using SRS/SRT. There is also insufficient evidence regarding the benefits/harms in the use of SRS/SRT at the time of progression or recurrence.

#### **5. Reirradiation in recurrent high-grade gliomas**

Tumor recurrence is inevitable in HGG patients, but diagnostic of progressive disease from radiation necrosis or other radiation-induced imaging changes could be a big challenge. Treatment decisions for patients with recurrent or progressive HGG must be individualized, since therapy is not curative and there are no randomized trials that directly compare active intervention vs. supportive care. Reoperation is an important treatment modality and may involve either biopsy (for diagnostic purposes) or repeat debulking of tumor, but only 20–30% of recurrent HGG patients are candidates for another surgery [54]. Focal RT approaches are often employed with limited volume recurrences; however, the role of reirradiation in patients with recurrent HGG is uncertain, and there is a lack of prospective data. Based on retrospective series, selected patients with small recurrent tumors and a good performance status may benefit from repeat radiation using modern high-precision techniques [55]. In a small series of 101 patients with recurrent HGG, the median survival was 12 months for patients with grade III tumors and 8 months for those with grade IV lesions. In this study SBRT was performed with a median dose of 36 Gy (range 15–62) [56].

**121**

*Role of Radiotherapy in High Grade Glioma DOI: http://dx.doi.org/10.5772/intechopen.80923*

The toxicity of RT usually divided into acute and late effects, effects differentiated by time that occur, during radiation or up to 3 months afterward, early-delayed effects that appear up to 6 months after radiation, and late effects that can develop 6 months or more after the completion of radiation. Usually, acute reactions are reversible, and late reactions are generally irreversible. Most common acute radiation morbidity during cranial irradiation includes fatigue, erythema, alopecia, headache, and nausea with or without vomiting; these are usually not severe and are self-limiting [49]. The factors influencing the likelihood of developing complications include the volume of normal brain tissue treated and the total radiation dose. Fatigue is one of the most common side effects of cranial irradiation. In a prospective study with 70 consecutive patients receiving radical cranial irradiation, most of the patients were treated for GBM, and their results suggested that 90% of the patients experienced ≥ grade 1 symptoms (disturbance with some tiredness, but activity not curtailed), and approximately half experienced mild to moderate symptoms like decreased activity and increased tiredness, sleeping much of the day or most activities curtailed. The symptoms typically began within 2 weeks of the start of RT, peaked at approximately 6–8 weeks, and then slowly resolved over the next several months. Corticosteroids or antiemetic are used to prevent or abbreviate the symptoms. Late effects including cognitive impairments and radiation necrosis are worrisome and may become manifest many years after RT [57]. Cranial irradiation can result in a spectrum of neurocognitive deficits in the years following treatment in children and in adults. The data of radiation-induced cognitive impairment is mostly learned from studies that are conducted in low-grade glioma patients. Cognitive functioning in patients with brain tumor was affected by the antiepileptic drug use, extent of surgery, tumor localization, and age [57]. Radiation necrosis is a serious and uncommon late toxicity that typically develops 1–3 years after radiation, but in rare cases it has been reported more than 10 years after radiation [58]. The probability of radiation necrosis is strict dependence on the dose. Focal brain radiation with doses around 70 Gy using conventional 2 Gy fractionation risk of focal radiation necrosis is usually estimated in 5% in 5 years [59]. The risk of radiation necrosis probably increases with concurrent chemo-

The standard of care for HGG adults, up to age 70 with good performance status, is conformal fractionated radiotherapy (6000 cGy in 30 daily fractions) with the addition of concurrent and adjuvant temozolomide chemotherapy following maximal safe debulking of the tumor. Elderly patients, older than 70 years or with poor performance status, hypofractionated RT has similar efficacy for survival as

The optimal treatment volume for HGG patients remains controversial and varies among cooperative groups; dose escalation above 60 Gy or stereotactic radiosurgery has not shown any survival benefits. Treatment decisions for patients with recurrent or progressive HGG must be individualized, since therapy is not curative and there are no randomized trials that directly compare active intervention vs.

**6. Toxicity of radiotherapy**

therapy or radio sensitizers [60].

compared to conventional radiotherapy.

**7. Conclusion**

supportive care.

### **6. Toxicity of radiotherapy**

*Primary Intracranial Tumors*

vs. 40 Gy in 15 daily fractions over 3 weeks) [48].

time of progression or recurrence.

**5. Reirradiation in recurrent high-grade gliomas**

effects for patients with probability longer-term survival [49].

**4. Stereotactic radiotherapy and radiosurgery (SRS)**

with Newly Diagnosed Glioblastoma Multiforme showed no differences in overall survival time, progression-free survival time, and quality of life between patients receiving the two radiotherapy regimens (25 Gy in five daily fractions over 1 week

There are no data comparing optimal dose and schedule in grade III gliomas vs. GBM. However, many radiation oncologists use a dose of 59.4 Gy in 1.8 Gy fractions for grade III tumors vs. 60 Gy in 2 Gy fractions for grade IV tumors with the expectation that dose reduction per fraction may lead to reduced late normal tissue

Stereotactic radiotherapy or radiosurgery (SRS) uses three-dimensional planning techniques to precisely deliver narrowly collimated beams of ionizing radiation in a single high-dose fraction to small lesions [50, 51]. This technique in primary treatment of HGG was used in some trials a boost (additional dose). The treatment was composed of 50 Gy conventional RT and four SRT boost fractions of either 5 or 7 Gy. SRT was administered once weekly during the final 4 weeks of therapy. The results suggested that while the regimen was safe, there was no survival benefit compared to the standard of care. Some retrospective studies suggest that it may be used in patients with recurrent HGG previously irradiated. A number of small prospective and retrospective series suggest that SRS may prolong survival in this setting, either alone or in combination with chemotherapy [52]. It is important to know the bias of these studies including the initial radiation dose, extent of initial and second surgical resections, tumor volume at the time of SRS, and timing and use of chemotherapy and the time between initial radiation therapy and retreatment have clear implications on patient outcomes but are variably reported [52, 53]. Patients newly diagnosed with progressive/recurrent gliomas, there is insufficient evidence in terms of the benefits/harms of using SRS/SRT. There is also insufficient evidence regarding the benefits/harms in the use of SRS/SRT at the

Tumor recurrence is inevitable in HGG patients, but diagnostic of progressive disease from radiation necrosis or other radiation-induced imaging changes could be a big challenge. Treatment decisions for patients with recurrent or progressive HGG must be individualized, since therapy is not curative and there are no randomized trials that directly compare active intervention vs. supportive care. Reoperation is an important treatment modality and may involve either biopsy (for diagnostic purposes) or repeat debulking of tumor, but only 20–30% of recurrent HGG patients are candidates for another surgery [54]. Focal RT approaches are often employed with limited volume recurrences; however, the role of reirradiation in patients with recurrent HGG is uncertain, and there is a lack of prospective data. Based on retrospective series, selected patients with small recurrent tumors and a good performance status may benefit from repeat radiation using modern high-precision techniques [55]. In a small series of 101 patients with recurrent HGG, the median survival was 12 months for patients with grade III tumors and 8 months for those with grade IV lesions. In this study SBRT was performed with a median dose of 36 Gy (range 15–62) [56].

**120**

The toxicity of RT usually divided into acute and late effects, effects differentiated by time that occur, during radiation or up to 3 months afterward, early-delayed effects that appear up to 6 months after radiation, and late effects that can develop 6 months or more after the completion of radiation. Usually, acute reactions are reversible, and late reactions are generally irreversible. Most common acute radiation morbidity during cranial irradiation includes fatigue, erythema, alopecia, headache, and nausea with or without vomiting; these are usually not severe and are self-limiting [49]. The factors influencing the likelihood of developing complications include the volume of normal brain tissue treated and the total radiation dose. Fatigue is one of the most common side effects of cranial irradiation. In a prospective study with 70 consecutive patients receiving radical cranial irradiation, most of the patients were treated for GBM, and their results suggested that 90% of the patients experienced ≥ grade 1 symptoms (disturbance with some tiredness, but activity not curtailed), and approximately half experienced mild to moderate symptoms like decreased activity and increased tiredness, sleeping much of the day or most activities curtailed. The symptoms typically began within 2 weeks of the start of RT, peaked at approximately 6–8 weeks, and then slowly resolved over the next several months. Corticosteroids or antiemetic are used to prevent or abbreviate the symptoms. Late effects including cognitive impairments and radiation necrosis are worrisome and may become manifest many years after RT [57]. Cranial irradiation can result in a spectrum of neurocognitive deficits in the years following treatment in children and in adults. The data of radiation-induced cognitive impairment is mostly learned from studies that are conducted in low-grade glioma patients. Cognitive functioning in patients with brain tumor was affected by the antiepileptic drug use, extent of surgery, tumor localization, and age [57]. Radiation necrosis is a serious and uncommon late toxicity that typically develops 1–3 years after radiation, but in rare cases it has been reported more than 10 years after radiation [58]. The probability of radiation necrosis is strict dependence on the dose. Focal brain radiation with doses around 70 Gy using conventional 2 Gy fractionation risk of focal radiation necrosis is usually estimated in 5% in 5 years [59]. The risk of radiation necrosis probably increases with concurrent chemotherapy or radio sensitizers [60].

#### **7. Conclusion**

The standard of care for HGG adults, up to age 70 with good performance status, is conformal fractionated radiotherapy (6000 cGy in 30 daily fractions) with the addition of concurrent and adjuvant temozolomide chemotherapy following maximal safe debulking of the tumor. Elderly patients, older than 70 years or with poor performance status, hypofractionated RT has similar efficacy for survival as compared to conventional radiotherapy.

The optimal treatment volume for HGG patients remains controversial and varies among cooperative groups; dose escalation above 60 Gy or stereotactic radiosurgery has not shown any survival benefits. Treatment decisions for patients with recurrent or progressive HGG must be individualized, since therapy is not curative and there are no randomized trials that directly compare active intervention vs. supportive care.

*Primary Intracranial Tumors*

#### **Author details**

Henrique Balloni Department of Radiation Oncology of Oncoville Oncoville, Curitiba PR, Brazil

\*Address all correspondence to: henriqueballoni@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**123**

ijrobp.2006.05.021

8153665

*Role of Radiotherapy in High Grade Glioma DOI: http://dx.doi.org/10.5772/intechopen.80923*

[1] Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England Journal of Medicine. 2005;**352**(10):987-996. DOI: 10.1056/ [7] Chang EL, Akyurek S, Avalos T, et al. Evaluation of peritumoral edema in the delineation of radiotherapy clinical target volumes for glioblastoma. International Journal of Radiation Oncology, Biology, Physics.

2007;**68**(1):144-150. DOI: 10.1016/j.

[8] McDonald MW, Shu HK, Curran WJ Jr, Crocker IR. Pattern of failure after limited margin radiotherapy and temozolomide for glioblastoma. International Journal of Radiation Oncology, Biology, Physics. 2011;**79**(1):130-136. DOI: 10.1016/j.

ijrobp.2006.12.009

ijrobp.2009.10.048

jns.1983.58.2.0159

jns.1987.66.6.0865

[13] Lu S, Ahn D, Johnson G, Law M, Zagzag D, Grossman

[9] Ghose A, Lim G, Husain S. Treatment for glioblastoma multiforme: Current guidelines and Canadian practice. Current Oncology. 2010;**17**(6):52-58. PMID: 21151410

[10] Burger PC, Dubois PJ, Schold SC Jr, et al. Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme. Journal of Neurosurgery. 1983;**58**(2):159-169. DOI: 10.3171/

[11] Halperin EC, Bentel G, Heinz ER, Burger PC. Radiation therapy treatment planning in supratentorial glioblastoma multiforme: An analysis based on post mortem topographic anatomy with CT correlations. International Journal of Radiation Oncology, Biology, Physics. 1989;**17**(6):1347-1350. PMID:2557310

[12] Kelly PJ, Daumas-Duport C, Kispert DB, Kall BA, Scheithauer BW, Illig JJ. Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. Journal of Neurosurgery. 1987;**66**(6):865-874. DOI: 10.3171/

[2] Walker MD, Alexander E Jr, Hunt WE, et al. Evaluation of BCNU and/ or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. Journal of Neurosurgery. 1978;**49**(3):333-343. DOI: 10.3171/

[3] Shapiro WR, Green SB, Burger PC, et al. Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two

DOI: 10.3171/jns.1989.71.1.0001

[4] Heesters MA, Wijrdeman HK, Struikmans H, Witkamp T, Moerland MA. Brain tumor delineation based on CT and MR imaging. Implications for radiotherapy treatment planning. Strahlentherapie und Onkologie. 1993;**169**(12):729-733. PMI 8284745

[5] Leibel SA, Scott CB, Loeffler JS. Contemporary approaches to the treatment of malignant gliomas with radiation therapy. Seminars in Oncology. 1994;**21**(2):198-219. PMID:

[6] Colman H, Berkey BA, Maor MH, et al. Phase II radiation therapy oncology group trial of conventional radiation therapy followed by treatment with recombinant interferon-beta for supratentorial glioblastoma: Results of RTOG 9710. International Journal of Radiation Oncology, Biology, Physics. 2006;**66**(3):818-824. DOI: 10.1016/j.

radiotherapy regimens in postoperative treatment of malignant glioma. Brain tumor cooperative group trial 8001. Journal of Neurosurgery. 1989;**71**(1):1-9.

NEJMoa043330

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*Primary Intracranial Tumors*

**122**

**Author details**

Henrique Balloni

provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Radiation Oncology of Oncoville Oncoville, Curitiba PR, Brazil

\*Address all correspondence to: henriqueballoni@gmail.com

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[55] National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology

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2015;**7**(12):e413

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*Primary Intracranial Tumors*

[39] Mehta MP, Masciopinto J, Rozental J, Levin A, Chappell R, Bastin K, et al. Stereotactic radiosurgery for glioblastoma multiforme: Report of a prospective study evaluating prognostic Radiation Oncology, Biology, Physics.

[46] Minniti G, De Sanctis V, Muni R, Rasio D, Lanzetta G, Bozzao A, et al. Hypofractionated radiotherapy followed by adjuvant chemotherapy with temozolomide in elderly patients with glioblastoma. Journal of Neuro-

[47] Malmstrom A, Gronberg BH, Marosi C, Stupp R, Frappaz D,

Schultz H, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: The Nordic randomised, phase 3 trial. The Lancet Oncology.

[48] Roa W, Kepka L, Kumar N, Sinaika V, et al. International Atomic Energy Agency randomized phase III study of radiation therapy in elderly and/ or frail patients with newly diagnosed glioblastoma multiforme. Journal of Clinical Oncology. 2015;**33**(35):4145- 4150. DOI: 10.1200/JCO.2015.62.6606

[49] Lassman AB, Matceyevsky D, Corn BW. High-grade gliomas. In: Clinical Radiation Oncology. 4th ed. USA:

[51] Douglas JG, Stelzer KJ, Mankoff DA, Tralins KS, Krohn KA, Muzi M, et al. [F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: Clinical outcomes and patterns of failure. International Journal of Radiation

[50] Ten Haken RK, Thornton AF, Sandler HM, LaVigne ML, Quint DJ, Fraass BA, et al. A quantitative assessment of the addition of MRI to CT-based, 3-D treatment planning of brain tumors. Radiotherapy and

Oncology. 1992;**25**:121-133

Oncology. 2006;**64**:886

Oncology. 2009;**91**:95-100

2015;**92**:384-389

2012;**13**:916-926

Elsevier; 2016

factors and analyzing long-term survival advantage. International Journal of Radiation Oncology.

[40] Sneed PK, Lamborn KR, Larson DA, Prados MD, Malec MK, McDermott MW, et al. Demonstration of brachytherapy boost dose-response

relationships in glioblastoma

[41] Shin KH, Muller PJ, Geggie PH. Superfractionation radiation therapy in the treatment of malignant astrocytoma. Cancer.

multiforme. International Journal of Radiation Oncology, Biology, Physics.

[42] Lorentini S, Amelio D, Giri MG, Fellin F, Meliado G, Rizzotti A, et al. IMRT or 3D-CRT in glioblastoma? A dosimetric criterion for patient selection. Technology in Cancer

Research & Treatment. 2013;**12**:411-420

[43] Khan L, Soliman H, Sahgal A, Perry J, Xu W, Tsao MN. External beam radiation dose escalation for high grade glioma. Cochrane Database of Systematic Reviews. 2016;**8**:011475

[44] Roa W, Brasher PM, Bauman G, Anthes M, Bruera E, Chan A, et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: A prospective randomized

clinical trial. Journal of Clinical Oncology. 2004;**22**:1583-1588

[45] Arvold ND, Tanguturi SK, Aizer AA, Wen PY, Reardon DA, Lee EQ, et al. Hypofractionated versus standard radiation therapy with or without temozolomide for older glioblastoma patients. International Journal of

1994;**30**:541-549

1996;**35**:37-44

1983;**52**:2040-2043

**126**

[52] Redmond KJ, Mehta M. Stereotactic radiosurgery for glioblastoma. Cureus. 2015;**7**(12):e413

[53] Murovic JA, Chang SD. Outcomes after stereotactic radiosurgery and various adjuvant treatments for recurrent glioblastoma multiforme: A current literature review and comparison of multiple factors that impact outcome. World Neurosurgery. 2012;**78**:588-591

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### *Edited by Erasmo Barros Da Silva Junior and Jerônimo Buzetti Milano*

This book covers specific chapters with fundamental and current concepts about the main primary intracranial tumors, aimed at general neurosurgeons, neurologists, oncologists, radiotherapists, and residents. They are everyday situations from the subspecialist routine that can become challenging for professionals outside referenced centers or working alone.

Published in London, UK © 2019 IntechOpen © eugenesergeev / iStock

Primary Intracranial Tumors

Primary Intracranial Tumors

*Edited by Erasmo Barros Da Silva Junior* 

*and Jerônimo Buzetti Milano*