**4. Surgical management**

**Positron emission tomography (PET)** can be used to provide additional metabolic information of the tumor. This technique is based on the detection of radioactivity emitted by biochemically active molecules labeled with radiotracers. Different molecular processes can be investigated including glucose consumption, expression of amino acid transporters, proliferation rate, membrane biosynthesis and hypoxia. The glucose analog 18F-fluorodeoxyglucose (18F FDG) is the most commonly used radiotracer for PET to measure the local metabolic rate of glucose. Increased glucose metabolism is a feature of high-grade glioma (HGG) and a positive correlation between glycolysis rate and malignancy was demonstrated. Radiolabeled amino acids (like 11C Methionine—11C MET) have been introduced as suitable tracers in brain tumors, because amino acid transport as well as protein synthesis were both demonstrated to be enhanced in HGG. Even more, 11C MET has increased specificity and sensitivity, highlighting areas of cellular proliferation correlating well with the Ki-67 labeling index of proliferation and with microvascular density. PET can help distinguish GBMs from other brain lesions pre-operatively, can reveal malignant transformation in low-grade gliomas (LGG), and can evaluate the tumor extension for an appropriate site for biopsy, for surgery planning or for radiation therapy planning. PET is also important in assessment of treatment response, being

**Figure 5.** Left temporal glioblastoma. (a) CT scan without contrast; (b) CT scan with contrast; (c) MRI – Axial T2-weighted image; (d) MRI – Coronal FLAIR sequence; (e) MRI – Axial T1-weighted image with contrast; (f) MRI – Coronal

T1-weighted image with contrast.

10 Brain Tumors - An Update

beneficial for differentiation of tumor tissue from post-therapeutic changes.

In patients with a suspected diagnosis of GBMs, **initial management** is intended to control symptoms and prepare the patients for surgery. Corticosteroid therapy reduces peritumoral edema and alleviates symptoms of raised intracranial pressure and neurologic Neuroimaging modalities provide a lot of data about mass lesion, but cannot reliably predict the diagnosis of tumor type and grade. Histological assessment is required. Thus, **a representative tissue sample should be obtained by biopsy or resection** to have a correct diagnosis before specific adjunctive therapies have been initiated. The neurosurgeon is involved in decision-making regarding the appropriate surgical procedure for patients with GBM. Based on preoperative evaluation, he must indicate either an open surgical resection for both diagnosis and treatment or only a biopsy for diagnosis. Special consideration should be given to some important factors, including age of the patient, location and size of the tumor, neurological status, functional impairment (quantified by Karnofsky Performance Status (KPS) Scale), significant comorbidity and patient and family preferences. Patients with GBM should have **surgery for maximal tumor removal** whenever safe, because this could prolong their survival when compared with biopsy, subtotal or partial resection. **Biopsy** is only indicated in cases of "inoperability" of the tumor, because of the associated risks are minimal. The image-guided stereotactic techniques are preferred over open biopsy.

should be recommended whenever is possible, regardless of age. Relative contraindications include inaccessible or eloquent location, poor performance status and important comorbidities. Typically, tumors located in the basal ganglia, thalamus, corpus callosum, brain stem or

Current Trends in Glioblastoma Treatment http://dx.doi.org/10.5772/intechopen.75049 13

**Proper patient selection and preoperative planning** are very important for the success of the surgical intervention. The decision to undergo radical surgery needs to be reasonable and the surgical approach must be individualized for each patient. Careful assessment of the preoperative MRI imaging studies is essential for preoperative planning. The tumor location determines the type of approach to be used and the optimal trajectory to the lesion. The neurosurgeon should measure the tumor dimensions in all three axes on the contrast-enhanced MRI and compare them with on-site measurements for a good estimation of the extent of resection (EOR). If there is concern regarding proximity of the tumor to eloquent areas, a functional MRI can help to highlight the location of critical brain regions. Consequently, the surgeon can plan the operative technique and can take the decision to perform intraoperative mapping (sometimes an awake craniotomy is needed). The blood oxygenation level-dependent functional MRI (BOLDfMRI) is used in the clinical practice for presurgical mapping of motor areas and language areas (lateralization and localization). It works by recording subtle changes in blood oxygenation and flow that occur in response to a particular neural activity.

Maximal safe tumor resection represents the mainstay in GBM treatment. **Tumor removal** involves standard neurosurgical techniques. A good knowledge of surgical anatomy and a meticulous microsurgical technique, while preserving brain functions are essential. To increase the precision and the safety of the surgery, the specialist can use various technologies which allow intraoperative guidance. Neurosurgery for patients with GBM should be conducted in accredited facilities, that have the appropriate neurosurgical equipment and

Ideally, **the extent of resection (EOR)** should be assessed after surgery. This must be carried out by a contrast-enhanced MRI within 24–48 hours postoperatively, in order to distinguish between residual GBM, postoperative reactive changes and parenchymal damage as a result of surgery. Postoperative contrast-enhancing tumor mass is typically used to delineate residual GBM and completeness of removal. It is better to use volumetric analysis of the preoperative and postoperative tumor to accurately measure EOR and residual volume (RV). Reactive postoperative changes can be seen as early as 18 hours on MRI, but usually does not appear in the first 3–4 days. The EOR was identified as a strong prognostic factor for survival in GBM, together with patient's age and patient's functional status. Surgical removal has a critical role in GBM management because the only potentially modifiable risk factor associated with survival is EOR. The gross-total resection is not always possible. Thus, several studies have been conducted to evaluate EOR threshold which may serve as minimum surgical goal to achieve. Other studies demonstrated that EOR is not an ideal indicator to the success of the surgery, because it is a percentage value, reported to initial volume of the tumor, which can vary widely. Contrast-enhancing RV is considered a more clinically relevant measure and a stronger predictor of survival than EOR, representing the tumor mass existing prior to starting medical therapy. Chaichana et al. in 2014 evaluated newly diagnosed GBM patients who

trained staff and where there is a specific multidisciplinary team.

multiple tumors are biopsied only.

It produces activation maps.

#### **4.1. Stereotactic biopsy**

Stereotactic biopsy enables safe retrieval of sufficient material to allow pathologic diagnosis from precise targets in GBMs with the help of MRI or CT scan. Framed or frameless stereotactic biopsy can be performed. The main indications are inaccessible tumor location (deep-seated lesion), multiple or bilateral disease, potential unacceptable surgical morbidity because of eloquent adjacent brain areas, poor performance status (KPS < 60), lesion in a surgically poor candidate because of significant medical problems. When the diagnosis of GBM versus other space-occupying lesions is in doubt, biopsy may be a better initial step. Stereotactic biopsy is a minimally invasive technique, with low risk and good diagnostic accuracy, which can provide valuable information, guiding further treatment. However, an average morbidity rate of 4.1% (range, 0.7– 7%) and a mortality rate of 0.9% (range, 0.2–2.3%) have been demonstrated [11]. Owing to histological heterogeneity, it leads to an inaccurate or imprecise diagnosis in about 10% of cases. There are approximately 15–20% of patients who undergo only biopsy as a surgical procedure [12].

#### **4.2. Open surgical resection**

To date, surgery for resection remains **the first and the most important treatment modality** in GBMs. **The goal of surgery** should be to remove as much of the tumor as possible, while minimizing damage to surrounding healthy brain. Unfortunately, surgery is not curative. Because of the highly aggressive and invasive nature of the GBM, a complete resection is not possible. Despite the relative lack of appropriately designed trials, experience strongly supports the fact that gross-total resection (GTR) of the entire area of gadolinium-enhancement tumor is associated with improved outcome. Therefore, the current trend is to perform maximal tumor removal whenever possible, while minimizing the risk for unacceptable neurological deficit, aimed to both improve the quality of life and prolong survival.

There are **some reasons for surgery** on lesions thought to be GBMs. The first indication is to obtain a histological diagnosis. Owing to glioma histological heterogeneity, multiple biological samples from separate places of the tumor should be taken and examined. Open resection can provide a larger tissue specimen as compared to biopsy. Provision of tumor for research and scientific analysis also could be beneficial for the patient. The second indication is to perform a surgical decompression that can relieve intracranial hypertension, can improve neurologic functions and can prevent death due to brain herniation. The third indication is to reduce the tumor mass as much as possible. Reduction of the tumor burden provides a rapid drop in the global tumoral cell population, removes resistant cells and prolongs survival. Extensive resection of the tumor may potentiate or facilitate radiation therapy, chemotherapy, immunotherapy or other modalities of treatment. The fourth indication is to deliver adjuvant therapies, including intratumoral chemotherapy, intracavitary brachytherapy, gene therapy, immunotherapy, photodynamic therapy, etc. Radical surgery to the extent feasible should be recommended whenever is possible, regardless of age. Relative contraindications include inaccessible or eloquent location, poor performance status and important comorbidities. Typically, tumors located in the basal ganglia, thalamus, corpus callosum, brain stem or multiple tumors are biopsied only.

and patient and family preferences. Patients with GBM should have **surgery for maximal tumor removal** whenever safe, because this could prolong their survival when compared with biopsy, subtotal or partial resection. **Biopsy** is only indicated in cases of "inoperability" of the tumor, because of the associated risks are minimal. The image-guided stereotactic techniques are pre-

Stereotactic biopsy enables safe retrieval of sufficient material to allow pathologic diagnosis from precise targets in GBMs with the help of MRI or CT scan. Framed or frameless stereotactic biopsy can be performed. The main indications are inaccessible tumor location (deep-seated lesion), multiple or bilateral disease, potential unacceptable surgical morbidity because of eloquent adjacent brain areas, poor performance status (KPS < 60), lesion in a surgically poor candidate because of significant medical problems. When the diagnosis of GBM versus other space-occupying lesions is in doubt, biopsy may be a better initial step. Stereotactic biopsy is a minimally invasive technique, with low risk and good diagnostic accuracy, which can provide valuable information, guiding further treatment. However, an average morbidity rate of 4.1% (range, 0.7– 7%) and a mortality rate of 0.9% (range, 0.2–2.3%) have been demonstrated [11]. Owing to histological heterogeneity, it leads to an inaccurate or imprecise diagnosis in about 10% of cases. There are approximately 15–20% of patients who undergo only biopsy as a surgical procedure [12].

To date, surgery for resection remains **the first and the most important treatment modality** in GBMs. **The goal of surgery** should be to remove as much of the tumor as possible, while minimizing damage to surrounding healthy brain. Unfortunately, surgery is not curative. Because of the highly aggressive and invasive nature of the GBM, a complete resection is not possible. Despite the relative lack of appropriately designed trials, experience strongly supports the fact that gross-total resection (GTR) of the entire area of gadolinium-enhancement tumor is associated with improved outcome. Therefore, the current trend is to perform maximal tumor removal whenever possible, while minimizing the risk for unacceptable neurological deficit,

There are **some reasons for surgery** on lesions thought to be GBMs. The first indication is to obtain a histological diagnosis. Owing to glioma histological heterogeneity, multiple biological samples from separate places of the tumor should be taken and examined. Open resection can provide a larger tissue specimen as compared to biopsy. Provision of tumor for research and scientific analysis also could be beneficial for the patient. The second indication is to perform a surgical decompression that can relieve intracranial hypertension, can improve neurologic functions and can prevent death due to brain herniation. The third indication is to reduce the tumor mass as much as possible. Reduction of the tumor burden provides a rapid drop in the global tumoral cell population, removes resistant cells and prolongs survival. Extensive resection of the tumor may potentiate or facilitate radiation therapy, chemotherapy, immunotherapy or other modalities of treatment. The fourth indication is to deliver adjuvant therapies, including intratumoral chemotherapy, intracavitary brachytherapy, gene therapy, immunotherapy, photodynamic therapy, etc. Radical surgery to the extent feasible

aimed to both improve the quality of life and prolong survival.

ferred over open biopsy.

12 Brain Tumors - An Update

**4.1. Stereotactic biopsy**

**4.2. Open surgical resection**

**Proper patient selection and preoperative planning** are very important for the success of the surgical intervention. The decision to undergo radical surgery needs to be reasonable and the surgical approach must be individualized for each patient. Careful assessment of the preoperative MRI imaging studies is essential for preoperative planning. The tumor location determines the type of approach to be used and the optimal trajectory to the lesion. The neurosurgeon should measure the tumor dimensions in all three axes on the contrast-enhanced MRI and compare them with on-site measurements for a good estimation of the extent of resection (EOR). If there is concern regarding proximity of the tumor to eloquent areas, a functional MRI can help to highlight the location of critical brain regions. Consequently, the surgeon can plan the operative technique and can take the decision to perform intraoperative mapping (sometimes an awake craniotomy is needed). The blood oxygenation level-dependent functional MRI (BOLDfMRI) is used in the clinical practice for presurgical mapping of motor areas and language areas (lateralization and localization). It works by recording subtle changes in blood oxygenation and flow that occur in response to a particular neural activity. It produces activation maps.

Maximal safe tumor resection represents the mainstay in GBM treatment. **Tumor removal** involves standard neurosurgical techniques. A good knowledge of surgical anatomy and a meticulous microsurgical technique, while preserving brain functions are essential. To increase the precision and the safety of the surgery, the specialist can use various technologies which allow intraoperative guidance. Neurosurgery for patients with GBM should be conducted in accredited facilities, that have the appropriate neurosurgical equipment and trained staff and where there is a specific multidisciplinary team.

Ideally, **the extent of resection (EOR)** should be assessed after surgery. This must be carried out by a contrast-enhanced MRI within 24–48 hours postoperatively, in order to distinguish between residual GBM, postoperative reactive changes and parenchymal damage as a result of surgery. Postoperative contrast-enhancing tumor mass is typically used to delineate residual GBM and completeness of removal. It is better to use volumetric analysis of the preoperative and postoperative tumor to accurately measure EOR and residual volume (RV). Reactive postoperative changes can be seen as early as 18 hours on MRI, but usually does not appear in the first 3–4 days. The EOR was identified as a strong prognostic factor for survival in GBM, together with patient's age and patient's functional status. Surgical removal has a critical role in GBM management because the only potentially modifiable risk factor associated with survival is EOR. The gross-total resection is not always possible. Thus, several studies have been conducted to evaluate EOR threshold which may serve as minimum surgical goal to achieve. Other studies demonstrated that EOR is not an ideal indicator to the success of the surgery, because it is a percentage value, reported to initial volume of the tumor, which can vary widely. Contrast-enhancing RV is considered a more clinically relevant measure and a stronger predictor of survival than EOR, representing the tumor mass existing prior to starting medical therapy. Chaichana et al. in 2014 evaluated newly diagnosed GBM patients who underwent surgery and found that the minimum EOR of 70% and the maximal RV of 5 cm3 showed statistical significance for prolonged survival and delayed recurrence [13]. Grabowsky et al. in 2014 reported that RV of 2 cm3 or less confers survival benefit to the patient [14]. There are models that argue for a continuous relationship between EOR and median survival, suggesting that there is a survival advantage associated with any degree of resection [15]. This is evident for the practice of maximal safe resection for GBM.

**Intraoperative MRI** systems are available, but the equipment is expensive and therefore the access is somewhat restricted for many neurosurgeons and patients alike. It has the advantage to avoid potential errors caused by brain shift. It provides information about the completeness of tumor resection during surgery and allows the surgeon to perform an additional tumor excision, if needed. However, it has a limited ability to delineate between residual glioma and adjacent normal brain. The system has been shown to improve the extent of tumor removal.

Current Trends in Glioblastoma Treatment http://dx.doi.org/10.5772/intechopen.75049 15

Intraoperative functional mapping and monitoring are essential for safe excision of GBM localized near eloquent cortex. It can accurately identify individual eloquent brain areas, including somatosensory cortex, motor cortex and language cortex, enabling the neurosurgeon to avoid these regions during tumor resection and thereby minimizing the risk of neurological morbidity. One of the most important advantages of this method over the imaging techniques is allowing assessment of the cortical and subcortical function in real-time. In addition, continuous monitoring of the patient's neurological findings during surgery is very useful for intraoperative feedback to the surgeon. Using these functional methods, the edge of resection can exceed the anatomical borders of the tumor (contrast-enhancing regions) to reach the functional border

**Localization of the primary somatosensory cortex** can be achieved by somatosensory evoked potentials (SSEPs) mapping, performed under general anesthesia or in awake patient. Techniques are similar to those used for routine diagnostic studies. Evoked potentials are recorded by stimulating peripheral afferent nerves (median nerve, posterior tibial nerve, etc.), usually electrically. Recording electrodes are placed on the cortical surface (typically proximal to the lesion). When recording SSEPs, the primary sensory cortex and primary motor cortex generate potentials that are mirror images of each other. This "phase reversal" across the central sulcus aids in the localization of the primary motor cortex. Localization of the primary somatosensory cortex can also be performed by direct cortical electrical stimulation of the postcentral region. The awake patient communicates the presence or absence of the sensory

**Localization of the primary motor cortex** can be accomplished using the SSEPs "phase reversal" technique or by direct cortical electrical stimulation (with patient under general anesthesia). It is recommended to use both techniques, starting with central sulcus identification and continuing with cortical stimulation of precentral regions and recording the muscle motor evoked potentials (mMEPs) from the corresponding muscles or observing clinical movements [19]. The former technique is preferred, because the stimulation threshold for obtaining mMEPs is smaller than that for obtaining clinical movements [8, 17, 19]. Thus, the risk of eliciting local or generalized seizure activity is decreased. During the cortical stimulation, simultaneous electrocorticogram (EcoG) recording is required for the safety of the patient. It is used to identify spontaneous or stimulation-induced epileptic discharges (after discharges), marking a subclinical seizure activity. It is important to have an adequate serum anticonvulsant level pre-operatively and, if necessary, additional intravenous boluses of antiepileptic drugs may be considered [8]. It is of paramount importance to distinguish primary from

of the tumor (placed in the peritumoral tissues, invaded by the tumoral cells) [18].

*4.3.2. Intraoperative functional mapping and monitoring*

symptoms triggered by stimulation.

Surgery is associated with some **risk**. Complications encountered in open surgery for GBM are those of craniotomy in general. There are reported morbidity rates ranging from 5 to 15% and mortality rates from 1 to 5% [8].

#### **4.3. Intraoperative neurosurgical guidance**

The key issue for glioma surgery is to accurately delineate the tumor into the operative field, which can be a challenge for the neurosurgeon. Many useful tools have been created to help the surgeon differentiate between tumor and normal tissue. It is important to adapt modern technologies to successfully guide maximal surgical resection without postoperative neurological deficit. Multiple studies suggest that extensive resection is beneficial for the patient. But an excessive excision should be avoided, since it can induce permanent neurological dysfunction. At the same time, an incomplete resection can be therapeutically ineffective. The ideal goal of neurosurgery is to maximize the resection of the tumor mass safely, without impairing eloquent functions and quality of life. For higher efficacy and lower risk, the current concept of neurosurgery is an "information-guided surgery", using multimodal intraoperative information to identify the positions of the eloquent brain areas accurately and in real-time [16, 17]. Anatomical information from navigation, ultrasonography and intraoperative MRI, functional information from mapping and monitoring and histopathological data must all be considered to prevent unexpected deficits and promote extensive resection.

#### *4.3.1. Image-based navigation*

**MRI neuronavigation (frameless stereotactic navigation)** is based on preoperative MR-imaging data, taken with fiducial markers that are left in place on the scalp. This data is projected into the operative field for better anatomical orientation. It is useful for surgical planning and image guidance, particularly when the tumor cannot be seen on the cortical surface of the brain. However, it is rendered unreliable when variations in brain volume or shifts of the intracranial content appear during the surgery, because this technology is based on a preoperative set of images, without updating during surgery.

**Intraoperative ultrasonography** is helpful when the tumor is not isoechoic with the brain or the density difference is greater (when there is a hematoma or a cystic component into the mass lesion). It is a dynamic imaging modality that can guide the neurosurgeon in real-time during resection. It has the advantage that brain shift and brain relaxation that occur during the excision of the lesion do not influence the accuracy of the procedure. Three-dimensional sonography with navigation software solves any orientation problems.

**Intraoperative MRI** systems are available, but the equipment is expensive and therefore the access is somewhat restricted for many neurosurgeons and patients alike. It has the advantage to avoid potential errors caused by brain shift. It provides information about the completeness of tumor resection during surgery and allows the surgeon to perform an additional tumor excision, if needed. However, it has a limited ability to delineate between residual glioma and adjacent normal brain. The system has been shown to improve the extent of tumor removal.

#### *4.3.2. Intraoperative functional mapping and monitoring*

underwent surgery and found that the minimum EOR of 70% and the maximal RV of 5 cm3 showed statistical significance for prolonged survival and delayed recurrence [13]. Grabowsky

are models that argue for a continuous relationship between EOR and median survival, suggesting that there is a survival advantage associated with any degree of resection [15]. This is

Surgery is associated with some **risk**. Complications encountered in open surgery for GBM are those of craniotomy in general. There are reported morbidity rates ranging from 5 to 15%

The key issue for glioma surgery is to accurately delineate the tumor into the operative field, which can be a challenge for the neurosurgeon. Many useful tools have been created to help the surgeon differentiate between tumor and normal tissue. It is important to adapt modern technologies to successfully guide maximal surgical resection without postoperative neurological deficit. Multiple studies suggest that extensive resection is beneficial for the patient. But an excessive excision should be avoided, since it can induce permanent neurological dysfunction. At the same time, an incomplete resection can be therapeutically ineffective. The ideal goal of neurosurgery is to maximize the resection of the tumor mass safely, without impairing eloquent functions and quality of life. For higher efficacy and lower risk, the current concept of neurosurgery is an "information-guided surgery", using multimodal intraoperative information to identify the positions of the eloquent brain areas accurately and in real-time [16, 17]. Anatomical information from navigation, ultrasonography and intraoperative MRI, functional information from mapping and monitoring and histopathological data must all be considered to prevent unexpected deficits and promote

**MRI neuronavigation (frameless stereotactic navigation)** is based on preoperative MR-imaging data, taken with fiducial markers that are left in place on the scalp. This data is projected into the operative field for better anatomical orientation. It is useful for surgical planning and image guidance, particularly when the tumor cannot be seen on the cortical surface of the brain. However, it is rendered unreliable when variations in brain volume or shifts of the intracranial content appear during the surgery, because this technology is based

**Intraoperative ultrasonography** is helpful when the tumor is not isoechoic with the brain or the density difference is greater (when there is a hematoma or a cystic component into the mass lesion). It is a dynamic imaging modality that can guide the neurosurgeon in real-time during resection. It has the advantage that brain shift and brain relaxation that occur during the excision of the lesion do not influence the accuracy of the procedure. Three-dimensional

on a preoperative set of images, without updating during surgery.

sonography with navigation software solves any orientation problems.

or less confers survival benefit to the patient [14]. There

et al. in 2014 reported that RV of 2 cm3

14 Brain Tumors - An Update

and mortality rates from 1 to 5% [8].

extensive resection.

*4.3.1. Image-based navigation*

**4.3. Intraoperative neurosurgical guidance**

evident for the practice of maximal safe resection for GBM.

Intraoperative functional mapping and monitoring are essential for safe excision of GBM localized near eloquent cortex. It can accurately identify individual eloquent brain areas, including somatosensory cortex, motor cortex and language cortex, enabling the neurosurgeon to avoid these regions during tumor resection and thereby minimizing the risk of neurological morbidity. One of the most important advantages of this method over the imaging techniques is allowing assessment of the cortical and subcortical function in real-time. In addition, continuous monitoring of the patient's neurological findings during surgery is very useful for intraoperative feedback to the surgeon. Using these functional methods, the edge of resection can exceed the anatomical borders of the tumor (contrast-enhancing regions) to reach the functional border of the tumor (placed in the peritumoral tissues, invaded by the tumoral cells) [18].

**Localization of the primary somatosensory cortex** can be achieved by somatosensory evoked potentials (SSEPs) mapping, performed under general anesthesia or in awake patient. Techniques are similar to those used for routine diagnostic studies. Evoked potentials are recorded by stimulating peripheral afferent nerves (median nerve, posterior tibial nerve, etc.), usually electrically. Recording electrodes are placed on the cortical surface (typically proximal to the lesion). When recording SSEPs, the primary sensory cortex and primary motor cortex generate potentials that are mirror images of each other. This "phase reversal" across the central sulcus aids in the localization of the primary motor cortex. Localization of the primary somatosensory cortex can also be performed by direct cortical electrical stimulation of the postcentral region. The awake patient communicates the presence or absence of the sensory symptoms triggered by stimulation.

**Localization of the primary motor cortex** can be accomplished using the SSEPs "phase reversal" technique or by direct cortical electrical stimulation (with patient under general anesthesia). It is recommended to use both techniques, starting with central sulcus identification and continuing with cortical stimulation of precentral regions and recording the muscle motor evoked potentials (mMEPs) from the corresponding muscles or observing clinical movements [19]. The former technique is preferred, because the stimulation threshold for obtaining mMEPs is smaller than that for obtaining clinical movements [8, 17, 19]. Thus, the risk of eliciting local or generalized seizure activity is decreased. During the cortical stimulation, simultaneous electrocorticogram (EcoG) recording is required for the safety of the patient. It is used to identify spontaneous or stimulation-induced epileptic discharges (after discharges), marking a subclinical seizure activity. It is important to have an adequate serum anticonvulsant level pre-operatively and, if necessary, additional intravenous boluses of antiepileptic drugs may be considered [8]. It is of paramount importance to distinguish primary from supplementary motor areas as it is known that damage of the motor strip will cause a permanent postoperative motor deficit, while damage of the supplementary and premotor areas will result in a temporary postoperative deficit. Once the motor strip was identified, direct cortical stimulation or subcortical stimulation can be used for continuous evaluation of the functional integrity of the motor pathways during glioma resection.

*4.3.3. Enhanced visual tumor demarcation*

autofluorescence [29].

about changes into the operative field and still be affordable.

free survival was 41 versus 21.1% (p < 0.003) [35].

The ideal technique for sharper intraoperative delineation between tumor and the surrounding cerebral tissue should provide real-time information during resection, without concern

Current Trends in Glioblastoma Treatment http://dx.doi.org/10.5772/intechopen.75049 17

Intraoperative tumoral tissue fluorescence due to specific enhancing agents provides a realtime GBM discrimination in situ. The differences are visualized using specially designed microscopes, equipped with appropriate filters to detect fluorescent light emission. Fluorescence is the emission of light with a short wavelength by a substance that has absorbed light of a longer wavelength. Fluorochrome is a fluorescent dye, used to stain biological material before microscopic examination. In neurosurgery of the gliomas, a specific fluorochrome is associated with glioma tissue (selectively if possible) and then illuminated by light. Fluorescent dye will emit light, which will be perceived by the surgeon using special filters. There are four types of approaches to intraoperative fluorescence: (1) tissue fluorescence induced by specific metabolic activity; (2) tissue fluorescence-based on passive permeability; (3) tissue fluorescence due to targeted fluorescent probes accumulated into the tumor tissue; and (4)

**Tissue fluorescence induced by specific metabolic activity** is the basis to use of 5-aminolevulinic acid (5-ALA) in fluorescence-guided surgery. 5-ALA is an endogenous amino acid, the first compound in the porphyrin synthesis pathway. It is finally converted to protoporphyrin IX (PPIX), which chelates with iron in presence of enzyme ferrochelatase to produce heme (component of hemoproteins). GBM cells lack or have reduced ferrochelatase activity and this results in accumulation of protoporphyrin IX into the tumor tissue after oral administration of 5-ALA. Protoporphyrin IX is clearly visualized by its red fluorescence under blue-violet light conditions, enabling differentiation of viable tumor from normal adjacent brain. 5-ALA is the only agent that has been approved in fluorescence-guided neurosurgery in Europe, Canada and Japan, and is commonly used in surgery of GBMs. It induces GBM tissue fluorescence, having high sensitivity, specificity, and positive predictive values for identifying malignant glioma tumor tissue [30, 31]. In recurrent malignant gliomas, fluorescence is observed in anaplastic foci, in regions of gliosis or invaded by inflammatory cells, but not in normal brain. Prior alternative treatment such as radiotherapy or chemotherapy does not invalidate 5-ALAinduced fluorescence [32]. Fluorescence can discriminate malignant glioma cells down to a tumor cell density of approximately 10% [29, 33]. It is now demonstrated that visible fluorescence clearly extends beyond the border of preoperative MRI contrast-enhancement, PPIX accumulation being more sensitive than gadolinium enhancement [33, 34]. Thus, an extensive glioma resection beyond radiologically evident tumor can be performed. 5-ALA-guided resection of GBM was found to be beneficial, enabling surgeons to achieve a double rate of complete resections of malignant gliomas in comparison with conventional techniques [31, 35]. A randomized controlled multicenter phase III trial conducted by Stummer et al. involving 270 patients in 17 centers has examined a group undergoing 5-ALA fluorescence-guided surgery and a group undergoing conventional white light-guided surgery. The authors reported that gross-total resection evaluated on postoperative imaging was 65% in cases undergoing fluorescence guidance compared with 36% in the white light group (p < 0.001), and progression-

**Localization of the language cortex** is performed under awake craniotomy (AC), by cortical and subcortical direct electrical stimulation (DES). A "positive mapping" strategy can be used: a large craniotomy exposes the brain a good distance from the tumor and makes it possible to identify "positive" language sites (areas where a cortical stimulation induces a language function) prior to excision. Lately, a "negative mapping" strategy emerged as preferable. It supposes to identify "negative" language sites, meaning regions where a cortical stimulation blocks a language function. This technique allows a smaller, tailored craniotomy, with a minimal cortical exposure around the tumor (up to 2 cm of surrounding brain) and a less extensive mapping. It is a more time-efficient neurosurgical procedure [17, 20, 21].

It is important to emphasize that stimulation mapping is used to identify essential language cortex, whose injury will lead to permanent deficit. But there are also multiple nonessential speech areas. The essential language cortex is obviously different from involved language cortex identified by functional imaging techniques, such as functional MRI (fMRI) and positron emission tomography (PET). Although these imaging techniques have advanced considerably, they have some limitations and cannot replace intraoperative mapping. Patients who speak multiple languages have separate language sites for each of their different languages [8]. Different language tasks performed by a patient may lead to delineate distinct language sites. There is significant individual variability in the location of the language areas, sometimes the Broca area or the Wernicke area having a location beyond the classic anatomical boundaries or more than two essential speech areas being identified. Quinones-Hinojosa et al. found a variability of more than 4 cm in the location of speech arrest when using classical neuroanatomic landmarks [22, 23]. Furthermore, cerebral topography is distorted by the tumor mass effect and brain plasticity can induce a functional reassignment [17, 20, 23]. Thus, intraoperative identification of the language areas is essential for extensively and safely removing GBMs located near these eloquent regions in the dominant-hemisphere. It is best to continuously monitor the patient's ability to speak, especially during the part of the excision which is close to the identified language sites (within 2 cm). If the distance between resection border and the nearest language area is more than 1 cm, significantly fewer permanent language deficits occur [20, 24]. A subcortical stimulation can be used into the resection cavity to guide the removal technique (when stimulation block the language function, the location is very close to the subcortical language pathways – 5 mm or less) [17, 25].

A new intraoperative method to assess integrity of functional interconnections between language areas during surgery was proposed by Yamao et al. [17, 26, 27]. The authors monitored the integrity of the dorsal language pathway (arcuate fasciculus) using cortico-cortical evoked potentials (CCEPs). The technique is based on the electrical stimulation of the anterior perisylvian language area while recording the average response from posterior perisylvian language area. It is clinically useful for evaluating the integrity of the language network and have the advantages that is task-free, do not require the cooperation of the patient and therefore can be performed also under general anesthesia [27, 28].

#### *4.3.3. Enhanced visual tumor demarcation*

supplementary motor areas as it is known that damage of the motor strip will cause a permanent postoperative motor deficit, while damage of the supplementary and premotor areas will result in a temporary postoperative deficit. Once the motor strip was identified, direct cortical stimulation or subcortical stimulation can be used for continuous evaluation of the

**Localization of the language cortex** is performed under awake craniotomy (AC), by cortical and subcortical direct electrical stimulation (DES). A "positive mapping" strategy can be used: a large craniotomy exposes the brain a good distance from the tumor and makes it possible to identify "positive" language sites (areas where a cortical stimulation induces a language function) prior to excision. Lately, a "negative mapping" strategy emerged as preferable. It supposes to identify "negative" language sites, meaning regions where a cortical stimulation blocks a language function. This technique allows a smaller, tailored craniotomy, with a minimal cortical exposure around the tumor (up to 2 cm of surrounding brain) and a less extensive mapping. It is a more time-efficient neurosurgical procedure [17, 20, 21].

It is important to emphasize that stimulation mapping is used to identify essential language cortex, whose injury will lead to permanent deficit. But there are also multiple nonessential speech areas. The essential language cortex is obviously different from involved language cortex identified by functional imaging techniques, such as functional MRI (fMRI) and positron emission tomography (PET). Although these imaging techniques have advanced considerably, they have some limitations and cannot replace intraoperative mapping. Patients who speak multiple languages have separate language sites for each of their different languages [8]. Different language tasks performed by a patient may lead to delineate distinct language sites. There is significant individual variability in the location of the language areas, sometimes the Broca area or the Wernicke area having a location beyond the classic anatomical boundaries or more than two essential speech areas being identified. Quinones-Hinojosa et al. found a variability of more than 4 cm in the location of speech arrest when using classical neuroanatomic landmarks [22, 23]. Furthermore, cerebral topography is distorted by the tumor mass effect and brain plasticity can induce a functional reassignment [17, 20, 23]. Thus, intraoperative identification of the language areas is essential for extensively and safely removing GBMs located near these eloquent regions in the dominant-hemisphere. It is best to continuously monitor the patient's ability to speak, especially during the part of the excision which is close to the identified language sites (within 2 cm). If the distance between resection border and the nearest language area is more than 1 cm, significantly fewer permanent language deficits occur [20, 24]. A subcortical stimulation can be used into the resection cavity to guide the removal technique (when stimulation block the language function, the location is very close to the subcortical language pathways – 5 mm or less) [17, 25].

A new intraoperative method to assess integrity of functional interconnections between language areas during surgery was proposed by Yamao et al. [17, 26, 27]. The authors monitored the integrity of the dorsal language pathway (arcuate fasciculus) using cortico-cortical evoked potentials (CCEPs). The technique is based on the electrical stimulation of the anterior perisylvian language area while recording the average response from posterior perisylvian language area. It is clinically useful for evaluating the integrity of the language network and have the advantages that is task-free, do not require the cooperation of the patient and therefore can be

performed also under general anesthesia [27, 28].

functional integrity of the motor pathways during glioma resection.

16 Brain Tumors - An Update

The ideal technique for sharper intraoperative delineation between tumor and the surrounding cerebral tissue should provide real-time information during resection, without concern about changes into the operative field and still be affordable.

Intraoperative tumoral tissue fluorescence due to specific enhancing agents provides a realtime GBM discrimination in situ. The differences are visualized using specially designed microscopes, equipped with appropriate filters to detect fluorescent light emission. Fluorescence is the emission of light with a short wavelength by a substance that has absorbed light of a longer wavelength. Fluorochrome is a fluorescent dye, used to stain biological material before microscopic examination. In neurosurgery of the gliomas, a specific fluorochrome is associated with glioma tissue (selectively if possible) and then illuminated by light. Fluorescent dye will emit light, which will be perceived by the surgeon using special filters. There are four types of approaches to intraoperative fluorescence: (1) tissue fluorescence induced by specific metabolic activity; (2) tissue fluorescence-based on passive permeability; (3) tissue fluorescence due to targeted fluorescent probes accumulated into the tumor tissue; and (4) autofluorescence [29].

**Tissue fluorescence induced by specific metabolic activity** is the basis to use of 5-aminolevulinic acid (5-ALA) in fluorescence-guided surgery. 5-ALA is an endogenous amino acid, the first compound in the porphyrin synthesis pathway. It is finally converted to protoporphyrin IX (PPIX), which chelates with iron in presence of enzyme ferrochelatase to produce heme (component of hemoproteins). GBM cells lack or have reduced ferrochelatase activity and this results in accumulation of protoporphyrin IX into the tumor tissue after oral administration of 5-ALA. Protoporphyrin IX is clearly visualized by its red fluorescence under blue-violet light conditions, enabling differentiation of viable tumor from normal adjacent brain. 5-ALA is the only agent that has been approved in fluorescence-guided neurosurgery in Europe, Canada and Japan, and is commonly used in surgery of GBMs. It induces GBM tissue fluorescence, having high sensitivity, specificity, and positive predictive values for identifying malignant glioma tumor tissue [30, 31]. In recurrent malignant gliomas, fluorescence is observed in anaplastic foci, in regions of gliosis or invaded by inflammatory cells, but not in normal brain. Prior alternative treatment such as radiotherapy or chemotherapy does not invalidate 5-ALAinduced fluorescence [32]. Fluorescence can discriminate malignant glioma cells down to a tumor cell density of approximately 10% [29, 33]. It is now demonstrated that visible fluorescence clearly extends beyond the border of preoperative MRI contrast-enhancement, PPIX accumulation being more sensitive than gadolinium enhancement [33, 34]. Thus, an extensive glioma resection beyond radiologically evident tumor can be performed. 5-ALA-guided resection of GBM was found to be beneficial, enabling surgeons to achieve a double rate of complete resections of malignant gliomas in comparison with conventional techniques [31, 35]. A randomized controlled multicenter phase III trial conducted by Stummer et al. involving 270 patients in 17 centers has examined a group undergoing 5-ALA fluorescence-guided surgery and a group undergoing conventional white light-guided surgery. The authors reported that gross-total resection evaluated on postoperative imaging was 65% in cases undergoing fluorescence guidance compared with 36% in the white light group (p < 0.001), and progressionfree survival was 41 versus 21.1% (p < 0.003) [35].

**Tissue fluorescence based on passive permeability** uses fluorescein or indocyanine green, which has not been approved for intracranial use. Fluorescein is a typical marker of compromised blood-brain barrier (BBB), rather than a selective tumor marker, therefore its presence is highly nonspecific. It displays a yellow-green fluorescence visualized by the naked eye. Given its limited specificity, there is a great risk to remove normal, functional brain tissue, and given its sensitivity concerns, there is a risk of leaving residual tumor [36]. Recently, a dual-labeling approach has been proposed, using both PPIX and fluorescein fluorescence simultaneously. The advantage is that PPIX provides a reliable tumor detection and fluorescein gives a better background visualization, as it would be expected to accelerate surgery, while maintaining safety and efficacy [37]. Indocyanine green enables evaluation of tumoral and peritumoral blood flow and vascularization. It has the advantage of emitting light in the near-infrared region of the spectrum, therefore the fluorochrome can be visualized deeper in the tumoral tissue. However, the visualization requires special technologies.

finished. But the maximal removal of the glioma is the key component in the specific treatment, a smaller volume of postoperative residual tumor being associated with an improved prognosis. One of the difficulties of achieving an optimal excision is failure to delineate the resection margins. Nevertheless, histopathological assessment is also available during the surgery, providing important diagnostic information. Even if such information is less reliable compared with that of postoperative approaches, sometimes **intraoperative sampling** is the sole source of diagnostic arguments for deciding the extent of resection. Precision increases with the number of tissue sections. Traditional histopathological techniques made intraoperative include frozen section and imprint cytology. They are time-consuming (requiring nearly 30 mins), laborious

Current Trends in Glioblastoma Treatment http://dx.doi.org/10.5772/intechopen.75049 19

**Mass spectrometry-based molecular analysis** can rapidly provide detailed molecular information about tumor and adjacent brain tissue, allowing an intraoperative diagnosis and guidance in detection of the boundaries between glioma and normal brain. The desorption electrospray ionization mass spectrometry (DESI-MS) is a mass spectrometric imaging technique for characterizing lipid profile within tumor specimens. Because DESI-MS can be performed rapidly (minutes) and routinely, in the ambient conditions, with minimal pretreatment of biological samples, it can be used during surgery. It quickly provides a valuable diagnosis of tumor type based on lipid pattern [44]. It can also detect oncometabolites: 2-hydroxyglutarate and N-acetylaspartate. 2-hydroxyglutarate is present in small amounts in normal brain tissue, but its concentrations are extremely high in gliomas with mutations in IDH1 and IDH2 [45–47]. It could be used as a biomarker and serve as an important prognostic indicator. Detection of 2-hydroxyglutarate in operative field with precise spatial distribution could also help define surgical margins. DESI-MS provide valuable information that is unattainable by traditional histopathological techniques.

Given that GBM is typically a solitary tumor, with local recurrence and very rare metastases, the disease is a proper candidate for local treatment. On the other hand, availability of drugs which can cross the BBB has severely limited the effective therapies against GBM. Strategies to bypass this barrier have been developed. Localized drug delivery into a postoperative tumor bed is an attractive option for administration of therapeutics while avoiding systemic side effects. Furthermore, this way provides a means for administration of new, tumor-selective

Controlled-release polymer systems, like carmustine wafers (Gliadel wafers) can be implanted in the resection cavity. Another local approach is catheter-based convection-enhanced delivery (CED) of conventional or novel agents through continuous low-positive-pressure bulk flow. Intracavitary delivery of highly localized doses of irradiation is feasible through GliaSite

Standard therapy in newly diagnosed GBM involves maximal safe surgical resection followed by radiotherapy (RT) with concurrent and adjuvant TMZ. Despite this first-line treatment, recurrence inevitably occurs, most patients experiencing it after 7–8 months of primary

and subjective. It is desirable that they are performed by a skilled pathologist.

**4.4. Intratumoral therapies**

system brachytherapy.

**4.5. Recurrence**

molecules that are often largely excluded by brain.

**Tissue fluorescence due to targeted fluorescent probes** accumulated into the malignant tumor tissue is an ongoing subject of research. There are some fluorescent agents targeted or being retained by brain tumor cells undergoing clinical testing. Their effective application in clinical settings requires development of detection instrumentation and additional studies. Agents that show promise for intraoperative discrimination of GBM include Tumor Paint (chlorotoxin linked to a fluorophore), Angiopep-2 targeting agents, epidermal growth factor receptor (EGFR)-targeted agents, PTPμ-targeted SBK agents, the fluorescently labeled poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor (CLR1502) and αvβ3 integrin-targeted agents [38, 39].

**Microspectrofluorometry** can be used to measure the autofluorescence spectrum of biological tissues both *ex vivo* on resected samples and *in vivo*, during surgery, by means of fiber optic probe. It is a dye-free method, based on the intrinsic autofluorescence properties of a tissue. In glioma, the autofluorescence profile is distinct from normal brain, due to changes of biochemical composition and histological organization. There are differences in both spectral shape and signal amplitude relative to normal cortex and white matter. These differences allow the use of autofluorescence in situ as a parameter for distinguishing neoplastic from normal condition and so to better delineate GBM resection margins [40–42].

**Confocal microscopy (laser scanning confocal microscopy – LSCM)** may provide *in vivo* images by optical sectioning, characterized by higher resolution and contrast, with magnification up to 1000x. These images enable intraoperative visualization of tumor histopathological features and cell morphology in real-time, in three dimensions, without the need for extensive traditional tissue processing [36]. Intraoperative confocal imaging correlates with histopathological analysis, the diagnostic accuracy being of up to 93% [43]. The major application of confocal microscopy is for imaging tissues labeled with fluorescent probes. In GBM surgery, confocal microscopy combined with tissue fluorescence provides a reliable identification of tumor cells and tumor-brain interfaces.

#### *4.3.4. Intraoperative sampling*

The diagnostic of GBM is usually confirmed by standard postoperative histopathological examination of tissue sections with results only available several days after the surgery has finished. But the maximal removal of the glioma is the key component in the specific treatment, a smaller volume of postoperative residual tumor being associated with an improved prognosis. One of the difficulties of achieving an optimal excision is failure to delineate the resection margins. Nevertheless, histopathological assessment is also available during the surgery, providing important diagnostic information. Even if such information is less reliable compared with that of postoperative approaches, sometimes **intraoperative sampling** is the sole source of diagnostic arguments for deciding the extent of resection. Precision increases with the number of tissue sections. Traditional histopathological techniques made intraoperative include frozen section and imprint cytology. They are time-consuming (requiring nearly 30 mins), laborious and subjective. It is desirable that they are performed by a skilled pathologist.

**Mass spectrometry-based molecular analysis** can rapidly provide detailed molecular information about tumor and adjacent brain tissue, allowing an intraoperative diagnosis and guidance in detection of the boundaries between glioma and normal brain. The desorption electrospray ionization mass spectrometry (DESI-MS) is a mass spectrometric imaging technique for characterizing lipid profile within tumor specimens. Because DESI-MS can be performed rapidly (minutes) and routinely, in the ambient conditions, with minimal pretreatment of biological samples, it can be used during surgery. It quickly provides a valuable diagnosis of tumor type based on lipid pattern [44]. It can also detect oncometabolites: 2-hydroxyglutarate and N-acetylaspartate. 2-hydroxyglutarate is present in small amounts in normal brain tissue, but its concentrations are extremely high in gliomas with mutations in IDH1 and IDH2 [45–47]. It could be used as a biomarker and serve as an important prognostic indicator. Detection of 2-hydroxyglutarate in operative field with precise spatial distribution could also help define surgical margins. DESI-MS provide valuable information that is unattainable by traditional histopathological techniques.

#### **4.4. Intratumoral therapies**

**Tissue fluorescence based on passive permeability** uses fluorescein or indocyanine green, which has not been approved for intracranial use. Fluorescein is a typical marker of compromised blood-brain barrier (BBB), rather than a selective tumor marker, therefore its presence is highly nonspecific. It displays a yellow-green fluorescence visualized by the naked eye. Given its limited specificity, there is a great risk to remove normal, functional brain tissue, and given its sensitivity concerns, there is a risk of leaving residual tumor [36]. Recently, a dual-labeling approach has been proposed, using both PPIX and fluorescein fluorescence simultaneously. The advantage is that PPIX provides a reliable tumor detection and fluorescein gives a better background visualization, as it would be expected to accelerate surgery, while maintaining safety and efficacy [37]. Indocyanine green enables evaluation of tumoral and peritumoral blood flow and vascularization. It has the advantage of emitting light in the near-infrared region of the spectrum, therefore the fluorochrome can be visualized deeper in

**Tissue fluorescence due to targeted fluorescent probes** accumulated into the malignant tumor tissue is an ongoing subject of research. There are some fluorescent agents targeted or being retained by brain tumor cells undergoing clinical testing. Their effective application in clinical settings requires development of detection instrumentation and additional studies. Agents that show promise for intraoperative discrimination of GBM include Tumor Paint (chlorotoxin linked to a fluorophore), Angiopep-2 targeting agents, epidermal growth factor receptor (EGFR)-targeted agents, PTPμ-targeted SBK agents, the fluorescently labeled poly (ADP-ribose)

polymerase 1 (PARP-1) inhibitor (CLR1502) and αvβ3 integrin-targeted agents [38, 39].

normal condition and so to better delineate GBM resection margins [40–42].

tumor cells and tumor-brain interfaces.

*4.3.4. Intraoperative sampling*

18 Brain Tumors - An Update

**Microspectrofluorometry** can be used to measure the autofluorescence spectrum of biological tissues both *ex vivo* on resected samples and *in vivo*, during surgery, by means of fiber optic probe. It is a dye-free method, based on the intrinsic autofluorescence properties of a tissue. In glioma, the autofluorescence profile is distinct from normal brain, due to changes of biochemical composition and histological organization. There are differences in both spectral shape and signal amplitude relative to normal cortex and white matter. These differences allow the use of autofluorescence in situ as a parameter for distinguishing neoplastic from

**Confocal microscopy (laser scanning confocal microscopy – LSCM)** may provide *in vivo* images by optical sectioning, characterized by higher resolution and contrast, with magnification up to 1000x. These images enable intraoperative visualization of tumor histopathological features and cell morphology in real-time, in three dimensions, without the need for extensive traditional tissue processing [36]. Intraoperative confocal imaging correlates with histopathological analysis, the diagnostic accuracy being of up to 93% [43]. The major application of confocal microscopy is for imaging tissues labeled with fluorescent probes. In GBM surgery, confocal microscopy combined with tissue fluorescence provides a reliable identification of

The diagnostic of GBM is usually confirmed by standard postoperative histopathological examination of tissue sections with results only available several days after the surgery has

the tumoral tissue. However, the visualization requires special technologies.

Given that GBM is typically a solitary tumor, with local recurrence and very rare metastases, the disease is a proper candidate for local treatment. On the other hand, availability of drugs which can cross the BBB has severely limited the effective therapies against GBM. Strategies to bypass this barrier have been developed. Localized drug delivery into a postoperative tumor bed is an attractive option for administration of therapeutics while avoiding systemic side effects. Furthermore, this way provides a means for administration of new, tumor-selective molecules that are often largely excluded by brain.

Controlled-release polymer systems, like carmustine wafers (Gliadel wafers) can be implanted in the resection cavity. Another local approach is catheter-based convection-enhanced delivery (CED) of conventional or novel agents through continuous low-positive-pressure bulk flow. Intracavitary delivery of highly localized doses of irradiation is feasible through GliaSite system brachytherapy.

#### **4.5. Recurrence**

Standard therapy in newly diagnosed GBM involves maximal safe surgical resection followed by radiotherapy (RT) with concurrent and adjuvant TMZ. Despite this first-line treatment, recurrence inevitably occurs, most patients experiencing it after 7–8 months of primary treatment. There are no well-defined management protocols for recurrent GBM. Options for second-line treatment are limited and include repeat surgery, re-irradiation, chemotherapy, novel therapies, supportive care or, better, a combination of these.

**5. Radiation therapy**

radiotherapy (RT) plus concomitant and adjuvant TMZ.

**The SoC for newly diagnosed GBM** consists of maximal safe surgical resection followed by

Current Trends in Glioblastoma Treatment http://dx.doi.org/10.5772/intechopen.75049 21

Following gross-tumor removal, the final histological diagnosis is established, and RT should start. **The optimal time to initiate** radiation is controversial. There are studies showing worse outcomes and even decreased survival when radiation is delayed [52, 53]. Irwin et al. found that a 6 weeks delay (from 2 weeks postoperative to 8 weeks) reduces median survival by 11 weeks for a "typical" patient [52]. But there also studies showing no association between timing of radiation initiation and outcomes [54, 55] and studies suggesting a possible benefit of delay (however, up to a reference range of time) [56, 57]. Blumenthal et al. analyzed the relationship between the delay of RT and the outcome on a large cohort of more than 2800 patients. They observed no obvious reduction in survival with increasing delay (within relatively narrow temporal limits—6 weeks). Indeed, median survival time was unexpectedly greater in the group with the longest interval (>4 weeks) than in those with the shortest delay (≤2 weeks), respectively, 12.5 months versus 9.2 months (P < 0.0001). The authors do not exclude the possibility that an adjuvant treatment initiated beyond 6 weeks postoperatively may be detrimental [56]. In other studies, Han et al. found a narrow range of time (from 30 to 34 days after surgery) where there is prolonged overall survival and prolonged progression-free survival compared with early initiation of concurrent chemoradiation [57, 58]. In common practice, the patient commonly waits about 4 weeks before adjuvant therapies. It is

generally agreed that a postoperative delay of 6 weeks may not be critical.

good performance status (Karnofsky Performance Status (KPS) ≥ 60).

monly recurs within 2 cm of the original tumor location in 80–90% of cases.

chemotherapy alone may be an option.

**Concomitant TMZ and RT** (known as the Stupp regimen) have been shown to be more effective than radiation alone with minimal additional toxicity. **After the end of radiation, an adjuvant treatment with TMZ is indicated.** Patients who received RT and concurrent TMZ presented a median survival of 14.6 months versus 12.1 months with RT alone [59]. Furthermore, the two-year survival rate was 26.5% with RT plus TMZ versus 10.4% with RT alone. This is the current SoC for patients with newly diagnosed GBM up to age 70, with a

RT using three-dimensional conformal beam or intensity-modulated RT is used now. The typical total dose delivered is 60 Gy in 2 Gy fractions, administered 5 days per week for 6 weeks and there is no evidence that higher doses improve outcome [60, 61]. The RT involved fields should include the tumor bed with a 2–3 cm margin, based on the observation that GBM com-

The optimal management of **elderly patients** is controversial. In practice, for patients >70 years old or for patients <70 years old with a poor performance status (KPS < 60), an alternative hypofractionated regimen can be considered. For elderly not suitable for radiation,

Despite maximal multimodal treatment, GBM invariably recur, disease progression occurring within the first year in about 70% of cases. In selected cases of **recurrences**, a second course of radiation may be possible, but tolerance of local brain tissue to radiation is limited and there

**The standard neuroimaging modality** for the follow-up of GBM is contrast-enhanced MRI, which is performed every 2–3 months while the patient is on therapy. Criteria to assess treatment response and progression have been established by the Response Assessment in Neuro-Oncology (RANO) Working Group [48]. Progression is defined as at least 25% increase in the contrast-enhancing MRI lesion (the product of the maximal cross-sectional enhancing diameters of tumor area). Diagnosing a true progressive tumor growth after chemoradiation by MRI alone remains a challenge, because it is very difficult to distinguish between post-treatment radiation effects (such as pseudoprogression or radiation necrosis) and tumor recurrence. Post-treatment radiation effects can be divided into pseudoprogression and radiation necrosis. Pseudoprogression appears several weeks up to 3 months after RT (5.5–31%), whereas radiation necrosis occurs 3 months to years after irradiation (3–24%) [49]. Radiation necrosis is a space-occupying necrotic lesion, with mass effect and neurological dysfunction. It is irreversible and progressive. Its features on MRI are often identical to that of recurrent GBM. The differentiation is very important, because the management is different. Advanced MRI techniques such as DWI, DTI and PWI provide additional information. Metabolic imaging techniques like PET, single-photon emission computed tomography (SPECT) and MR spectroscopy (MRS) are helpful in differentiating between tumor recurrence and therapy-related changes. Tumor recurrence appears as a lesion metabolically active, while radiation necrosis appears metabolically inactive. However, no imaging modality has sufficient specificity and tissue biopsy remains the gold standard to obtain a definitive diagnosis.

GBMs typically recur focally and in many cases surgery is possible. **Repeat surgery** is performed in approximately 25% of cases. Although a repeat surgery is associated with a higher complication rates than the initial surgery, this increase is rather small and clearly acceptable [50, 51]. However, its efficacy is debated. Many recent studies reported a survival benefit and an improvement of quality of life resulting from repeat resections in selected patients. Performing an overview of the current literature on second surgery for recurrent GBM, Montemurro et al. found the median overall survival from diagnosis being 18.5 months and the median survival from second surgery being 9.7 months [51]. Extent of resection at reoperation has been demonstrated to improve overall survival, thus a maximum safe excision should be the surgical goal. The decision of a second surgery should be individualized and should involve a multidisciplinary team approach. The age and the preoperative performance status are the most important predictors of a prolonged survival. A more favorable prognosis following surgery for recurrence is associated with a younger age (< 60 years) and a good preoperative performance status (KPS ≥ 70) [51]. Reoperation is not recommended for patients with involvement of eloquent brain regions.

Thus, patients with recurrent GBM may benefit from resection of tumor whenever safely possible. Repeat surgery can help in providing symptom relief and differentiating tumor recurrence from pseudoprogression, radiation necrosis, respectively. But surgery should be followed by adjuvant therapies.
