Toxicity of Cranial and Spinal Cord Irradiation

*Jason Naziri and Steven J. DiBiase*

## **Abstract**

Along with surgery and chemotherapy, radiation therapy is an essential treatment option for metastatic and primary tumors of the central nervous system. Radiation toxicity may be compartmentalized into three subcategories including acute toxicities, early-delayed and late delayed effects. Radiation induced toxicity spans from self-limiting fatigue to more serious delayed side effects of radionecrosis. Stereotactic radiosurgery has recently emerged as a highly focused delivery method of tumoricidal irradiation with promising results compared to whole brain irradiation in many cases. Recognizing and understanding toxicity from cranial irradiation can help guide therapy as ever evolving new technologies develop within this integral component of cancer treatment.

**Keywords:** cranial irradiation, CNS toxicity, stereotactic radiosurgery, radionecrosis, radiation induced brain toxicity

## **1. Introduction**

Treatment of central nervous system (CNS) tumors involves surgery, chemotherapy, radiation therapy, immunotherapy, or a combination of these modalities. Radiation therapy is a highly effect treatment that plays a role in the management of brain metastases, gliomas, primary central nervous system lymphomas, and meningiomas among other brain tumors.

Radiation toxicity can be divided into three subcategories including acute toxicities, usually arising within 6 weeks of treatment, early-delayed effects (up to 4 months post-irradiation) and late delayed starting 4 months after completion of radiation therapy to several years later.

Central nervous system toxicity can be better understood by compartmentalizing toxicities based on cell biology. Injury to brain parenchyma effected by radiation includes neuronal cells, glial cells, and vasculature. Surprisingly, side effects of radiation are likely not due to damage directly to neuronal cells [1]. This is in part due to the paucity of cell replication of most neurons. As such, radiation toxicity primarily effects glial oligodendrocytes which are the insulating myelin producing cells and glial astrocytes responsible for the essential blood brain barrier. Endothelial vasculature of post-capillary venules within brain parenchyma are also highly susceptible to damaging effects of ionizing radiation. Increased cranial pressure and edema caused by radiation is deemed to be related to damage to endothelial cells [2]. In addition to direct damage to the endothelia, the tight junctions of endothelial cells are another component of the blood-brain barrier. The saliency of

the blood brain barrier and the susceptibility to damage by irradiation, makes it a point of focus when discussing CNS toxicity.

Not all neuronal cells are uniformly resilient to ionizing radiation. Recent studies have shown extreme sensitivity to even low-dose irradiation to the hippocampus. This is due to damage to highly proliferative neuronal progenitor cells. Specifically, the subgranular zone (SGZ) of the dentate gyrus has been shown to be extremely susceptible to damage to progenitor cells. Research for why these phenomena exists is ongoing. In addition to direct damage to neural progenitor cells, recent studies have linked neuronal damage to endothelial vasculature within the SGZ. Loss of integrity of inter-endothelial tight junctions (and eventually the blood brain barrier) causes edema and an inflammatory response that prevents the proliferation of neuronal progenitor cells. Clinical manifestations of impairment within this very crucial part of the CNS (the dentate gyrus of the hippocampus which is responsible for transitioning short term memories into long term memories) is linked to the irreversible late delayed side effect of cognitive dysfunction [3–5]. It is worth mentioning that these sequelae of radiation to the hippocampus can manifest even with doses as low as 2 Gy or less [6, 7]. Strategies to preserve neurocognitive function in patients receiving whole brain radiation therapy now include hippocampal sparing techniques [8, 9]. Hippocampal avoidance is one of many creative strategies postulated by radiation oncologists to aid in minimizing toxicity. Modern radiation delivery techniques are beyond the scope of this chapter. Some of these modalities used to avoid sensitive anatomic regions and decrease healthy tissue exposure include IMRT, stereotactic radiosurgery, and proton therapy. These novel modalities of radiation therapy continue to be refined in hopes of decreasing brain injury and increasing local control.

Astrocytes also play an important role in support and function of neurons. The cell line responsible for proliferation and differentiation of astrocytes and oligodendrocytes is the oligodendrocyte type-2 astrocyte progenitor cell (O-2A) [2]. In addition to being a crucial component of the BBB, astrocytes have been shown to be homeostatic regulators providing multiple heterogeneous functions including protecting brain parenchyma from reactive oxygen species [10]. Neuroinflammation and reactive astrogliosis caused by irradiation to astrocytes and O-2A, disrupt the BBB and likely play a role in edema.

Therapeutic techniques investigating the loss of neurogenesis are also underway. Inflammation is primarily instigated by microglial cells. Decreasing the inflammatory load within the SGZ by using a nonsteroidal anti-inflammatory, namely indomethacin in this case, helped preserve neuronal progenitor cells [6]. Reducing the inflammatory load caused by radiation may decrease CNS toxicity which in this study was cognitive decline. Prophylactic nonsteroidal anti-inflammatory drugs are not currently standard of care in preventing radiation side effects.

As mentioned earlier, glial cells are by far the most abundant types of cells within the CNS and responsible for neuronal support and protection. Glial progenitor cells which gives rise to oligodendrocytes and astrocytes are vulnerable targets of damage induced by radiation. In addition to glial progenitors, fully differentiated oligodendrocytes are also known to be sensitive to radiation. Enough damage to the DNA of oligodendrocytes can induce a P53 dependent apoptosis [2, 11]. Taking these two cell lines into consideration, damage to myelin producing oligodendrocytes in addition to glial progenitor cells responsible for generating new oligodendrocytes and astrocytes leads to CNS toxicity [2]. Treatment strategies to ameliorate CNS toxicity focused on re-establishing the efficacy of glial progenitor cells are ongoing. To date, optimal treatment for CNS toxicity is still unknown and strategies for managing side effects have yet to be delineated.

When considering the source of CNS toxicities, it is important to take into consideration the timeframe of manifestations, the specific presentation of symptoms,

**123**

irreversible and progressive.

*Toxicity of Cranial and Spinal Cord Irradiation DOI: http://dx.doi.org/10.5772/intechopen.85396*

ible and resolve spontaneously.

**2.2 Alopecia and radiation dermatitis**

**2.1 Fatigue**

options.

as well as whether the volume treated and dose deliver are compatible with side effects to the CNS. Other modalities of treatment including chemotherapy and immunotherapy as well as tumor progression can also have adverse effects on brain parenchyma on a cell biologic level. Deciphering the cause of CNS injury is not completely understood but should be taken into consideration in guiding treatment

Early side effects of radiation treatment are considered to manifest during or within 6 weeks of completion of radiation therapy. Acute side effects are usually transient and self-limiting, due to transient demyelination [3]. Symptoms are rare but may include fatigue, nausea, vomiting, headache, and focal neurologic deficits. These reported side effects were historically common with patients receiving doses >2 Gy per fraction. Reflected in current NCCN guidelines, most clinicians do not deliver conventional doses that exceed 2 Gy in one fraction as to avoid side effects. Acute radiation toxicities are rare with modern techniques with reports of grade 3 and 4 acute toxicities occurring in <5% of patients and are usually self-limiting [12]. Side effects occurring within 4 months of radiation treatment are considered early delayed effects and most commonly involve transient demyelination and somnolence. Similar to acute toxicities, early to late side effects are usually revers-

One of the most common side effect of radiation therapy to the central nervous system is fatigue and lethargy. Similar to patterns of irradiation outside of the CNS, side effects are cumulative and initially start to present 2 weeks into therapy [13, 14]. Fatigue usually starts around 2 weeks of therapy, peaks at or around completion of therapy, and resolves within several months. A severe form of fatigue, lethargy, and lack of concentration is known as somnolence syndrome (SS). SS typical occurs as an early delayed toxicity approximately 5–6 weeks after completion of radiation therapy. In one study, patients receiving a hypofractionated treatment plan compared to conventional fractionation experienced more severe fatigue [15].

Another common side effect of acute radiation toxicity is hair loss. Alopecia from radiation only occurs in areas where hair follicles are exposed to radiation and therefore can be sparse depending on scalp exposure. Alopecia can be permanent or temporary with higher doses to the scalp signifying permanent hair loss [16]. Radiation dermatitis is a desquamating rash that can occur to areas of the scalp exposed to radiation. Most cases are mild and are treated with moisturizing ointments. In severe

rare cases of moist desquamation, topical antibiotic ointment may be used.

Late-delayed side effects are of the most concern when discussing radiation toxicity. These effects occur starting after 4 months of treatment up to decades later. Unlike acute and early-delayed side effects, late-delayed side effects are largely

**3. Late-delayed toxicities of cranial irradiation**

**2. Acute and early-delayed toxicities of cranial irradiation**

as well as whether the volume treated and dose deliver are compatible with side effects to the CNS. Other modalities of treatment including chemotherapy and immunotherapy as well as tumor progression can also have adverse effects on brain parenchyma on a cell biologic level. Deciphering the cause of CNS injury is not completely understood but should be taken into consideration in guiding treatment options.

## **2. Acute and early-delayed toxicities of cranial irradiation**

Early side effects of radiation treatment are considered to manifest during or within 6 weeks of completion of radiation therapy. Acute side effects are usually transient and self-limiting, due to transient demyelination [3]. Symptoms are rare but may include fatigue, nausea, vomiting, headache, and focal neurologic deficits. These reported side effects were historically common with patients receiving doses >2 Gy per fraction. Reflected in current NCCN guidelines, most clinicians do not deliver conventional doses that exceed 2 Gy in one fraction as to avoid side effects. Acute radiation toxicities are rare with modern techniques with reports of grade 3 and 4 acute toxicities occurring in <5% of patients and are usually self-limiting [12].

Side effects occurring within 4 months of radiation treatment are considered early delayed effects and most commonly involve transient demyelination and somnolence. Similar to acute toxicities, early to late side effects are usually reversible and resolve spontaneously.

## **2.1 Fatigue**

*Brain and Spinal Tumors - Primary and Secondary*

point of focus when discussing CNS toxicity.

BBB and likely play a role in edema.

the blood brain barrier and the susceptibility to damage by irradiation, makes it a

Not all neuronal cells are uniformly resilient to ionizing radiation. Recent studies have shown extreme sensitivity to even low-dose irradiation to the hippocampus. This is due to damage to highly proliferative neuronal progenitor cells. Specifically, the subgranular zone (SGZ) of the dentate gyrus has been shown to be extremely susceptible to damage to progenitor cells. Research for why these phenomena exists is ongoing. In addition to direct damage to neural progenitor cells, recent studies have linked neuronal damage to endothelial vasculature within the SGZ. Loss of integrity of inter-endothelial tight junctions (and eventually the blood brain barrier) causes edema and an inflammatory response that prevents the proliferation of neuronal progenitor cells. Clinical manifestations of impairment within this very crucial part of the CNS (the dentate gyrus of the hippocampus which is responsible for transitioning short term memories into long term memories) is linked to the irreversible late delayed side effect of cognitive dysfunction [3–5]. It is worth mentioning that these sequelae of radiation to the hippocampus can manifest even with doses as low as 2 Gy or less [6, 7]. Strategies to preserve neurocognitive function in patients receiving whole brain radiation therapy now include hippocampal sparing techniques [8, 9]. Hippocampal avoidance is one of many creative strategies postulated by radiation oncologists to aid in minimizing toxicity. Modern radiation delivery techniques are beyond the scope of this chapter. Some of these modalities used to avoid sensitive anatomic regions and decrease healthy tissue exposure include IMRT, stereotactic radiosurgery, and proton therapy. These novel modalities of radiation therapy continue to be refined in hopes of decreasing brain injury and increasing local control. Astrocytes also play an important role in support and function of neurons. The cell line responsible for proliferation and differentiation of astrocytes and oligodendrocytes is the oligodendrocyte type-2 astrocyte progenitor cell (O-2A) [2]. In addition to being a crucial component of the BBB, astrocytes have been shown to be homeostatic regulators providing multiple heterogeneous functions including protecting brain parenchyma from reactive oxygen species [10]. Neuroinflammation and reactive astrogliosis caused by irradiation to astrocytes and O-2A, disrupt the

Therapeutic techniques investigating the loss of neurogenesis are also underway.

Inflammation is primarily instigated by microglial cells. Decreasing the inflammatory load within the SGZ by using a nonsteroidal anti-inflammatory, namely indomethacin in this case, helped preserve neuronal progenitor cells [6]. Reducing the inflammatory load caused by radiation may decrease CNS toxicity which in this study was cognitive decline. Prophylactic nonsteroidal anti-inflammatory drugs are

As mentioned earlier, glial cells are by far the most abundant types of cells within the CNS and responsible for neuronal support and protection. Glial progenitor cells which gives rise to oligodendrocytes and astrocytes are vulnerable targets of damage induced by radiation. In addition to glial progenitors, fully differentiated oligodendrocytes are also known to be sensitive to radiation. Enough damage to the DNA of oligodendrocytes can induce a P53 dependent apoptosis [2, 11]. Taking these two cell lines into consideration, damage to myelin producing oligodendrocytes in addition to glial progenitor cells responsible for generating new oligodendrocytes and astrocytes leads to CNS toxicity [2]. Treatment strategies to ameliorate CNS toxicity focused on re-establishing the efficacy of glial progenitor cells are ongoing. To date, optimal treatment for CNS toxicity is still unknown and strategies

When considering the source of CNS toxicities, it is important to take into consideration the timeframe of manifestations, the specific presentation of symptoms,

not currently standard of care in preventing radiation side effects.

for managing side effects have yet to be delineated.

**122**

One of the most common side effect of radiation therapy to the central nervous system is fatigue and lethargy. Similar to patterns of irradiation outside of the CNS, side effects are cumulative and initially start to present 2 weeks into therapy [13, 14]. Fatigue usually starts around 2 weeks of therapy, peaks at or around completion of therapy, and resolves within several months. A severe form of fatigue, lethargy, and lack of concentration is known as somnolence syndrome (SS). SS typical occurs as an early delayed toxicity approximately 5–6 weeks after completion of radiation therapy. In one study, patients receiving a hypofractionated treatment plan compared to conventional fractionation experienced more severe fatigue [15].

## **2.2 Alopecia and radiation dermatitis**

Another common side effect of acute radiation toxicity is hair loss. Alopecia from radiation only occurs in areas where hair follicles are exposed to radiation and therefore can be sparse depending on scalp exposure. Alopecia can be permanent or temporary with higher doses to the scalp signifying permanent hair loss [16]. Radiation dermatitis is a desquamating rash that can occur to areas of the scalp exposed to radiation. Most cases are mild and are treated with moisturizing ointments. In severe rare cases of moist desquamation, topical antibiotic ointment may be used.

## **3. Late-delayed toxicities of cranial irradiation**

Late-delayed side effects are of the most concern when discussing radiation toxicity. These effects occur starting after 4 months of treatment up to decades later. Unlike acute and early-delayed side effects, late-delayed side effects are largely irreversible and progressive.

#### **3.1 Cumulative effects**

Decline in neurocognitive function in patients with brain tumors is a multifactorial phenomenon. The connection between radiation toxicity and cognitive decline has been well documented. Nevertheless, it is important, however, to consider other factors as well as cumulative effects contributing to cognitive decline. Many patients treated with radiation are also treated in combination with chemotherapy. Multiple new targeted therapies have also been approved for use. Given that each of these individually may cause CNS side effects, it is of utmost importance for healthcare providers to be able to recognize toxicity and delineate whether symptoms are indeed being caused by treatments (either in combination or individually). Furthermore, there are multiple other reasons for why patients may have CNS complications, including tumor progression and advancement of pathologies unrelated to malignancy (dementia, depression, polypharmacy, anxiety, etc.).

#### **3.2 Long term delayed effects**

There exist patients who have undergone radiation treatment with an overall survival of multiple years and even decades. For many, cognitive deficits have not arisen even after 6 years of follow-up [6, 13]. Most patients even after 6 years have maintained a stable neurocognitive status. Differences in cognitive deficits were seen, however, in patients with low-grade gliomas who received radiation compared to patients who were radiation naïve after a 12 year follow up [6]. It is worth mentioning however that patients who do receive adjuvant radiation in low grade gliomas are more likely to have local control, better progression free survival and overall survival [14]. Multiple considerations should be taken into account when deciding the correct treatment plan for each individual patient. In the case of low grade gliomas, radiation and chemotherapy with procarbazine, CCNU, and vincristine is recommended by current NCCN guidelines. Given that neurocognitive effects are being reported over a decade after radiation treatment and less so at 6 years, additional long term delayed effects are of more trepidation now compared to years prior.

### **4. Stereotactic radiosurgery**

Advances in the technique and technology of radiation treatment to the brain has given rise to stereotactic radiosurgery. The use of localized radiosurgery in the setting of metastatic disease compared to whole-brain radiotherapy is an ongoing and complex discussion. In general, brain metastases arise from hematologic dissemination and have a poor overall prognosis [17]. Whole brain radiation has been utilized given the assumed likelihood of "seeding" or micrometasis to areas of the brain outside of visible metastasis seen on imaging. As mentioned earlier however, whole brain radiation therapy has high rates of toxicity, the most serious being cognitive impairment without the added benefit of overall survival [18–20]. It is worth mentioning that the concept of oligometastases has arisen among oncologists whereby disease may in fact be truly limited and treated as such. SRS alone, or in combination with whole brain radiation therapy, has thus become a viable option in single lesions or oligometastases. Being a localized modality of treatment, SRS alone has a higher likelihood of intracranial progression when compared with SRS in combination with WBRT. There has not been shown an increase in overall survival nor a better side effect profile with the addition WBRT to SRS vs. SRS

**125**

*Toxicity of Cranial and Spinal Cord Irradiation DOI: http://dx.doi.org/10.5772/intechopen.85396*

diameter and treated volume [25, 27, 28].

patients with larger lesions [25, 29].

hypofractionated treatment.

radionecrosis for V12 of less than 10 cm3

SRS after resection.

treatment of metastasis is being widely used [19, 21, 22].

preferred.

alone [19, 20]. Researchers have also concluded that the addition of WBRT results in excess morbidity and a decreased quality-of-life resulting in a 35% increase in neurocognitive deficit compared to SRS alone at 12 months. In one study, there was also a non-statistically significant survival benefit with SRS alone compared to SRS with WBRT [20]. Even with the better distant control of the addition of WBRT to SRS, the increase in morbidity does not outweigh the benefits and thus SRS alone is

Another viable option for limited brain metastases is surgical resection. Given similar outcomes in overall survival with surgical resection, decreased cost and, most importantly, less invasive nature of treatment compared to neurosurgery, SRS

The most common long term side effect of SRS is radionecrosis. While in certain cases radionecrosis can cause serious neurocognitive deficits requiring steroids or even surgical resection, certain patients remain asymptomatic and are diagnosed on imaging studies. Only about one third of patients with radionecrosis present with symptomatic neurologic deficits [23, 24]. Image based diagnoses can be difficult to distinguish from other phenomena including self-limiting inflammation [25]. There is a wide range of reported data on the rate of actuarial radionecrosis. In recent studies with adequate follow-up, rates vary from as low as 1.5% [26] to as high 34% [19, 25, 27] The main risk factor of radionecrosis are total dose, maximum tumor

Given the variability in data and to help gain a better understanding of risk factors for radionecrosis, it may be salient to delineate the setting in which SRS is being administered. Prevalence of radionecrosis can be divided based on single fraction treatments, hypo fractionated treatments (usually three fractions), and adjuvant

In patients receiving single fractionation SRS, the risk of radionecrosis are reported to be higher compared to hypofractionated [24]. Additionally, local control in hypofractionated regimens have had similar outcomes. Current NCCN guidelines recommend either single fraction or multi-fractionated SRS for the treatment of brain metastases, with multiple fractions utilized more commonly in

Not all patients radiologically diagnosed with radionecrosis are symptomatic. For patients that are symptomatic common manifestations include headache, seizures, motor deficits, sensory deficits, ataxia, and speech deficits [25].

In the past decade, SRS has more frequently been utilized in the post-resection adjuvant setting of brain metastases rather than WBRT. In hopes of optimizing local control and overall survival, SRS is administered to the tumor bed with the goal of covering subtotal resections and unrevealed disease that may have been left behind. In this setting, the prevalence of radionecrosis is varied with trends towards decreased toxicity with hypofractionated schedules compared to single fraction SRS [23, 26, 30]. The region of the brain being irradiated may have implications of morbidity as well. Infratentorial metastases are particularly problematic in that they portend worse outcomes and have a higher rate of radionecrosis [30]. Patients with higher risk of radionecrosis, including large tumors >3 cm, should be considered for

Another method of predicting radionecrosis in patients being treated with SRS is looking at volumes of brain parenchyma receiving a specific dose. Specifically, volumes receiving 10 Gy (V10) and 12 Gy (V12) have demonstrated strong predictive value in single fraction SRS [24, 25, 31]. The risk of radionecrosis can be predicted using specific volumes that receive certain doses. For example, risk of

is 22% compared to more than 10 cm3

#### *Toxicity of Cranial and Spinal Cord Irradiation DOI: http://dx.doi.org/10.5772/intechopen.85396*

*Brain and Spinal Tumors - Primary and Secondary*

Decline in neurocognitive function in patients with brain tumors is a multifactorial phenomenon. The connection between radiation toxicity and cognitive decline has been well documented. Nevertheless, it is important, however, to consider other factors as well as cumulative effects contributing to cognitive decline. Many patients treated with radiation are also treated in combination with chemotherapy. Multiple new targeted therapies have also been approved for use. Given that each of these individually may cause CNS side effects, it is of utmost importance for healthcare providers to be able to recognize toxicity and delineate whether symptoms are indeed being caused by treatments (either in combination or individually). Furthermore, there are multiple other reasons for why patients may have CNS complications, including tumor progression and advancement of pathologies unrelated

to malignancy (dementia, depression, polypharmacy, anxiety, etc.).

There exist patients who have undergone radiation treatment with an overall survival of multiple years and even decades. For many, cognitive deficits have not arisen even after 6 years of follow-up [6, 13]. Most patients even after 6 years have maintained a stable neurocognitive status. Differences in cognitive deficits were seen, however, in patients with low-grade gliomas who received radiation compared to patients who were radiation naïve after a 12 year follow up [6]. It is worth mentioning however that patients who do receive adjuvant radiation in low grade gliomas are more likely to have local control, better progression free survival and overall survival [14]. Multiple considerations should be taken into account when deciding the correct treatment plan for each individual patient. In the case of low grade gliomas, radiation and chemotherapy with procarbazine, CCNU, and vincristine is recommended by current NCCN guidelines. Given that neurocognitive effects are being reported over a decade after radiation treatment and less so at 6 years, additional long term delayed effects are of more trepidation now compared

Advances in the technique and technology of radiation treatment to the brain has given rise to stereotactic radiosurgery. The use of localized radiosurgery in the setting of metastatic disease compared to whole-brain radiotherapy is an ongoing and complex discussion. In general, brain metastases arise from hematologic dissemination and have a poor overall prognosis [17]. Whole brain radiation has been utilized given the assumed likelihood of "seeding" or micrometasis to areas of the brain outside of visible metastasis seen on imaging. As mentioned earlier however, whole brain radiation therapy has high rates of toxicity, the most serious being cognitive impairment without the added benefit of overall survival [18–20]. It is worth mentioning that the concept of oligometastases has arisen among oncologists whereby disease may in fact be truly limited and treated as such. SRS alone, or in combination with whole brain radiation therapy, has thus become a viable option in single lesions or oligometastases. Being a localized modality of treatment, SRS alone has a higher likelihood of intracranial progression when compared with SRS in combination with WBRT. There has not been shown an increase in overall survival nor a better side effect profile with the addition WBRT to SRS vs. SRS

**3.1 Cumulative effects**

**3.2 Long term delayed effects**

to years prior.

**4. Stereotactic radiosurgery**

**124**

alone [19, 20]. Researchers have also concluded that the addition of WBRT results in excess morbidity and a decreased quality-of-life resulting in a 35% increase in neurocognitive deficit compared to SRS alone at 12 months. In one study, there was also a non-statistically significant survival benefit with SRS alone compared to SRS with WBRT [20]. Even with the better distant control of the addition of WBRT to SRS, the increase in morbidity does not outweigh the benefits and thus SRS alone is preferred.

Another viable option for limited brain metastases is surgical resection. Given similar outcomes in overall survival with surgical resection, decreased cost and, most importantly, less invasive nature of treatment compared to neurosurgery, SRS treatment of metastasis is being widely used [19, 21, 22].

The most common long term side effect of SRS is radionecrosis. While in certain cases radionecrosis can cause serious neurocognitive deficits requiring steroids or even surgical resection, certain patients remain asymptomatic and are diagnosed on imaging studies. Only about one third of patients with radionecrosis present with symptomatic neurologic deficits [23, 24]. Image based diagnoses can be difficult to distinguish from other phenomena including self-limiting inflammation [25]. There is a wide range of reported data on the rate of actuarial radionecrosis. In recent studies with adequate follow-up, rates vary from as low as 1.5% [26] to as high 34% [19, 25, 27] The main risk factor of radionecrosis are total dose, maximum tumor diameter and treated volume [25, 27, 28].

Given the variability in data and to help gain a better understanding of risk factors for radionecrosis, it may be salient to delineate the setting in which SRS is being administered. Prevalence of radionecrosis can be divided based on single fraction treatments, hypo fractionated treatments (usually three fractions), and adjuvant SRS after resection.

In patients receiving single fractionation SRS, the risk of radionecrosis are reported to be higher compared to hypofractionated [24]. Additionally, local control in hypofractionated regimens have had similar outcomes. Current NCCN guidelines recommend either single fraction or multi-fractionated SRS for the treatment of brain metastases, with multiple fractions utilized more commonly in patients with larger lesions [25, 29].

Not all patients radiologically diagnosed with radionecrosis are symptomatic. For patients that are symptomatic common manifestations include headache, seizures, motor deficits, sensory deficits, ataxia, and speech deficits [25].

In the past decade, SRS has more frequently been utilized in the post-resection adjuvant setting of brain metastases rather than WBRT. In hopes of optimizing local control and overall survival, SRS is administered to the tumor bed with the goal of covering subtotal resections and unrevealed disease that may have been left behind. In this setting, the prevalence of radionecrosis is varied with trends towards decreased toxicity with hypofractionated schedules compared to single fraction SRS [23, 26, 30]. The region of the brain being irradiated may have implications of morbidity as well. Infratentorial metastases are particularly problematic in that they portend worse outcomes and have a higher rate of radionecrosis [30]. Patients with higher risk of radionecrosis, including large tumors >3 cm, should be considered for hypofractionated treatment.

Another method of predicting radionecrosis in patients being treated with SRS is looking at volumes of brain parenchyma receiving a specific dose. Specifically, volumes receiving 10 Gy (V10) and 12 Gy (V12) have demonstrated strong predictive value in single fraction SRS [24, 25, 31]. The risk of radionecrosis can be predicted using specific volumes that receive certain doses. For example, risk of radionecrosis for V12 of less than 10 cm3 is 22% compared to more than 10 cm3

which more than doubles the risk to 55% [32]. Novel studies have proposed using V12 as the standard method of reporting dose to assess toxicity [25]. For patients receiving V12 of <8.5 cm3 , the risk of radionecrosis increase to >10% and patients should be considered for hypofractionated rather than single fraction SRS [25].

Options in the treatment of radionecrosis includes steroids, hyperbaric oxygen, and surgery. There exist novel therapies such as bevacizumab and focused interstitial laser thermal therapy with variable efficacy in treatment [33].

Stereotactic radiosurgery (SRS) is usually well-tolerated and risks of high grade toxicity are low. The most important sequelae of SRS is radiation necrosis. Risks and benefits must be weighed out on an individualized basis using an evidence based and patient centered approach.

## **5. Hypopituitarism induced by radiation**

Endocrine deficiencies have also been reported in lesions irradiated near the hypothalamic-pituitary axis or pituitary gland. The prevalence of endocrinopathies are higher with nasopharyngeal cancers compared to intracerebral tumors, yet there were no differences in the rate of endocrine dysfunction based on underlying tumor type [34]. Endocrinopathies may include panhypopituitarism, hypothalamic hypothyroidism, and hypothalamic hypogonadism among others. A significant portion of the pediatric population treated with radiation therapy are vulnerable to pituitary dysfunction, most commonly growth hormone deficiency revealing short stature and retarded growth [35].

Patients with the pituitary adenomas are commonly treated with either single fraction SRS or hypofractionated SRS with similar rates of efficacy in tumor control and prevalence in new-onset hypopituitarism. Rates of hypopituitarism vary but are reported to be as high as 66% in conventional radiotherapy and significantly lower with stereotactic radiosurgery 5–37% [35–39].

Endocrine dysfunction is considered a late-delay side effect, but current literature is lacking in predicting a timeline for when hypopituitarism can occur. Follow up with dynamic serum hormonal values is of paramount importance given higher likelihood of developing endocrinopathies with longer follow up [35, 37].

#### **6. Radiation induced optic neuropathy and stereotactic radiosurgery**

Certain tumor types treated with SRS expose the optic nerves to high doses of radiation that may induce a decrease in visual acuity and blindness. Deterioration of vision may be reversible in an acute setting and is more likely to be permanent >6 months after treatment. Optic neuropathy from radiation is usually painless and can be monocular or biocular depending on whether optic nerves or the optic chiasm are exposed to radiation. Doses of radiation to optic nerves are closely monitored and circumvented as best as possible for patients receiving treatment for meningiomas, pituitary adenomas, and craniopharyngiomas.

Significant risk factors for radiation-induced optic neuropathy include prior radiation re-exposure to the optic chiasm. Prior EBRT and SRS are both risk factors for radiation induced optic neuropathy. Although multiple centers consider <8 Gy to be the upper limit of acceptable tolerability, single fractions of <12 Gy have been validated by recent literature [40–42]. A large recent analysis of pooled data consider the risk of radiation induced optic neuropathy to be 0–2% in patients with no prior irradiation to the optic apparatus and a single fraction <12 Gy [42] and even lower (<1%) for patients with a single fraction of <10 Gy [43].

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**7. Toxicities of spinal cord irradiation**

have been given without acute effects [32].

to occur in the acute period of toxicity [47].

concern is delayed-onset radionecrosis of the spinal cord.

planning and treatment.

*Radiation myelopathy* is the term commonly used for side effects of radiation toxicity to the spinal cord. Late effects of radiation myelopathy are a serious concern for radiation oncologists during treatment planning of CNS as well as extra-neural tumors within the treatment field. This is, in part, due to higher doses of radiation required for certain tumors (lung, certain head and neck, mediastinal tumors). Moreover, metastatic disease to the spine often requires radiation therapy and is becoming more common thanks to the advent of immunotherapy [44]. Long term effects may cause life limiting sequelae and are of paramount concern to radiation

Adverse facts of spinal cord irradiation are largely determined by the radiation treatment field and can affect both the central and peripheral nervous system. Just as side effects can be subdivided by timeframe in radiation toxicity to the brain, toxicities of spinal cord irradiation are classified as early toxicity, early-delayed effects, and long term effects. Accordingly, the durations are during treatment and up to a couple weeks after treatment, within 3 months of treatment, and more than 3 months after treatment. Although acute central nervous system damage has been reported following acute brain irradiation, there is no clinical or experimental evidence that radiation induces acute spinal cord toxicity. Single doses of up to 100 Gy

Significant advances have been made in the treatment of spinal malignancies extrapolating progress made from cranial stereotactic techniques of within millimeter precision high dose focal treatment plans. Recently, SRS has also been utilized for metastasis to the spinal cord. It is important to note that metastasis to the spinal bone, although extremely painful at times, does not carry the risk of neurologic

Side effects using SRS are extremely rare for spinal tumors. Short-term toxicity although more common, are still at low rates and are usually self-limiting [45]. One study showed no long term side effects with SRS patients with spinal metastasis. It seems as if long-term toxicity from radiation using SRS and dose sparing techniques to organs at risk is extremely rare with modern treatment techniques and attention to dose volume parameters. The complication of vertebral compression fracture (VCF) is multifactorial including older age portending to higher incidences osteoporosis but may be attributed to, in part, radiation therapy [46]. Doses above 20 Gy in a single fraction have been implicated as a risk factor. The risk of VCF tends

The main factors associated with risk of neurologic deficit relate to total dose, length of spinal cord irradiated, fractionation scheme and total duration of treatment. An absolute threshold for development of myelopathy cannot be stated. There has not been an established threshold; however the risk of myelopathy varies from 0.2 to 5% at 5 years [39]. Another side effects or radiation to the spine is characterized by acute paralysis presumably secondary to ischemia. Brown-Séquard syndrome is another rare syndrome that has been documented and is characterized by paralysis and loss of proprioception to the ipsilateral side and loss of pain and temperature to the contralateral side. Similar to irradiation to the brain, the greatest

Common types of side effects for single dose SRS with 10–16 Gy include: neurologic signs of motor weakness and sensory changes of the extremities [48]. There was no detectable acute or subacute radiation toxicity in this series noted clinically during the maximum follow-up time of 24 months. Other more disabling manifestations of radiation injury, including acute paralysis secondary to ischemia, hemorrhage within the spinal cord, and a lower motor neuron syndrome, are much less

compromise posed by spinal cord tumors or spinal impingement.

*Brain and Spinal Tumors - Primary and Secondary*

receiving V12 of <8.5 cm3

and patient centered approach.

stature and retarded growth [35].

**5. Hypopituitarism induced by radiation**

lower with stereotactic radiosurgery 5–37% [35–39].

which more than doubles the risk to 55% [32]. Novel studies have proposed using V12 as the standard method of reporting dose to assess toxicity [25]. For patients

should be considered for hypofractionated rather than single fraction SRS [25]. Options in the treatment of radionecrosis includes steroids, hyperbaric oxygen, and surgery. There exist novel therapies such as bevacizumab and focused intersti-

Stereotactic radiosurgery (SRS) is usually well-tolerated and risks of high grade toxicity are low. The most important sequelae of SRS is radiation necrosis. Risks and benefits must be weighed out on an individualized basis using an evidence based

Endocrine deficiencies have also been reported in lesions irradiated near the hypothalamic-pituitary axis or pituitary gland. The prevalence of endocrinopathies are higher with nasopharyngeal cancers compared to intracerebral tumors, yet there were no differences in the rate of endocrine dysfunction based on underlying tumor type [34]. Endocrinopathies may include panhypopituitarism, hypothalamic hypothyroidism, and hypothalamic hypogonadism among others. A significant portion of the pediatric population treated with radiation therapy are vulnerable to pituitary dysfunction, most commonly growth hormone deficiency revealing short

Patients with the pituitary adenomas are commonly treated with either single fraction SRS or hypofractionated SRS with similar rates of efficacy in tumor control and prevalence in new-onset hypopituitarism. Rates of hypopituitarism vary but are reported to be as high as 66% in conventional radiotherapy and significantly

Endocrine dysfunction is considered a late-delay side effect, but current literature is lacking in predicting a timeline for when hypopituitarism can occur. Follow up with dynamic serum hormonal values is of paramount importance given higher

likelihood of developing endocrinopathies with longer follow up [35, 37].

meningiomas, pituitary adenomas, and craniopharyngiomas.

even lower (<1%) for patients with a single fraction of <10 Gy [43].

**6. Radiation induced optic neuropathy and stereotactic radiosurgery**

Certain tumor types treated with SRS expose the optic nerves to high doses of radiation that may induce a decrease in visual acuity and blindness. Deterioration of vision may be reversible in an acute setting and is more likely to be permanent >6 months after treatment. Optic neuropathy from radiation is usually painless and can be monocular or biocular depending on whether optic nerves or the optic chiasm are exposed to radiation. Doses of radiation to optic nerves are closely monitored and circumvented as best as possible for patients receiving treatment for

Significant risk factors for radiation-induced optic neuropathy include prior radiation re-exposure to the optic chiasm. Prior EBRT and SRS are both risk factors for radiation induced optic neuropathy. Although multiple centers consider <8 Gy to be the upper limit of acceptable tolerability, single fractions of <12 Gy have been validated by recent literature [40–42]. A large recent analysis of pooled data consider the risk of radiation induced optic neuropathy to be 0–2% in patients with no prior irradiation to the optic apparatus and a single fraction <12 Gy [42] and

tial laser thermal therapy with variable efficacy in treatment [33].

, the risk of radionecrosis increase to >10% and patients

**126**

## **7. Toxicities of spinal cord irradiation**

*Radiation myelopathy* is the term commonly used for side effects of radiation toxicity to the spinal cord. Late effects of radiation myelopathy are a serious concern for radiation oncologists during treatment planning of CNS as well as extra-neural tumors within the treatment field. This is, in part, due to higher doses of radiation required for certain tumors (lung, certain head and neck, mediastinal tumors). Moreover, metastatic disease to the spine often requires radiation therapy and is becoming more common thanks to the advent of immunotherapy [44]. Long term effects may cause life limiting sequelae and are of paramount concern to radiation planning and treatment.

Adverse facts of spinal cord irradiation are largely determined by the radiation treatment field and can affect both the central and peripheral nervous system. Just as side effects can be subdivided by timeframe in radiation toxicity to the brain, toxicities of spinal cord irradiation are classified as early toxicity, early-delayed effects, and long term effects. Accordingly, the durations are during treatment and up to a couple weeks after treatment, within 3 months of treatment, and more than 3 months after treatment. Although acute central nervous system damage has been reported following acute brain irradiation, there is no clinical or experimental evidence that radiation induces acute spinal cord toxicity. Single doses of up to 100 Gy have been given without acute effects [32].

Significant advances have been made in the treatment of spinal malignancies extrapolating progress made from cranial stereotactic techniques of within millimeter precision high dose focal treatment plans. Recently, SRS has also been utilized for metastasis to the spinal cord. It is important to note that metastasis to the spinal bone, although extremely painful at times, does not carry the risk of neurologic compromise posed by spinal cord tumors or spinal impingement.

Side effects using SRS are extremely rare for spinal tumors. Short-term toxicity although more common, are still at low rates and are usually self-limiting [45]. One study showed no long term side effects with SRS patients with spinal metastasis.

It seems as if long-term toxicity from radiation using SRS and dose sparing techniques to organs at risk is extremely rare with modern treatment techniques and attention to dose volume parameters. The complication of vertebral compression fracture (VCF) is multifactorial including older age portending to higher incidences osteoporosis but may be attributed to, in part, radiation therapy [46]. Doses above 20 Gy in a single fraction have been implicated as a risk factor. The risk of VCF tends to occur in the acute period of toxicity [47].

The main factors associated with risk of neurologic deficit relate to total dose, length of spinal cord irradiated, fractionation scheme and total duration of treatment. An absolute threshold for development of myelopathy cannot be stated. There has not been an established threshold; however the risk of myelopathy varies from 0.2 to 5% at 5 years [39]. Another side effects or radiation to the spine is characterized by acute paralysis presumably secondary to ischemia. Brown-Séquard syndrome is another rare syndrome that has been documented and is characterized by paralysis and loss of proprioception to the ipsilateral side and loss of pain and temperature to the contralateral side. Similar to irradiation to the brain, the greatest concern is delayed-onset radionecrosis of the spinal cord.

Common types of side effects for single dose SRS with 10–16 Gy include: neurologic signs of motor weakness and sensory changes of the extremities [48]. There was no detectable acute or subacute radiation toxicity in this series noted clinically during the maximum follow-up time of 24 months. Other more disabling manifestations of radiation injury, including acute paralysis secondary to ischemia, hemorrhage within the spinal cord, and a lower motor neuron syndrome, are much less

common, with only a few case reports in the literature. The treatment of radiation myelopathy has not been well studied. High dose corticosteroids are considered first line therapy.

## **8. Conclusions**

Radiation therapy is highly effective in CNS malignancies. Nevertheless, the rate limiting step in treatment is associated with adverse side effects to healthy tissue. As the treatment of CNS malignancies advance with novel therapies and ever evolving therapeutic combinations, the goal of minimizing treatment side effects remains the same. Significant progress has been made in attempting to understand the dynamic mechanisms of brain injury caused by irradiation to healthy tissue. As patients continue to live longer, central nervous system side effects are of utmost importance to recognize and treat. Radiation oncologists among other cancer specialists are putting keen focus and effort towards increasing and optimizing quality-of-life in addition to overall survival in cancer patients.

## **Conflict of interest**

Authors do not have conflicts of interest to declare.

## **Author details**

Jason Naziri\* and Steven J. DiBiase Weill Cornell Medical College, New York Presbyterian, New York, USA

\*Address all correspondence to: Jnaziri2@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.

**129**

*Toxicity of Cranial and Spinal Cord Irradiation DOI: http://dx.doi.org/10.5772/intechopen.85396*

> [10] Baxter PS, Hardingham GE. Adaptive regulation of the brain's antioxidant defences by neurons and astrocytes. Free Radical Biology & Medicine. 2016;**100**:147-152

[11] Chow BM, Li YQ, Wong CS. Radiation-induced apoptosis in the adult central nervous system is p53-dependent. Cell Death and Differentiationr. 2000;**7**(8):712-720

2011;**29**(3):272-278

2016;**21**(6):560-566

[12] Gore EM et al. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: Primary analysis of radiation therapy oncology group study RTOG 0214. Journal of Clinical Oncology.

[13] Harjani RR, Gururajachar JM, Krishnaswamy U. Comprehensive assessment of somnolence syndrome in patients undergoing radiation to the brain. Reports of Practical Oncology and Radiotherapy.

[14] Powell C et al. Somnolence syndrome in patients receiving radical radiotherapy for primary brain tumours: A prospective study. Radiotherapy and

Oncology. 2011;**100**(1):131-136

[15] Faithfull S, Brada M. Somnolence syndrome in adults following cranial irradiation for primary brain tumours. Clinical Oncology (Royal College of Radiologists). 1998;**10**(4):250-254

[16] Lawenda BD et al. Permanent alopecia after cranial irradiation: Doseresponse relationship. International Journal of Radiation Oncology, Biology,

Physics. 2004;**60**(3):879-887

[17] Nieder C et al. Postoperative treatment and prognosis of patients with resected single brain metastasis: How useful are established prognostic

**References**

[1] Li YQ, Jay V, Wong CS. Oligodendrocytes in the adult rat spinal cord undergo radiationinduced apoptosis. Cancer Research.

1996;**56**(23):5417-5422

2001;**85**(9):1233-1239

2007;**46**(2):167-172

2007;**18**(1):115-127, x

2003;**63**(14):4021-4027

2009;**8**(9):810-818

Oncology. 2018;**8**:415

[6] Mizumatsu S et al. Extreme

[7] Douw L et al. Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: Longterm follow-up. Lancet Neurology.

Oncology. 2008;**87**(3):279-286

[4] Limoli CL et al. Redox changes induced in hippocampal precursor cells by heavy ion irradiation. Radiation and Environmental Biophysics.

[2] Belka C et al. Radiation induced CNS toxicity—Molecular and cellular mechanisms. British Journal of Cancer.

[3] Kim JH et al. Mechanisms of radiationinduced brain toxicity and implications for future clinical trials. Journal of Neuro-

[5] Fike JR, Rola R, Limoli CL. Radiation response of neural precursor cells. Neurosurgery Clinics of North America.

sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Research.

[8] Robin TP, Rusthoven CG. Strategies to preserve cognition in patients with brain metastases: A review. Frontiers in

[9] Gondi V et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): A phase II multiinstitutional trial. Journal of Clinical Oncology. 2014;**32**(34):3810-3816

*Toxicity of Cranial and Spinal Cord Irradiation DOI: http://dx.doi.org/10.5772/intechopen.85396*

## **References**

*Brain and Spinal Tumors - Primary and Secondary*

line therapy.

**8. Conclusions**

**Conflict of interest**

**Author details**

common, with only a few case reports in the literature. The treatment of radiation myelopathy has not been well studied. High dose corticosteroids are considered first

Radiation therapy is highly effective in CNS malignancies. Nevertheless, the rate limiting step in treatment is associated with adverse side effects to healthy tissue. As the treatment of CNS malignancies advance with novel therapies and ever evolving therapeutic combinations, the goal of minimizing treatment side effects remains the same. Significant progress has been made in attempting to understand the dynamic mechanisms of brain injury caused by irradiation to healthy tissue. As patients continue to live longer, central nervous system side effects are of utmost importance to recognize and treat. Radiation oncologists among other cancer specialists are putting keen focus and effort towards increasing and optimizing

quality-of-life in addition to overall survival in cancer patients.

Authors do not have conflicts of interest to declare.

**128**

provided the original work is properly cited.

\*Address all correspondence to: Jnaziri2@gmail.com

Jason Naziri\* and Steven J. DiBiase

© 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,

Weill Cornell Medical College, New York Presbyterian, New York, USA

[1] Li YQ, Jay V, Wong CS. Oligodendrocytes in the adult rat spinal cord undergo radiationinduced apoptosis. Cancer Research. 1996;**56**(23):5417-5422

[2] Belka C et al. Radiation induced CNS toxicity—Molecular and cellular mechanisms. British Journal of Cancer. 2001;**85**(9):1233-1239

[3] Kim JH et al. Mechanisms of radiationinduced brain toxicity and implications for future clinical trials. Journal of Neuro-Oncology. 2008;**87**(3):279-286

[4] Limoli CL et al. Redox changes induced in hippocampal precursor cells by heavy ion irradiation. Radiation and Environmental Biophysics. 2007;**46**(2):167-172

[5] Fike JR, Rola R, Limoli CL. Radiation response of neural precursor cells. Neurosurgery Clinics of North America. 2007;**18**(1):115-127, x

[6] Mizumatsu S et al. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Research. 2003;**63**(14):4021-4027

[7] Douw L et al. Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: Longterm follow-up. Lancet Neurology. 2009;**8**(9):810-818

[8] Robin TP, Rusthoven CG. Strategies to preserve cognition in patients with brain metastases: A review. Frontiers in Oncology. 2018;**8**:415

[9] Gondi V et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): A phase II multiinstitutional trial. Journal of Clinical Oncology. 2014;**32**(34):3810-3816

[10] Baxter PS, Hardingham GE. Adaptive regulation of the brain's antioxidant defences by neurons and astrocytes. Free Radical Biology & Medicine. 2016;**100**:147-152

[11] Chow BM, Li YQ, Wong CS. Radiation-induced apoptosis in the adult central nervous system is p53-dependent. Cell Death and Differentiationr. 2000;**7**(8):712-720

[12] Gore EM et al. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: Primary analysis of radiation therapy oncology group study RTOG 0214. Journal of Clinical Oncology. 2011;**29**(3):272-278

[13] Harjani RR, Gururajachar JM, Krishnaswamy U. Comprehensive assessment of somnolence syndrome in patients undergoing radiation to the brain. Reports of Practical Oncology and Radiotherapy. 2016;**21**(6):560-566

[14] Powell C et al. Somnolence syndrome in patients receiving radical radiotherapy for primary brain tumours: A prospective study. Radiotherapy and Oncology. 2011;**100**(1):131-136

[15] Faithfull S, Brada M. Somnolence syndrome in adults following cranial irradiation for primary brain tumours. Clinical Oncology (Royal College of Radiologists). 1998;**10**(4):250-254

[16] Lawenda BD et al. Permanent alopecia after cranial irradiation: Doseresponse relationship. International Journal of Radiation Oncology, Biology, Physics. 2004;**60**(3):879-887

[17] Nieder C et al. Postoperative treatment and prognosis of patients with resected single brain metastasis: How useful are established prognostic scores? Clinical Neurology and Neurosurgery. 2011;**113**(2):98-103

[18] Chang EL et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled trial. The Lancet Oncology. 2009;**10**(11):1037-1044

[19] Aoyama H et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: A randomized controlled trial. JAMA. 2006;**295**(21):2483-2491

[20] Brown PD et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: A randomized clinical trial. JAMA. 2016;**316**(4):401-409

[21] Frazier JL et al. Stereotactic radiosurgery in the management of brain metastases: An institutional retrospective analysis of survival. International Journal of Radiation Oncology, Biology, Physics. 2010;**76**(5):1486-1492

[22] Rades D et al. A matched-pair analysis comparing whole-brain radiotherapy plus stereotactic radiosurgery versus surgery plus whole-brain radiotherapy and a boost to the metastatic site for one or two brain metastases. International Journal of Radiation Oncology, Biology, Physics. 2009;**73**(4):1077-1081

[23] Dore M et al. Stereotactic radiotherapy following surgery for brain metastasis: Predictive factors for local control and radionecrosis. Cancer Radiothérapie. 2017;**21**(1):4-9

[24] Minniti G et al. Single-fraction versus multifraction (3 × 9 Gy) stereotactic radiosurgery for large (>2 cm) brain metastases: A

comparative analysis of local control and risk of radiation-induced brain necrosis. International Journal of Radiation Oncology, Biology, Physics. 2016;**95**(4):1142-1148

[25] Minniti G et al. Stereotactic radiosurgery for brain metastases: Analysis of outcome and risk of brain radionecrosis. Radiation Oncology. 2011;**6**:48

[26] Ahmed KA et al. Fractionated stereotactic radiotherapy to the postoperative cavity for radioresistant and radiosensitive brain metastases. Journal of Neuro-Oncology. 2014;**118**(1):179-186

[27] Kohutek ZA et al. Long-term risk of radionecrosis and imaging changes after stereotactic radiosurgery for brain metastases. Journal of Neuro-Oncology. 2015;**125**(1):149-156

[28] Korytko T et al. 12 Gy gamma knife radiosurgical volume is a predictor for radiation necrosis in non-AVM intracranial tumors. International Journal of Radiation Oncology, Biology, Physics. 2006;**64**(2):419-424

[29] National Comprehensive Cancer Network. Central Nervous System Cancer. 2018. Version 2.2018

[30] Keller A et al. Risk of radionecrosis after hypofractionated stereotactic radiotherapy targeting the postoperative resection cavity of brain metastases. Cancer Radiothérapie. 2017;**21**(5):377-388

[31] Blonigen BJ et al. Irradiated volume as a predictor of brain radionecrosis after linear accelerator stereotactic radiosurgery. International Journal of Radiation Oncology, Biology, Physics. 2010;**77**(4):996-1001

[32] Petrovich Z et al. Survival and pattern of failure in brain metastasis treated with stereotactic gamma knife

**131**

*Toxicity of Cranial and Spinal Cord Irradiation DOI: http://dx.doi.org/10.5772/intechopen.85396*

radiosurgery. Journal of Neurosurgery.

Journal of Radiation Oncology, Biology,

Physics. 2013;**87**(3):524-527

2003;**55**(5):1177-1181

[41] Stafford SL et al. A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. International Journal of Radiation Oncology, Biology, Physics.

[42] Milano MT et al. Single- and multi-fraction stereotactic radiosurgery dose tolerances of the optic pathways. International Journal of Radiation Oncology, Biology, Physics. 2018

[43] Hiniker SM et al. Dose-response modeling of the visual pathway tolerance to single-fraction and hypofractionated stereotactic radiosurgery. Seminars in Radiation Oncology. 2016;**26**(2):97-104

[44] Thariat J et al. Advances in radiation oncology for metastatic bone disease. Bulletin du Cancer.

[45] Rock JP et al. The evolving role of stereotactic radiosurgery and stereotactic radiation therapy for patients with spine tumors. Journal of Neuro-Oncology. 2004;**69**(1-3):319-334

[46] Wenger M. Vertebroplasty for metastasis. Medical Oncology.

[48] Yin FF et al. Dosimetric characteristics of Novalis shaped beam surgery unit. Medical Physics.

2002;**29**(8):1729-1738

[47] Faruqi S et al. Vertebral compression fracture after spine stereotactic body radiation therapy: A review of the pathophysiology and risk factors. Neurosurgery. 2018;**83**(3):314-322

2003;**20**(3):203-209

2013;**100**(11):1187-1197

[33] Chao ST et al. Challenges with the diagnosis and treatment of cerebral radiation necrosis. International Journal of Radiation Oncology, Biology, Physics.

[34] Lam KS et al. Effects of cranial irradiation on hypothalamicpituitary function—A 5-year longitudinal study in patients with nasopharyngeal carcinoma. The Quarterly Journal of Medicine.

[35] Appelman-Dijkstra NM et al. Pituitary dysfunction in adult patients after cranial radiotherapy: Systematic review and meta-analysis. The

Journal of Clinical Endocrinology and Metabolism. 2011;**96**(8):2330-2340

[36] Li X et al. Safety and efficacy of fractionated stereotactic radiotherapy and stereotactic radiosurgery for treatment of pituitary adenomas: A systematic review and meta-analysis. Journal of the Neurological Sciences.

2002;**97**(5 Suppl):499-506

2013;**87**(3):449-457

1991;**78**(286):165-176

2017;**372**:110-116

[37] Toogood AA. Endocrine consequences of brain irradiation. Growth Hormone & IGF Research. 2004;**14**(Suppl A):S118-S124

[38] Paek SH et al. Integration of surgery with fractionated stereotactic

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

[39] Stereotactic Radiosurgery and Radiotehrapy of Pituitary Adenomas

radiotherapy for treatment of nonfunctioning pituitary

Clinical White Paper. 2014

[40] Leavitt JA et al. Long-term evaluation of radiation-induced optic neuropathy after single-fraction stereotactic radiosurgery. International

2005;**61**(3):795-808

*Toxicity of Cranial and Spinal Cord Irradiation DOI: http://dx.doi.org/10.5772/intechopen.85396*

*Brain and Spinal Tumors - Primary and Secondary*

comparative analysis of local control and risk of radiation-induced brain necrosis. International Journal of Radiation Oncology, Biology, Physics.

[25] Minniti G et al. Stereotactic radiosurgery for brain metastases: Analysis of outcome and risk of brain radionecrosis. Radiation Oncology.

[26] Ahmed KA et al. Fractionated stereotactic radiotherapy to the postoperative cavity for radioresistant and radiosensitive brain metastases.

[27] Kohutek ZA et al. Long-term risk of radionecrosis and imaging changes after stereotactic radiosurgery for brain metastases. Journal of Neuro-Oncology.

[28] Korytko T et al. 12 Gy gamma knife radiosurgical volume is a predictor for radiation necrosis in non-AVM intracranial tumors. International Journal of Radiation Oncology, Biology,

Journal of Neuro-Oncology.

Physics. 2006;**64**(2):419-424

radiotherapy targeting the

2017;**21**(5):377-388

2010;**77**(4):996-1001

[29] National Comprehensive Cancer Network. Central Nervous System Cancer. 2018. Version 2.2018

[30] Keller A et al. Risk of radionecrosis after hypofractionated stereotactic

postoperative resection cavity of brain metastases. Cancer Radiothérapie.

[31] Blonigen BJ et al. Irradiated volume as a predictor of brain radionecrosis after linear accelerator stereotactic radiosurgery. International Journal of Radiation Oncology, Biology, Physics.

[32] Petrovich Z et al. Survival and pattern of failure in brain metastasis treated with stereotactic gamma knife

2014;**118**(1):179-186

2015;**125**(1):149-156

2016;**95**(4):1142-1148

2011;**6**:48

scores? Clinical Neurology and Neurosurgery. 2011;**113**(2):98-103

trial. The Lancet Oncology. 2009;**10**(11):1037-1044

2006;**295**(21):2483-2491

[20] Brown PD et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: A randomized clinical trial. JAMA. 2016;**316**(4):401-409

[21] Frazier JL et al. Stereotactic radiosurgery in the management of brain metastases: An institutional retrospective analysis of survival. International Journal of Radiation Oncology, Biology, Physics. 2010;**76**(5):1486-1492

[22] Rades D et al. A matched-pair analysis comparing whole-brain radiotherapy plus stereotactic radiosurgery versus surgery plus

2009;**73**(4):1077-1081

[23] Dore M et al. Stereotactic radiotherapy following surgery for brain metastasis: Predictive factors for local control and radionecrosis. Cancer

Radiothérapie. 2017;**21**(1):4-9

[24] Minniti G et al. Single-fraction versus multifraction (3 × 9 Gy) stereotactic radiosurgery for large (>2 cm) brain metastases: A

whole-brain radiotherapy and a boost to the metastatic site for one or two brain metastases. International Journal of Radiation Oncology, Biology, Physics.

[19] Aoyama H et al. Stereotactic

radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: A randomized controlled trial. JAMA.

[18] Chang EL et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled

**130**

radiosurgery. Journal of Neurosurgery. 2002;**97**(5 Suppl):499-506

[33] Chao ST et al. Challenges with the diagnosis and treatment of cerebral radiation necrosis. International Journal of Radiation Oncology, Biology, Physics. 2013;**87**(3):449-457

[34] Lam KS et al. Effects of cranial irradiation on hypothalamicpituitary function—A 5-year longitudinal study in patients with nasopharyngeal carcinoma. The Quarterly Journal of Medicine. 1991;**78**(286):165-176

[35] Appelman-Dijkstra NM et al. Pituitary dysfunction in adult patients after cranial radiotherapy: Systematic review and meta-analysis. The Journal of Clinical Endocrinology and Metabolism. 2011;**96**(8):2330-2340

[36] Li X et al. Safety and efficacy of fractionated stereotactic radiotherapy and stereotactic radiosurgery for treatment of pituitary adenomas: A systematic review and meta-analysis. Journal of the Neurological Sciences. 2017;**372**:110-116

[37] Toogood AA. Endocrine consequences of brain irradiation. Growth Hormone & IGF Research. 2004;**14**(Suppl A):S118-S124

[38] Paek SH et al. Integration of surgery with fractionated stereotactic radiotherapy for treatment of nonfunctioning pituitary macroadenomas. International Journal of Radiation Oncology, Biology, Physics. 2005;**61**(3):795-808

[39] Stereotactic Radiosurgery and Radiotehrapy of Pituitary Adenomas Clinical White Paper. 2014

[40] Leavitt JA et al. Long-term evaluation of radiation-induced optic neuropathy after single-fraction stereotactic radiosurgery. International Journal of Radiation Oncology, Biology, Physics. 2013;**87**(3):524-527

[41] Stafford SL et al. A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. International Journal of Radiation Oncology, Biology, Physics. 2003;**55**(5):1177-1181

[42] Milano MT et al. Single- and multi-fraction stereotactic radiosurgery dose tolerances of the optic pathways. International Journal of Radiation Oncology, Biology, Physics. 2018

[43] Hiniker SM et al. Dose-response modeling of the visual pathway tolerance to single-fraction and hypofractionated stereotactic radiosurgery. Seminars in Radiation Oncology. 2016;**26**(2):97-104

[44] Thariat J et al. Advances in radiation oncology for metastatic bone disease. Bulletin du Cancer. 2013;**100**(11):1187-1197

[45] Rock JP et al. The evolving role of stereotactic radiosurgery and stereotactic radiation therapy for patients with spine tumors. Journal of Neuro-Oncology. 2004;**69**(1-3):319-334

[46] Wenger M. Vertebroplasty for metastasis. Medical Oncology. 2003;**20**(3):203-209

[47] Faruqi S et al. Vertebral compression fracture after spine stereotactic body radiation therapy: A review of the pathophysiology and risk factors. Neurosurgery. 2018;**83**(3):314-322

[48] Yin FF et al. Dosimetric characteristics of Novalis shaped beam surgery unit. Medical Physics. 2002;**29**(8):1729-1738

Chapter 9

Abstract

the disease.

1. Introduction

2. Epidemiology

133

Pediatric Medulloblastoma: A

Keywords: medulloblastomas, radiosensitive, conformal, radiotherapy

the cerebrospinal fluid to cranial and spinal subarachnoid spaces [3].

Harvey Cushing and Percival Bailey were the first who described the name medulloblastoma as "Spongioblastoma Cerebelli" in June, 1925 for posterior fossa tumors of preadolescents population. They reported 29 cerebellar vermis tumor in children and young adults. Later they renamed as "medulloblastoma" as the term "Spongioblastoma multiforme" was described by Globus and Strauss in 1925 for various adults cerebral tumors in which feature of considerable cellular differentiation was seen. This picture was found absent in tumors of cerebellar origin [1, 2]. World Health Organization (WHO) defined medulloblastoma as "invasive malignant embryonal tumor of the cerebellum with commonest manifestation seen in children". These neuroepithelial tumors have inherent tendency to spread through

Injuries followed by malignancy are the second leading cause of mortality among

children. After leukaemia's, brain tumors are the most common in children accounting for '25%' of all malignancies in children [4]. Most common malignant CNS tumor in children is medulloblastoma (MB) constituting 20% of primary brain tumors and approximately 40% of all tumors of the posterior fossa [5]. The incidence of medulloblastoma in adults is relatively low as compared to pediatric population. This constitutes 1% of all CNS tumors and this may be the cause of scanty data available in

Meenu Gupta and Mushtaq Ahmad

Radiation Oncologist Perspective

Pediatric medulloblastomas are radiosensitive and mostly curable tumors if they are non-metastasized. Postsurgery adjuvant radiation therapy remains the cornerstone therapy in the curative intent treatment. In case of children less than three years, pre-irradiation chemotherapy is given to defer radiotherapy till the child is three year old. Introduction of conformal radiotherapy in addition to technical improvements in surgery and radiotherapy, risks definition and molecular analysis of prognostic factors has most likely contributed to the improved survival rates. Children should ideally be referred in time to an appropriate higher center with adequate infrastructure, expertise and radiotherapy facilities for better outcome of

## Chapter 9

## Pediatric Medulloblastoma: A Radiation Oncologist Perspective

Meenu Gupta and Mushtaq Ahmad

## Abstract

Pediatric medulloblastomas are radiosensitive and mostly curable tumors if they are non-metastasized. Postsurgery adjuvant radiation therapy remains the cornerstone therapy in the curative intent treatment. In case of children less than three years, pre-irradiation chemotherapy is given to defer radiotherapy till the child is three year old. Introduction of conformal radiotherapy in addition to technical improvements in surgery and radiotherapy, risks definition and molecular analysis of prognostic factors has most likely contributed to the improved survival rates. Children should ideally be referred in time to an appropriate higher center with adequate infrastructure, expertise and radiotherapy facilities for better outcome of the disease.

Keywords: medulloblastomas, radiosensitive, conformal, radiotherapy

### 1. Introduction

Harvey Cushing and Percival Bailey were the first who described the name medulloblastoma as "Spongioblastoma Cerebelli" in June, 1925 for posterior fossa tumors of preadolescents population. They reported 29 cerebellar vermis tumor in children and young adults. Later they renamed as "medulloblastoma" as the term "Spongioblastoma multiforme" was described by Globus and Strauss in 1925 for various adults cerebral tumors in which feature of considerable cellular differentiation was seen. This picture was found absent in tumors of cerebellar origin [1, 2]. World Health Organization (WHO) defined medulloblastoma as "invasive malignant embryonal tumor of the cerebellum with commonest manifestation seen in children". These neuroepithelial tumors have inherent tendency to spread through the cerebrospinal fluid to cranial and spinal subarachnoid spaces [3].

## 2. Epidemiology

Injuries followed by malignancy are the second leading cause of mortality among children. After leukaemia's, brain tumors are the most common in children accounting for '25%' of all malignancies in children [4]. Most common malignant CNS tumor in children is medulloblastoma (MB) constituting 20% of primary brain tumors and approximately 40% of all tumors of the posterior fossa [5]. The incidence of medulloblastoma in adults is relatively low as compared to pediatric population. This constitutes 1% of all CNS tumors and this may be the cause of scanty data available in

adult MB group [6]. U.S data showed the incidence of the medulloblastoma is 1.5–2 cases/100,000 population. Three hundred and fifty new cases in the United States are seen each year. The peak incidence is seen in 1st decade of life and incidence is noted higher in the pediatric age group 3–4 years followed by 8–10 years of age.

vasogenic edema and sometimes evidence of hydrocephalus is seen. Contrast

MRI imaging of the entire neuraxis, brain and spine is recommended for suspected cases. MRI images show "Low-to-intermediate signal intensity" on T1-weighted images and "moderately high signal intensity" on T2-weighted images, compared to cerebellar white matter. Intratumoral haemorrhage, peritumoral oedema, tonsillar herniation, hydrocephalus and calcification are other associated findings. Multivoxel MR spectroscopy (MRS) of the primary tumor can assess the tumor metabolites like 'elevated Choline peaks and decreased Creatine and N-acetyl acetate peaks'. Even without frank necrosis, a small amount of lipid-lactate peak sometimes observed indicating an increase in metabolic activity. Due to densely packed cells within the tumor and nuclear: cytoplasm ratio is higher, MB causes restriction of diffusion. There is restriction of diffusion of water particles in the tumor. So there is high signal of the tumor in diffusion-weighted MR images [11]. As frequency of spine seeding is 35% at diagnosis, to rule out any leptomeningeal metastases, Sagittal fat-suppressed post- gadolinium contrast MRI of the spine should be performed prior to surgery (Figure 1). Guang-Yao Wu et al. published

Weighted Imaging are helpful for qualitative diagnosis of medulloblastoma [12]. Baseline hearing status with tests like Audiometry, IQ Testing and hormonal

Mostly medium and large sized tumors in posterior fossa are associated with

peritoneal (VP) shunt should generally be avoided as definitive resection of tumor efficiently relieves the obstruction by opening the CSF pathways. Ideal surgery of any tumor is complete surgical resection, but feasibility and safety is priority. In

Showing preoperative MRI. (A) T1 weighted image post- gadolinium with tumor arising from midline of cerebellum. (B) T2 FLAIR with mild hyper intensity and voxel showing the tumor area of interest for spectroscopy. (C) Drop metastasis. (D) Significantly increased choline peaks with decreased NAA and Cr peaks

hydrocephalus. In routine practice, prior to definitive surgery, ventriculo-

1

H-MRS) and Diffusion

enhanced images show homogeneous enhancement.

Pediatric Medulloblastoma: A Radiation Oncologist Perspective

DOI: http://dx.doi.org/10.5772/intechopen.84344

data showed that proton magnetic resonance spectroscopy (

levels with Serum TSH and GH can be tested.

4.1.2 MRI imaging

4.2 Neurosurgery

Figure 1.

135

on Spectroscopy.

CBTRUS (Central Brain Tumor Registry of the United States) showed that incidence is higher in males as compared to females (Males: 0.16 vs. Females: 0.12). But this trend is different in children who are less than one year old. There is rising trend of higher incidence (APC: 1.7, 95% CI 0.4, 4.0) and death risk (Hazard Ratio for Survival: 0.74 with pvalue0.09) seen in black race compared to whites which is non-significant [7, 8].

## 3. Clinical presentation

There is rapid initiation of clinical symptoms are secondary to the rapid proliferation of these cellular malignant tumors. Symptoms of medulloblastomas vary with age. Earlier age of onset is associated with behavioral changes. Other symptoms may include listlessness, moodiness or irritability, vomiting, and lack of social interactions. As medulloblastoma is rapidly growing tumor, this results in obstructive hydrocephalus which manifests as raised intracranial pressure (ICP). Children may be seen with macrocephaly, fullness of fontanelle, and delayed developmental milestones. Older children and adults have symptoms of raised intracranial pressure like headache, vomiting, especially upon awakening in the morning hours. Headache usually gets better during the day. As anatomical location of medulloblastoma is cerebellum but symptoms slightly vary within various sites of cerebellum. Truncal ataxia result from tumors located in midline of cerebellum and appendicular ataxia is associated with the hemispheric located tumors [1]. There can be stretching of sixth cranial nerve because of hydrocephalus resulting in double vision. Meningeal irritation causes tilting of head and stiffness of neck due to the tonsillar herniation. Trochlear nerve palsy related to tumor compression is another reason of head tilt. Patients with spinal metastasis had symptoms of backache, weakness of bilateral lower limb and loss of bowel and bladder control. Metastatic disease symptoms depend upon the site involvement [9]. Majority are sporadic cases but there are associated syndromes like Gorlin syndrome (nevoid basal-cell carcinoma syndrome), Blue rubber-bleb nevus syndrome, Rubinstein-Taybi syndrome and Turcot syndrome (glioma polyposis syndrome) [10].

#### 4. Management

Although radiology is good contributor of diagnosis still detailed history and physical examination remained important and has to be done before proceeding for any investigations. Alteration of child behavior, persistent symptoms and focal neurological deficit are warning signs and should be proceeded with neuroimaging for diagnosis.

#### 4.1 Imaging

#### 4.1.1 Computed tomographic

Computed tomographic (CT) appearance of a medulloblastoma is seen as welldefined vermian cerebellar mass which is hyperattenuated with surrounding

vasogenic edema and sometimes evidence of hydrocephalus is seen. Contrast enhanced images show homogeneous enhancement.

## 4.1.2 MRI imaging

adult MB group [6]. U.S data showed the incidence of the medulloblastoma is 1.5–2 cases/100,000 population. Three hundred and fifty new cases in the United States are seen each year. The peak incidence is seen in 1st decade of life and incidence is noted

CBTRUS (Central Brain Tumor Registry of the United States) showed that incidence is higher in males as compared to females (Males: 0.16 vs. Females: 0.12). But this trend is different in children who are less than one year old. There is rising trend of higher incidence (APC: 1.7, 95% CI 0.4, 4.0) and death risk (Hazard Ratio for Survival: 0.74 with pvalue0.09) seen in black race compared to whites which is

There is rapid initiation of clinical symptoms are secondary to the rapid proliferation of these cellular malignant tumors. Symptoms of medulloblastomas vary with age. Earlier age of onset is associated with behavioral changes. Other symptoms may include listlessness, moodiness or irritability, vomiting, and lack of social interactions. As medulloblastoma is rapidly growing tumor, this results in obstructive hydrocephalus which manifests as raised intracranial pressure (ICP). Children may be seen with macrocephaly, fullness of fontanelle, and delayed developmental milestones. Older children and adults have symptoms of raised intracranial pressure

like headache, vomiting, especially upon awakening in the morning hours. Headache usually gets better during the day. As anatomical location of medulloblastoma is cerebellum but symptoms slightly vary within various sites of cerebellum. Truncal ataxia result from tumors located in midline of cerebellum and appendicular ataxia is associated with the hemispheric located tumors [1]. There can be stretching of sixth cranial nerve because of hydrocephalus resulting in double vision. Meningeal irritation causes tilting of head and stiffness of neck due to the tonsillar herniation. Trochlear nerve palsy related to tumor compression is another reason of head tilt. Patients with spinal metastasis had symptoms of backache, weakness of bilateral lower limb and loss of bowel and bladder control. Metastatic disease symptoms depend upon the site involvement [9]. Majority are sporadic cases but there are associated syndromes like Gorlin syndrome (nevoid basal-cell carcinoma syndrome), Blue rubber-bleb nevus syndrome, Rubinstein-Taybi

syndrome and Turcot syndrome (glioma polyposis syndrome) [10].

Although radiology is good contributor of diagnosis still detailed history and physical examination remained important and has to be done before proceeding for any investigations. Alteration of child behavior, persistent symptoms and focal neurological deficit are warning signs and should be proceeded with neuroimaging

Computed tomographic (CT) appearance of a medulloblastoma is seen as well-

defined vermian cerebellar mass which is hyperattenuated with surrounding

higher in the pediatric age group 3–4 years followed by 8–10 years of age.

non-significant [7, 8].

4. Management

for diagnosis.

4.1 Imaging

134

4.1.1 Computed tomographic

3. Clinical presentation

Brain and Spinal Tumors - Primary and Secondary

MRI imaging of the entire neuraxis, brain and spine is recommended for suspected cases. MRI images show "Low-to-intermediate signal intensity" on T1-weighted images and "moderately high signal intensity" on T2-weighted images, compared to cerebellar white matter. Intratumoral haemorrhage, peritumoral oedema, tonsillar herniation, hydrocephalus and calcification are other associated findings. Multivoxel MR spectroscopy (MRS) of the primary tumor can assess the tumor metabolites like 'elevated Choline peaks and decreased Creatine and N-acetyl acetate peaks'. Even without frank necrosis, a small amount of lipid-lactate peak sometimes observed indicating an increase in metabolic activity. Due to densely packed cells within the tumor and nuclear: cytoplasm ratio is higher, MB causes restriction of diffusion. There is restriction of diffusion of water particles in the tumor. So there is high signal of the tumor in diffusion-weighted MR images [11]. As frequency of spine seeding is 35% at diagnosis, to rule out any leptomeningeal metastases, Sagittal fat-suppressed post- gadolinium contrast MRI of the spine should be performed prior to surgery (Figure 1). Guang-Yao Wu et al. published data showed that proton magnetic resonance spectroscopy ( 1 H-MRS) and Diffusion Weighted Imaging are helpful for qualitative diagnosis of medulloblastoma [12].

Baseline hearing status with tests like Audiometry, IQ Testing and hormonal levels with Serum TSH and GH can be tested.

## 4.2 Neurosurgery

Mostly medium and large sized tumors in posterior fossa are associated with hydrocephalus. In routine practice, prior to definitive surgery, ventriculoperitoneal (VP) shunt should generally be avoided as definitive resection of tumor efficiently relieves the obstruction by opening the CSF pathways. Ideal surgery of any tumor is complete surgical resection, but feasibility and safety is priority. In

#### Figure 1.

Showing preoperative MRI. (A) T1 weighted image post- gadolinium with tumor arising from midline of cerebellum. (B) T2 FLAIR with mild hyper intensity and voxel showing the tumor area of interest for spectroscopy. (C) Drop metastasis. (D) Significantly increased choline peaks with decreased NAA and Cr peaks on Spectroscopy.

such circumstances, it is recommended to attempt maximal safe resection and residual disease can be left behind rather than aggressive surgical resection approach that can precipitate significant morbidity. Benefit to risk ratio of complete surgical removal of tumor has to be assessed preoperatively [13, 14].

Wingless activated (WNT) MB

DOI: http://dx.doi.org/10.5772/intechopen.84344

Pediatric Medulloblastoma: A Radiation Oncologist Perspective

(lower rhombic lip) neuronal progenitors

Common age Older children <3 year and >16

case, large cell and anaplastic

Chromosome /6 3q gain, 9q loss, 10q

CTNNB1 DDX3X SMARCA4

Cell of origin Dorsal brainstem

Histopathology Classic. In few

Genetic aberrations

Molecular markers

5 year overall survival

Table 2.

Figure 2.

137

Modified Chang's staging system.

Future strategy Reduction in

therapy

Medulloblastoma as a group of molecularly distinct subtypes.

Sonic hedgehog (SHH) subgroup

Cerebellar external granular layer, neuron precursors

year, adult group

MYCN, GLI2, PTCH1, SUFU, MLL2, SMO,TP53, BCOR1, LDB1, GABRG1

loss

Beta-catenin SFRP1or GAB1 MYC

Recurrence Rarely seen Local Metastasis Metastasis

SHH pathway inhibitors

Metastasis Rarely present Not common High 35–40% at presentation

95% 75% 50% 75%

Nodular desmoplastic histology, classic, large cell and anaplastic

Prevalence 10% 30% 25% 35% Male:female 1:1 1:1 2:1 3:1

Group 3 Group 4

Cerebellum progenitors (upper rhombic lip)

Infants/children/adults

Classic, large cell and

OTX2, DDX31, CHD7, SNCAIP, MYCN, CDK6 GFI1/GFI1B, MLL2, KDM6A, MLL3, ZMYM3

Isochromosome 17q chr X

Robust and large data

research

loss, 17p loss

Unknown

anaplastic

Ventricular zone neural progenitors

Infants and children <16 year

Classic, large cell and anaplastic

MYC, PVT1, OTX2, MLL2, SMARCA4, CHD7

1q gain, 5q loss, 10q loss

activation in 50% of this subtype

Intensified therapy, novel therapeutics

## 4.2.1 Post surgery neuroimaging

Ideal timing of post surgery MRI imaging should be obtained immediately, within 24–48 h of tumor resection, for accurately identification of the extent of surgical resection and quantification of the status of the residual tumor. If immediate post surgery MRI imaging has not been obtained, then recommendation is to wait for at least 2–3 weeks, but no more than 4-weeks, for resolution of post surgical changes and this will further prevent false positive results. Recommendations for timing of postoperative CSF analysis for malignant cells are also same, at least 2– 3 weeks post surgery to prevent errors like false positive results [15, 16].

## 4.3 Histopathology

Classification of most of the CNS tumors are still relying on only histopathological features but in medulloblastomas, integration of additional molecular information has updated WHO classification from 2007 to 2016. Medulloblastoma is classified now by an integrative diagnosis including a histologically as well as genetically defined compound as shown in Table 1 [17].

Molecular classification provides additional clinical and prognostic information which has the potential for identification of innovative strategies and research for the management of this disease (Table 2) [18, 19].

#### 4.4 Staging

Medulloblastomas originally were staged only on surgical basis but "Modified Chang Staging" is the current standard and there is addition of imaging [20] explained in Figure 2.

Risk stratification based on clinico-radiological analysis is still widely practiced and remains valid for Radiation planning in institutions. COG and SIOP Group accepted the clinical prognostic variables [21] shown in Figure 3. Although with the inclusion of molecular sub-grouping and genetic analysis of disease, more robust information about risk stratification and outcome of disease can be concluded to some extent but this required availability of these facilities with expertise in institutions. Incomplete neuraxis staging should be classified as high risk disease.


Table 1.

WHO 2016 updated classification of medulloblastomas.


#### Pediatric Medulloblastoma: A Radiation Oncologist Perspective DOI: http://dx.doi.org/10.5772/intechopen.84344

#### Table 2.

such circumstances, it is recommended to attempt maximal safe resection and residual disease can be left behind rather than aggressive surgical resection

surgical removal of tumor has to be assessed preoperatively [13, 14].

3 weeks post surgery to prevent errors like false positive results [15, 16].

genetically defined compound as shown in Table 1 [17].

the management of this disease (Table 2) [18, 19].

4.2.1 Post surgery neuroimaging

Brain and Spinal Tumors - Primary and Secondary

4.3 Histopathology

4.4 Staging

Table 1.

136

explained in Figure 2.

approach that can precipitate significant morbidity. Benefit to risk ratio of complete

Ideal timing of post surgery MRI imaging should be obtained immediately, within 24–48 h of tumor resection, for accurately identification of the extent of surgical resection and quantification of the status of the residual tumor. If immediate post surgery MRI imaging has not been obtained, then recommendation is to wait for at least 2–3 weeks, but no more than 4-weeks, for resolution of post surgical changes and this will further prevent false positive results. Recommendations for timing of postoperative CSF analysis for malignant cells are also same, at least 2–

Classification of most of the CNS tumors are still relying on only histopathological features but in medulloblastomas, integration of additional molecular information has updated WHO classification from 2007 to 2016. Medulloblastoma is classified now by an integrative diagnosis including a histologically as well as

Molecular classification provides additional clinical and prognostic information which has the potential for identification of innovative strategies and research for

Medulloblastomas originally were staged only on surgical basis but "Modified

Risk stratification based on clinico-radiological analysis is still widely practiced and remains valid for Radiation planning in institutions. COG and SIOP Group accepted the clinical prognostic variables [21] shown in Figure 3. Although with the inclusion of molecular sub-grouping and genetic analysis of disease, more robust information about risk stratification and outcome of disease can be concluded to some extent but this required availability of these facilities with expertise in institutions. Incomplete neuraxis staging should be classified as high risk disease.

Chang Staging" is the current standard and there is addition of imaging [20]

Medulloblastoma, classic • Medulloblastoma, WNT-activated Desmoplastic/nodular medulloblastoma • Sonic Hedgehog (SHH) activated and

TP53-mutant

TP53-wildtype

• Sonic Hedgehog (SHH) activated and

Histopathologically defined MB Genetically defined MB

Medulloblastoma of extensive nodularity • Non-SHH/Non-WNT Large cell/anaplastic medulloblastoma • Medulloblastoma, group 3 Medulloblastoma, not otherwise specified (NOS) • Medulloblastoma, group 4

WHO 2016 updated classification of medulloblastomas.

Medulloblastoma as a group of molecularly distinct subtypes.

Figure 2. Modified Chang's staging system.

years. Patient can be in the supine or prone position during CSI treatment. Over the years, prone position was used universally. Nowadays supine position is

• Technically, there is better shielding of cribriform plate and inferior temporal

better management of airways and cardiopulmonary complications can be

• Old couches contain metal inserts and beam entrance posteriorly through the

Advantages of prone position is the junction between the spinal and cranial

For younger children, good sedation may be required. Expert play therapist may

In 2-dimensional planning, fluoroscopic guidance two-dimensional simulation is done. Immobilization is done with thermoplastic cast and universal prone head-rest is used. CSI board with Lucite base plate having semicircular Lucite structures are available for head rest and chin rest. Various degrees of neck extensions is possible which will prevent the exit of superior border of spinal field through the oral cavity.

• Two parallel opposed lateral portals for cranium and upper cervical spinal cord.

• In case of adults or larger children, matching of upper posterior spinal field

Craniospinal junction can be placed at higher level: C1/C2 interspace or lower level C5-C7. At higher level, overdose to spinal cord is low. Shoulders are excluded from the lateral fields by keeping the craniospinal junction at lower level (C5-C7). Also the exit dose to mandible, thyroid, pharynx and larynx is lowered. Inferior edge of S2 is mostly the anatomical landmark where lower border of spinal field (SF) is set. Single Craniospinal junction is set for smaller children. If length is >36 cm, two junctions are required which are craniospinal and spinal-spinal (SS) junction. Mostly SS junction is place at L2-L3 interspace. Multi-leaf collimators or

• Target volume coverage is more easily assured and delivery more

• For younger pediatric patients who require anaesthesia, there can be

• Without adequate portal imaging, setup accuracy is difficult.

This complex 2-dimensional CSI technique fundamentals are:

• Posterior spinal field matching with the cranial fields.

with the separate lower posterior spinal field.

head rest and treatment couch is not possible.

help in treatment for radiotherapy without sedation.

Chest wall can be supported by thermocols.

• Patient is more comfortable due to stable position.

Pediatric Medulloblastoma: A Radiation Oncologist Perspective

used increasingly.

lobes.

reduced.

reproducible.

Advantages of supine position [25]

DOI: http://dx.doi.org/10.5772/intechopen.84344

Limitations of supine position

fields can be better visualized.

5.1.1 Conventional planning

139

#### Figure 3.

The stratifying medulloblastoma patients clinically into high risk and standard (average) risk based on variables like age, resection and metastasis.

## 5. Radiation therapy

Medulloblastoma, the embryonal tumors of the central nervous system, are highly radiosensitive tumors. After 200 cGy, the survival fraction has been reported to be 27%. Although Dargeon in 1948 stated that "medulloblastomas … have a consistently unfavourable prognosis" but later careful observation of Edith Paterson regarding pattern of disease spread brings hope to this disease. Radiating brain and spinal cord in one undivided volume principle mentioned by Edith Paterson and Farr. was based on the post-mortem findings of brain and spinal cord deposits in untreated cases. In 1953, at the Christie Hospital a five-year survival rate for children who were treated with kV irradiation reported by Paterson and Farr was 41%. Since then the practice to irradiate the entire craniospinal axis is universally adopted [22, 23].

After resection of tumor, entire craniospinal axis irradiation followed by whole posterior fossa or tumor bed boost irradiation is recommended irrespective of clinically detectable disease. Being Radiosensitive, Radiotherapy is curative up to 70% of standard risk patients. For this pediatric age group disease, linear accelerators are better than telecobalt machines and these children should preferably be referred in time to well equipped higher center with radiotherapy facility and infrastructure to prevent unnecessary side effects. As treatment delays beyond 6– 7 weeks result in worse outcome, cobalt-60 therapy may be offered in those areas where linacs are not available. To prevent the adverse effects of radiotherapy in the developing nervous system, radiotherapy is avoided initially in children up to 3 years of age. CSI technique required accurate reproducibility and complex field matching techniques. Long and complex shaped target volume homogeneity is a technically challenging process.

#### Timing of radiotherapy

Improved survival for patients is associated with a shorter interval from surgery to the start of radiation therapy. After definitive surgery, treatment should be started within 4–7 weeks. International Society of Paediatric Oncology (SIOP) trials showed that increase in the risk of relapse is seen if radiotherapy treatment is delivered after 7 weeks [24].

#### 5.1 Radiotherapy planning techniques

Younger brains are much more sensitive to damage caused by radiotherapy. CT based conformal radiation therapy, 3DCRT, is standard of care exists for many

years. Patient can be in the supine or prone position during CSI treatment. Over the years, prone position was used universally. Nowadays supine position is used increasingly.

## Advantages of supine position [25]


## Limitations of supine position


Advantages of prone position is the junction between the spinal and cranial fields can be better visualized.

For younger children, good sedation may be required. Expert play therapist may help in treatment for radiotherapy without sedation.

## 5.1.1 Conventional planning

5. Radiation therapy

variables like age, resection and metastasis.

Brain and Spinal Tumors - Primary and Secondary

Figure 3.

technically challenging process. Timing of radiotherapy

delivered after 7 weeks [24].

138

5.1 Radiotherapy planning techniques

Medulloblastoma, the embryonal tumors of the central nervous system, are highly radiosensitive tumors. After 200 cGy, the survival fraction has been reported to be 27%. Although Dargeon in 1948 stated that "medulloblastomas … have a consistently unfavourable prognosis" but later careful observation of Edith Paterson regarding pattern of disease spread brings hope to this disease. Radiating brain and spinal cord in one undivided volume principle mentioned by Edith Paterson and Farr. was based on the post-mortem findings of brain and spinal cord deposits in untreated cases. In 1953, at the Christie Hospital a five-year survival rate for children who were treated with kV irradiation reported by Paterson and Farr was 41%. Since then the practice to

The stratifying medulloblastoma patients clinically into high risk and standard (average) risk based on

After resection of tumor, entire craniospinal axis irradiation followed by whole

Improved survival for patients is associated with a shorter interval from surgery

Younger brains are much more sensitive to damage caused by radiotherapy. CT based conformal radiation therapy, 3DCRT, is standard of care exists for many

to the start of radiation therapy. After definitive surgery, treatment should be started within 4–7 weeks. International Society of Paediatric Oncology (SIOP) trials showed that increase in the risk of relapse is seen if radiotherapy treatment is

posterior fossa or tumor bed boost irradiation is recommended irrespective of clinically detectable disease. Being Radiosensitive, Radiotherapy is curative up to 70% of standard risk patients. For this pediatric age group disease, linear accelerators are better than telecobalt machines and these children should preferably be referred in time to well equipped higher center with radiotherapy facility and infrastructure to prevent unnecessary side effects. As treatment delays beyond 6– 7 weeks result in worse outcome, cobalt-60 therapy may be offered in those areas where linacs are not available. To prevent the adverse effects of radiotherapy in the developing nervous system, radiotherapy is avoided initially in children up to 3 years of age. CSI technique required accurate reproducibility and complex field matching techniques. Long and complex shaped target volume homogeneity is a

irradiate the entire craniospinal axis is universally adopted [22, 23].

In 2-dimensional planning, fluoroscopic guidance two-dimensional simulation is done. Immobilization is done with thermoplastic cast and universal prone head-rest is used. CSI board with Lucite base plate having semicircular Lucite structures are available for head rest and chin rest. Various degrees of neck extensions is possible which will prevent the exit of superior border of spinal field through the oral cavity. Chest wall can be supported by thermocols.

This complex 2-dimensional CSI technique fundamentals are:


Craniospinal junction can be placed at higher level: C1/C2 interspace or lower level C5-C7. At higher level, overdose to spinal cord is low. Shoulders are excluded from the lateral fields by keeping the craniospinal junction at lower level (C5-C7). Also the exit dose to mandible, thyroid, pharynx and larynx is lowered. Inferior edge of S2 is mostly the anatomical landmark where lower border of spinal field (SF) is set. Single Craniospinal junction is set for smaller children. If length is >36 cm, two junctions are required which are craniospinal and spinal-spinal (SS) junction. Mostly SS junction is place at L2-L3 interspace. Multi-leaf collimators or

custom made lead blocks are utilized for orofacial region shielding. In order to know the divergence of spinal fields, the spinal fields are simulated first.

Conventional portals for PF boost

DOI: http://dx.doi.org/10.5772/intechopen.84344

5.1.2 Conformal radiotherapy planning

tures.

structures are better spared by conformal techniques.

Pediatric Medulloblastoma: A Radiation Oncologist Perspective

Employing Steady-State Acquisition) MRI sequences [30].

Treatment volumes

clinical target volume (CTV).

5.1.2.1 Whole brain treatment volume

Delineation of CTVcranial

3000/400.

used

141

The PF boost is given using two lateral opposing fields. Anterior radiotherapy borders are formed by the posterior clinoids, posteriorly by internal occipital protuberance, superiorly extended up to mid-point of foramen magnum and vertex (or 1 cm above tentorium) and inferiorly extended up to C2-C3 interspace (Figure 4B) [28].

In case of pediatric patients who are potential long term survivors, critical

Immobilization is done in supine position and patient is aligned straight keeping neck in the neutral position. A 4-clamp thermoplastic immobilization cast for the head and shoulder region along with appropriate neck rest should be used. A five point orfit for immobilization along with hyperextended head and depressed both shoulders can result in optimal sparing of the upper esophagus and laryngeal struc-

Traditionally, axial planning images of 5 mm thickness on CT simulator from the vertex till the upper thigh region were preferred. But in this era of high precision radiotherapy where CTV accuracy is important for optimal outcome, CT slice thickness is reduced in some anatomical sites of CSI field. Slice Thickness of 1– 2.5 mm from the vertex to the inferior border of third cervical vertebrae (C3) and 2–5 mm from the lower border of third cervical vertebrae (C3) to the upper anatomical region of the femur should be obtained. Skull base foramina delineation is of utmost important and for their identification, "1 mm slice thickness at the base of skull" is preferred. To improve better identification of cranial nerves dural sheaths, co-registration of planning imaging CT to MRI can be done [29]. CSF extensions within the dural reflections are better demonstrated by FIESTA (Fast Imaging

Due to the risk of CSF dissemination, entire arachnoid space is included in the

The frontal lobe and the cribriform plate must be included in the clinical target volume. Inclusion of superior orbital tissue is must in the radiation field for the adequate coverage of the frontal lobe and cribriform plate. As per SIOPE guidelines, "the geometric edge of shielding should extend at least 0.5 cm inferiorly below the

cribriform plate and at least 1 cm elsewhere below the base of the skull".

a. Brain along with its covering meninges are contoured till second cervical

vertebrae (C2). For outlining the inner table of the skull, CT bony window setting is used with window/level: 1500–2000/300–350 suggested by SIOPE group.

b.The most critical sites are the 'cribriform plate', the 'most inferior parts of the temporal lobes', and the 'whole pituitary fossa'. They all to be included in the CTVcranial delineation. For cribriform plate CT window/level suggested is

c. For inclusion of CSF within the dural sheath of cranial nerves, CTVcranial is modified. For second cranial (optic) nerve, window width 350/level 40 is to be

Various techniques used for matching craniospinal junction are:


The craniospinal junction should be feathering/moving weekly during craniospinal irradiation for homogenous dose distribution and further minimizing the hot or cold spots resulted from the gap-junction or set-up errors. With each shift, spinal field can be extended superiorly, and cranial fields can be decreased inferiorly by 0.5–1 cm. Similarly LB (lower border) of "superior spinal field" and SB (superior border) of "inferior spinal" field can be shifted superiorly. This all is done for spread out of dose homogeneity. Still the contribution of human errors is seen in many studies. As there is direct visualization of the optical field light on the skin surface in prone position, verification of beam delivery of CSI is relatively simple (Figure 4A) [26, 27].

## The posterior fossa (PF) boost volume

Depending on the risk-stratification of the disease, volume of the posterior fossa boost is decided. Those cases which are considered low risk and standard risk medulloblastomas, posterior fossa target volume includes pre-operative tumor bed with adequate margins. Most institutions add 1–1.5 cm margin to the tumor bed. Cases of high risk and very high risk disease require irradiation of the entire posterior fossa. Posterior fossa irradiation can easily be planned based on fluoroscopic imaging in low and middle income countries where there is no availability of multileaf collimators.

#### Figure 4.

(A) Gap feathering during craniospinal irradiation (CSI). Junction movement across the long treatment length allows homogenous dose distribution by reducing the overlap hot spot and gapping cold spots. If field length < 35 cm, 100 cm SSD is used and for field length >35 cm, 120 cm SSD is used. (B) Posterior fossa boost volume including whole infratentorial compartment.

Pediatric Medulloblastoma: A Radiation Oncologist Perspective DOI: http://dx.doi.org/10.5772/intechopen.84344

#### Conventional portals for PF boost

custom made lead blocks are utilized for orofacial region shielding. In order to know

• For matching the beam divergence of the lateral head portals with the superior

The craniospinal junction should be feathering/moving weekly during craniospinal irradiation for homogenous dose distribution and further minimizing the hot or cold spots resulted from the gap-junction or set-up errors. With each shift, spinal field can be extended superiorly, and cranial fields can be decreased inferiorly by 0.5–1 cm. Similarly LB (lower border) of "superior spinal field" and SB (superior border) of "inferior spinal" field can be shifted superiorly. This all is done for spread out of dose homogeneity. Still the contribution of human errors is seen in many studies. As there is direct visualization of the optical field light on the skin surface in prone position, verification of beam delivery of CSI is relatively simple (Figure 4A) [26, 27].

Depending on the risk-stratification of the disease, volume of the posterior fossa

(A) Gap feathering during craniospinal irradiation (CSI). Junction movement across the long treatment length allows homogenous dose distribution by reducing the overlap hot spot and gapping cold spots. If field length < 35 cm, 100 cm SSD is used and for field length >35 cm, 120 cm SSD is used. (B) Posterior fossa boost volume

boost is decided. Those cases which are considered low risk and standard risk medulloblastomas, posterior fossa target volume includes pre-operative tumor bed with adequate margins. Most institutions add 1–1.5 cm margin to the tumor bed. Cases of high risk and very high risk disease require irradiation of the entire posterior fossa. Posterior fossa irradiation can easily be planned based on fluoroscopic imaging in low and middle income countries where there is no availability of

.

the divergence of spinal fields, the spinal fields are simulated first. Various techniques used for matching craniospinal junction are:

beam edge of SF, Collimator rotation is done 7–10°

Brain and Spinal Tumors - Primary and Secondary

• Couch rotation 6°.

• Half beam blocks

• Asymmetric jaws

multileaf collimators.

Figure 4.

140

including whole infratentorial compartment.

• Penumbra trimmers

The posterior fossa (PF) boost volume

The PF boost is given using two lateral opposing fields. Anterior radiotherapy borders are formed by the posterior clinoids, posteriorly by internal occipital protuberance, superiorly extended up to mid-point of foramen magnum and vertex (or 1 cm above tentorium) and inferiorly extended up to C2-C3 interspace (Figure 4B) [28].

### 5.1.2 Conformal radiotherapy planning

In case of pediatric patients who are potential long term survivors, critical structures are better spared by conformal techniques.

Immobilization is done in supine position and patient is aligned straight keeping neck in the neutral position. A 4-clamp thermoplastic immobilization cast for the head and shoulder region along with appropriate neck rest should be used. A five point orfit for immobilization along with hyperextended head and depressed both shoulders can result in optimal sparing of the upper esophagus and laryngeal structures.

Traditionally, axial planning images of 5 mm thickness on CT simulator from the vertex till the upper thigh region were preferred. But in this era of high precision radiotherapy where CTV accuracy is important for optimal outcome, CT slice thickness is reduced in some anatomical sites of CSI field. Slice Thickness of 1– 2.5 mm from the vertex to the inferior border of third cervical vertebrae (C3) and 2–5 mm from the lower border of third cervical vertebrae (C3) to the upper anatomical region of the femur should be obtained. Skull base foramina delineation is of utmost important and for their identification, "1 mm slice thickness at the base of skull" is preferred. To improve better identification of cranial nerves dural sheaths, co-registration of planning imaging CT to MRI can be done [29]. CSF extensions within the dural reflections are better demonstrated by FIESTA (Fast Imaging Employing Steady-State Acquisition) MRI sequences [30].

### Treatment volumes

Due to the risk of CSF dissemination, entire arachnoid space is included in the clinical target volume (CTV).

#### 5.1.2.1 Whole brain treatment volume

The frontal lobe and the cribriform plate must be included in the clinical target volume. Inclusion of superior orbital tissue is must in the radiation field for the adequate coverage of the frontal lobe and cribriform plate. As per SIOPE guidelines, "the geometric edge of shielding should extend at least 0.5 cm inferiorly below the cribriform plate and at least 1 cm elsewhere below the base of the skull".

#### Delineation of CTVcranial


Foramina or canals of skull base which are significant for delineation of CTVcranial are cribriform plate, optical canal of sphenoid, superior orbital fissure, foramen ovale, internal auditory meatus (IAM), jugular foramen and hypoglossal canal. Entire components length of the optic nerves in the CTVcranial is included in most institutions where photons are used. But in those institutions where medulloblastomas are treated by protons, for prevention of any potential optical retinopathy risk, only the posterior length components of the optic nerves is included [31, 32].

Issues of the cribriform plate (CP)

PTV brain: 5 mm isotropic margin around CTV brain. CTV spine: entire arachnoid space with nerve roots.

DOI: http://dx.doi.org/10.5772/intechopen.84344

CTV brain: brain and its covering meninges till lower border of C2.

Pediatric Medulloblastoma: A Radiation Oncologist Perspective

PTV spine: 5–8 mm isotropic margin is recommended around the CTV-spine

5.1.2.2 CTVSpinal

According to a 1982 report from MSKCC, 15% of recurrences are subfrontal in medulloblastomas [33]. Hypothesis given by Donnal et al. was that the pooling of cells secondary to gravitational effect of prone position with maximum shielding of

The CTVSpinal (spinal target volume) includes the complete dural or thecal sac. Lateral extension of delineation is must to cover the intervertebral or neural foramina with their exiting nerve roots from the C2 cervical spine till the lower end of the thecal sac. Lower border of CTVSpinal is appreciated by the latest spinal MRI imaging. Children Oncology Group (ACNS0332, ACNS 0331, ACNS 0122) recommended the inferior border of CTVSpinal is '2 cm below the termination of the subdural space' which

High Risk and Very High Risk disease: The clinical target volume PF (CTVPF) boost encompassed the whole PF. The boost CTVPF extends superiorly up to the tentorium cerebelli, inferiorly to the foramen magnum, and posterolaterally to the occipital bony walls and temporal fossa. BS (Brain Stem) anterior border and midbrain cover the components of the posterior fossa anteriorly. The geometric margin of 0.5 cm around the CTVPF is taken for delineation of the PTV posterior fossa (PTVPF). PTVPF is limited to the bony confines of the skull, except at the foramen magnum where it extended to the level of C1. The PTVPF contoured anteriorly up to the posterior clinoids and inferiorly to the C1-C2 junction. PTV is modified at sella and pituitary gland is excluded from anterior extension of PF boost planning.

For low risk and standard risk, tumor bed, as defined on CT images, delineation with a margin of 1–2cm is recommended. For three-dimensional planning, two lateral opposing portals with editing/shaping using the multileaf collimators (MLCs) is recommended. Finally, these craniospinal and boost plans must be summated to produce a composite treatment plan and final dose-distribution is calculated [35, 36].

Children and adults are two different groups as far as radiotherapy treatment in

medulloblastoma is concerned. Proliferating tissues are more in children as

eyes can result in the recurrences at the region of cribriform plate [34].

is usually at bottom of second sacral vertebrae. The other SIOPE group trials recommended that the lower border of CTVSpinal must be determined by the spinal MRI imaging of the termination of the thecal or dural sac. This border should be kep. 1 cm inferior to this. Root canals in the Sacral CTVSpinal can be excluded. This recommendation is based on a MRI study conducted on ten volunteers who were healthy proved that there was no CSF around the nerve roots of sacral segments. If patients are to be treated by protons, then for skeletally immature patients, CTVSpine should include the vertebral bodies. This will decrease the risk of unequal vertebral growth. In skeletally mature patients, spinal TV should include the subarachnoid space of spine with a margin of 3–5 mm is summed up to the body of

vertebrae for set up uncertainties/variation (interfraction) [29].

Delineation of posterior fossa boost volume

5.2 Intensity modulated radiotherapy for CSI

143

As CSF flows up to the posterior aspect of eyeball which is better observed in MRI images, it is better to include whole optic nerves in CTV in routine practice of photon beam based radiotherapy in these cases. The cranial nerves which are wrapped without dural cuff are the third, fourth and sixth (oculomotor, trochlear and abducens) nerves. Nobel et al. studied the flow of cerebrospinal fluid beyond the inner table of skull into the IAM (internal auditory meatus), juglar foramen (JF) and hypoglossal canal (HC). Their study (on basis of 96 FIESTA MRI sequences) concluded that the CSF extension was up to '16 mm' in the internal auditory meatus which is not very far away from the cochlea. So the cochlear sparing by CSF exclusion within the internal acoustic canal should not be attempted. Their data also showed that the CSF extension was up to 11 mm in the juglar fossa from inner table of skull. There is no extension of CSF within these dural sheaths outside the outer table of the skull. It is not so easy to delineate dural sheath CSF on MRI but CT images with 1 mm thickness along the base of skull can show skull foramina and canals and they can easily be contoured on bony windows (Figure 5) [29].

#### Figure 5.

Showing conformal planning. (A) Cribriform plate is in close proximity to ocular structures. Shielding edge should be at least 0.5 cm below the cribriform plate and 1 cm elsewhere below base of skull to cover the temporal fossa and skull base foramina. (B) The petrous part of temporal bone showing Internal acoustic canal (IAC). (C) Various skull base foramina contoured in CTVcranial including dural cuffs of cranial nerves. (D) Cribriform plate must be in target volume. (E) Entire subarachnoid space, including nerve roots laterally must be included in CTVspinal. SFOP, French Paediatric Oncology Society; CP, cribriform plate; SOF, superior orbital fissure; FO, foramen ovale.

CTV brain: brain and its covering meninges till lower border of C2. PTV brain: 5 mm isotropic margin around CTV brain. CTV spine: entire arachnoid space with nerve roots. PTV spine: 5–8 mm isotropic margin is recommended around the CTV-spine

## Issues of the cribriform plate (CP)

According to a 1982 report from MSKCC, 15% of recurrences are subfrontal in medulloblastomas [33]. Hypothesis given by Donnal et al. was that the pooling of cells secondary to gravitational effect of prone position with maximum shielding of eyes can result in the recurrences at the region of cribriform plate [34].

### 5.1.2.2 CTVSpinal

Foramina or canals of skull base which are significant for delineation of CTVcranial are cribriform plate, optical canal of sphenoid, superior orbital fissure, foramen ovale, internal auditory meatus (IAM), jugular foramen and hypoglossal canal. Entire components length of the optic nerves in the CTVcranial is included in most institutions where photons are used. But in those institutions where medulloblastomas are treated by protons, for prevention of any potential optical retinopathy risk, only the posterior length components of the optic nerves is included

Brain and Spinal Tumors - Primary and Secondary

As CSF flows up to the posterior aspect of eyeball which is better observed in MRI images, it is better to include whole optic nerves in CTV in routine practice of photon beam based radiotherapy in these cases. The cranial nerves which are wrapped without dural cuff are the third, fourth and sixth (oculomotor, trochlear and abducens) nerves. Nobel et al. studied the flow of cerebrospinal fluid beyond the inner table of skull into the IAM (internal auditory meatus), juglar foramen (JF) and hypoglossal canal (HC). Their study (on basis of 96 FIESTA MRI sequences) concluded that the CSF extension was up to '16 mm' in the internal auditory meatus which is not very far away from the cochlea. So the cochlear sparing by CSF exclusion within the internal acoustic canal should not be attempted. Their data also showed that the CSF extension was up to 11 mm in the juglar fossa from inner table of skull. There is no extension of CSF within these dural sheaths outside the outer table of the skull. It is not so easy to delineate dural sheath CSF on MRI but CT images with 1 mm thickness along the base of skull can show skull foramina and canals and they can easily be contoured on bony windows (Figure 5) [29].

Showing conformal planning. (A) Cribriform plate is in close proximity to ocular structures. Shielding edge should be at least 0.5 cm below the cribriform plate and 1 cm elsewhere below base of skull to cover the temporal fossa and skull base foramina. (B) The petrous part of temporal bone showing Internal acoustic canal (IAC). (C) Various skull base foramina contoured in CTVcranial including dural cuffs of cranial nerves. (D) Cribriform plate must be in target volume. (E) Entire subarachnoid space, including nerve roots laterally must be included in CTVspinal. SFOP, French Paediatric Oncology Society; CP, cribriform plate; SOF, superior

[31, 32].

Figure 5.

142

orbital fissure; FO, foramen ovale.

The CTVSpinal (spinal target volume) includes the complete dural or thecal sac. Lateral extension of delineation is must to cover the intervertebral or neural foramina with their exiting nerve roots from the C2 cervical spine till the lower end of the thecal sac. Lower border of CTVSpinal is appreciated by the latest spinal MRI imaging. Children Oncology Group (ACNS0332, ACNS 0331, ACNS 0122) recommended the inferior border of CTVSpinal is '2 cm below the termination of the subdural space' which is usually at bottom of second sacral vertebrae. The other SIOPE group trials recommended that the lower border of CTVSpinal must be determined by the spinal MRI imaging of the termination of the thecal or dural sac. This border should be kep. 1 cm inferior to this. Root canals in the Sacral CTVSpinal can be excluded. This recommendation is based on a MRI study conducted on ten volunteers who were healthy proved that there was no CSF around the nerve roots of sacral segments.

If patients are to be treated by protons, then for skeletally immature patients, CTVSpine should include the vertebral bodies. This will decrease the risk of unequal vertebral growth. In skeletally mature patients, spinal TV should include the subarachnoid space of spine with a margin of 3–5 mm is summed up to the body of vertebrae for set up uncertainties/variation (interfraction) [29].

#### Delineation of posterior fossa boost volume

High Risk and Very High Risk disease: The clinical target volume PF (CTVPF) boost encompassed the whole PF. The boost CTVPF extends superiorly up to the tentorium cerebelli, inferiorly to the foramen magnum, and posterolaterally to the occipital bony walls and temporal fossa. BS (Brain Stem) anterior border and midbrain cover the components of the posterior fossa anteriorly. The geometric margin of 0.5 cm around the CTVPF is taken for delineation of the PTV posterior fossa (PTVPF). PTVPF is limited to the bony confines of the skull, except at the foramen magnum where it extended to the level of C1. The PTVPF contoured anteriorly up to the posterior clinoids and inferiorly to the C1-C2 junction. PTV is modified at sella and pituitary gland is excluded from anterior extension of PF boost planning.

For low risk and standard risk, tumor bed, as defined on CT images, delineation with a margin of 1–2cm is recommended. For three-dimensional planning, two lateral opposing portals with editing/shaping using the multileaf collimators (MLCs) is recommended. Finally, these craniospinal and boost plans must be summated to produce a composite treatment plan and final dose-distribution is calculated [35, 36].

#### 5.2 Intensity modulated radiotherapy for CSI

Children and adults are two different groups as far as radiotherapy treatment in medulloblastoma is concerned. Proliferating tissues are more in children as

compared to the adults. IMRT for adult population is a used as a routine practice for numerous malignancies but for pediatric patients, IMRT has to be used with great caution in view of low dose volumes. Spinal irradiation during CSI results in increased doses delivered to anterior thoracic and abdominal structures with conventional plans. Parker et al. published data showed that the PTV and dose homogeneity was better for the medulloblastoma CSI, IMRT plans. Dosimeteric analysis showed V95% for IMRT was 100%, 3D planning was 96% and 2D planning was 98%. Also V107% for IMRT was 3%, 3D planning 38% and 2D was 37%. The IMRT plans provided better sparing of heart and liver in terms of V (10 Gy) and above. Integral Dose analysis showed the IMRT plans were superior for liver and heart and the 3D plan were better for the body contour. Tomotherapy may be helpful in reducing high dose regions in OAR, but low dose of radiation to a large volume is a concern for pediatric patients [37].

#### IMRT planning

IMRT for craniospinal irradiation in adult medulloblastomas is delivered after summation of PTV brain plan and PTV spine plan. Usually the spinal PTV planning is done first with 'inverse planning technique' using the 5 posterior fields with 0°, 20° and 50°gantry angles. For the craniocaudal direction, the isocenter is kept at the "geometrical center of the PTV\_spine". For the depth and lateral position, it is usually set at the "midline and midplane" at the level of the interphase of second and third cervical vertebral body. Dose prescription and normalization is to the isocenter of the spine. For the cranial target, a separate plan is created. Cranial fields isocenter is set at the inferior most slice of the PTV brain. MLC positions can be modified for dose reduction to the nearby OARs and adequate coverage of the target volume. The geometric center of the PTV\_brain is defined as the reference point for dose prescription and normalization. Final composite plan for the whole cranio-spinal axis is obtained after dosimetrically summation of spinal and cranial plans. For taller patients, for upper and lower spine, IMRT plans are created separately [38].

with doses <54 Gy native to 91% in those patients on whom higher doses were delivered [41]. CSI dose reduction is feasible with the addition of chemotherapy as level 1 evidence based data released by Children's Cancer Study Group showed that the reduction of doses from 36- to 23.4 Gy resulted in significantly higher risk of

representative case of entire posterior fossa boost. Yellow represents 100%, red 95% and blue 70% of the isodose lines. IMRT is advantageous over 3DCRT for cochlear sparing. 3DCRT, three dimensional conformal

Coursey JCRT. Meenu et al. mid-axial dose distributions with (a) 3DCRT (b) IMRT for one of the

Radiotherapy doses to CSI depends upon the risk stratification of the disease at presentation. If risk stratification or accurate staging is incomplete then patient can be treated as high-risk disease. Radiation therapy doses according to the risk stratification are shown in Table 3 [43]. There are different long term toxicities between the adult and children. CSI dose reduction approach is avoided for adult patients. Still big data is required to justify the addition of adjuvant chemotherapy to radiotherapy in average risk adult patients as data showed that 70–80% of these patients have no progression of disease at 5 years when RT is used as a sole modality. Also

Pediatric age is more sensitive to radiation induced carcinogenesis as compared

As children anatomy is small so critical organs are very much close to the target volume. Also the scatter from the treatment volume is highly significant in children having small body area as compared to large body of adults. Particle beam therapy is a potential powerful tool for improving the therapeutic ratio. Goal of pediatric radiation oncologists is integral dose minimization to whole body and organs at risk. Advantage of protons over the photons is that they can modulate the dose to avoid very close OARs. For CSI, advantages of protons are because of absorption of low dose on tissue entry and the point of maximum dose deposition at the Bragg-peak. This results in the avoidance of dose deposition to anterior organs like thyroid, lungs, heart, gut, liver, esophagus, kidneys and urinary bladder. Also critical brain structures such as the lens, optic chiasma, pituitary, cochleae are better spared.

recurrences outside the posterior fossa [42].

radiotherapy; IMRT, intensity modulated radiotherapy.

Pediatric Medulloblastoma: A Radiation Oncologist Perspective

DOI: http://dx.doi.org/10.5772/intechopen.84344

to adults by a factor of at least 10 [44].

5.4 Proton therapy

145

Figure 6.

there are issues of hematological toxicities in adult patients.

#### Intensity modulated radiotherapy for posterior fossa boost

Meenu et al. re-planned seven previously irradiated patients of MB with seven field inverse planning IMRT for whole posterior fossa boost. Equidistant gantry angles (0°, 50°, 100°, 150°, 210°, 260°, 310°) were used with step and shoot IMRT on 6MV energy LINAC. Treatment isocenter was set at the geometrical center of the planning target volume. They compared with 3DCRT plan delivered by two lateral opposing beams with multileaf collimators for shaping. Their dosimeteric results showed there were decreased mean dose to most critical organ at risk, cochlea, with IMRT compared to the three dimensional radiotherapy plans with significant p values i.e. 0.032 for the cochlea of right ear and 0.020 for the left sided cochlea (Figure 6) [35] Similar results are found in published clinical studies conducted by Huang et al. where 13% of the IMRT group had grade 3 or 4 hearing loss as compared to 64% for the conventional group [39].

#### Organ at risk

OAR as demarcated on axial CT images include brain, eyes, lens, optic nerves, optic chiasma, cochlea, parotids, mandible, thyroid, esophagus, lungs, heart, breasts, liver, kidneys, bowel bag, rectum, bladder, gonads (ovary or testes), vertebral bodies, uterus plus pelvis (red bone marrow).

#### 5.3 Radiotherapy doses

Berry et al. reported a five year survival rate of 47% with lesser doses and ten year DFS of 77% once the posterior fossa doses delivered were >52 Gy [40]. Abacioglu et al. showed in adult medulloblastomas, control rate was 33% at 5 year

#### Figure 6.

compared to the adults. IMRT for adult population is a used as a routine practice for numerous malignancies but for pediatric patients, IMRT has to be used with great caution in view of low dose volumes. Spinal irradiation during CSI results in increased doses delivered to anterior thoracic and abdominal structures with conventional plans. Parker et al. published data showed that the PTV and dose homogeneity was better for the medulloblastoma CSI, IMRT plans. Dosimeteric analysis showed V95% for IMRT was 100%, 3D planning was 96% and 2D planning was 98%. Also V107% for IMRT was 3%, 3D planning 38% and 2D was 37%. The IMRT plans provided better sparing of heart and liver in terms of V (10 Gy) and above. Integral Dose analysis showed the IMRT plans were superior for liver and heart and the 3D plan were better for the body contour. Tomotherapy may be helpful in reducing high dose regions in OAR, but low dose of radiation to a large volume is a concern

IMRT for craniospinal irradiation in adult medulloblastomas is delivered after summation of PTV brain plan and PTV spine plan. Usually the spinal PTV planning is done first with 'inverse planning technique' using the 5 posterior fields with 0°, 20° and 50°gantry angles. For the craniocaudal direction, the isocenter is kept at the "geometrical center of the PTV\_spine". For the depth and lateral position, it is usually set at the "midline and midplane" at the level of the interphase of second and third cervical vertebral body. Dose prescription and normalization is to the isocenter of the spine. For the cranial target, a separate plan is created. Cranial fields isocenter is set at the inferior most slice of the PTV brain. MLC positions can be modified for dose reduction to the nearby OARs and adequate coverage of the target volume. The geometric center of the PTV\_brain is defined as the reference point for dose prescription and normalization. Final composite plan for the whole cranio-spinal axis is obtained after dosimetrically summation of spinal and cranial plans. For taller patients, for upper and lower spine, IMRT plans are created sepa-

Intensity modulated radiotherapy for posterior fossa boost

Huang et al. where 13% of the IMRT group had grade 3 or 4 hearing loss as

optic chiasma, cochlea, parotids, mandible, thyroid, esophagus, lungs, heart, breasts, liver, kidneys, bowel bag, rectum, bladder, gonads (ovary or testes),

year DFS of 77% once the posterior fossa doses delivered were >52 Gy [40]. Abacioglu et al. showed in adult medulloblastomas, control rate was 33% at 5 year

OAR as demarcated on axial CT images include brain, eyes, lens, optic nerves,

Berry et al. reported a five year survival rate of 47% with lesser doses and ten

compared to 64% for the conventional group [39].

vertebral bodies, uterus plus pelvis (red bone marrow).

Meenu et al. re-planned seven previously irradiated patients of MB with seven field inverse planning IMRT for whole posterior fossa boost. Equidistant gantry angles (0°, 50°, 100°, 150°, 210°, 260°, 310°) were used with step and shoot IMRT on 6MV energy LINAC. Treatment isocenter was set at the geometrical center of the planning target volume. They compared with 3DCRT plan delivered by two lateral opposing beams with multileaf collimators for shaping. Their dosimeteric results showed there were decreased mean dose to most critical organ at risk, cochlea, with IMRT compared to the three dimensional radiotherapy plans with significant p values i.e. 0.032 for the cochlea of right ear and 0.020 for the left sided cochlea (Figure 6) [35] Similar results are found in published clinical studies conducted by

for pediatric patients [37]. IMRT planning

Brain and Spinal Tumors - Primary and Secondary

rately [38].

Organ at risk

5.3 Radiotherapy doses

144

Coursey JCRT. Meenu et al. mid-axial dose distributions with (a) 3DCRT (b) IMRT for one of the representative case of entire posterior fossa boost. Yellow represents 100%, red 95% and blue 70% of the isodose lines. IMRT is advantageous over 3DCRT for cochlear sparing. 3DCRT, three dimensional conformal radiotherapy; IMRT, intensity modulated radiotherapy.

with doses <54 Gy native to 91% in those patients on whom higher doses were delivered [41]. CSI dose reduction is feasible with the addition of chemotherapy as level 1 evidence based data released by Children's Cancer Study Group showed that the reduction of doses from 36- to 23.4 Gy resulted in significantly higher risk of recurrences outside the posterior fossa [42].

Radiotherapy doses to CSI depends upon the risk stratification of the disease at presentation. If risk stratification or accurate staging is incomplete then patient can be treated as high-risk disease. Radiation therapy doses according to the risk stratification are shown in Table 3 [43]. There are different long term toxicities between the adult and children. CSI dose reduction approach is avoided for adult patients. Still big data is required to justify the addition of adjuvant chemotherapy to radiotherapy in average risk adult patients as data showed that 70–80% of these patients have no progression of disease at 5 years when RT is used as a sole modality. Also there are issues of hematological toxicities in adult patients.

#### 5.4 Proton therapy

Pediatric age is more sensitive to radiation induced carcinogenesis as compared to adults by a factor of at least 10 [44].

As children anatomy is small so critical organs are very much close to the target volume. Also the scatter from the treatment volume is highly significant in children having small body area as compared to large body of adults. Particle beam therapy is a potential powerful tool for improving the therapeutic ratio. Goal of pediatric radiation oncologists is integral dose minimization to whole body and organs at risk. Advantage of protons over the photons is that they can modulate the dose to avoid very close OARs. For CSI, advantages of protons are because of absorption of low dose on tissue entry and the point of maximum dose deposition at the Bragg-peak. This results in the avoidance of dose deposition to anterior organs like thyroid, lungs, heart, gut, liver, esophagus, kidneys and urinary bladder. Also critical brain structures such as the lens, optic chiasma, pituitary, cochleae are better spared.


centers, the proton center capacity to treat children and the availability of expertise

Chemotherapy is integral part of treatment and in standard risk cases CSI doses can be reduced. Children less than 3 years, chemotherapy is recommended till the child will attain the age of 3 years. Drugs like carboplatin, cyclophosphamide and etoposide is recommended. There are various regimens recommended (Box 1). In a published database analysis of medulloblastoma children (n = 816) age 3–8 years who received adjuvant chemotherapy after surgery, overall rate of RT deferral after surgery was 15.1%. Their practice was associated was decreased overall survival in this pediatric population even in the well-established era of chemotherapy. [48] At

• Autologous stem-cell rescue accompanied with high-dose chemotherapy with

• As a salvage therapy in cases of relapsed of recurrent medulloblastoma.

A detailed discussion about the chemotherapy and late effects of radiochemotherapy, management of adverse effects are outside the scope of this chapter. It is recommended and important to have multidisciplinary follow-up with pediatric

Follow up counseling is mandatory prior to initiation of treatment. MRI brain may be performed every three months and MRI spine may be obtained every six months in standard risk category of standard risk patients for the initial two years. These two investigations can be performed every 6 months up to five years, and then repeated every year. In high-risk group, MRI of whole brain and spine may be repeated every three months for the initial two years. Thorough clinical examination with every visit is necessary. In case of pediatric or adolescence groups following radiotherapy, neuroendocrine follow-up with evaluation of serum hormonal

Chemotherapy regimens (adjuvant) in MB children >3 years of age [49, 36].

and support structures must be evaluated by the referral physicians.

Pediatric Medulloblastoma: A Radiation Oncologist Perspective

DOI: http://dx.doi.org/10.5772/intechopen.84344

• In Infant medulloblastoma, to defer RT, till the age of 3-years

present, recommendations of chemotherapy are:

• Concurrent chemotherapy with radiotherapy

• Following RT as adjuvant settings

radiation oncologists and endocrinologists.

levels should be performed every six months.

Box 1.

7. Follow up

147

6. Chemotherapy

#### Table 3.

Radiotherapy doses according to risk stratification.

In grown up children, sparing the anterior portion of the vertebral body results in minimization of bone marrow dose (Figure 7).

Consensus report from the Stockholm pediatric proton therapy conference showed that treatment of choice for medulloblastoma is proton therapy [45]. Based on the review of the existing theoretical and early clinical outcomes evidence, results showed that proton craniospinal irradiation provide similar control of tumor with potentially decreased doses to the normal structures thus reduces the risk of side effects when compared with photon existing data [46]. Spot-scanned intensitymodulated proton therapy (IMPT) is advantageous over the photon therapy in terms of all radiobiological risk estimation [47].

Weight changes in medulloblastoma and adaptive proton therapy are coming up but at present there is scanty data available. Patient selection is of utmost important in proton therapy. Limitations of patients with their families to travel in these

#### Figure 7.

CSI Schematic Model. (A) Photons are absorbed and secondary electrons have large range in mm resulting in doses beyond the target volume. (B) Advantage of stopping of protons is due to the Bragg peak curve resulting in lower doses to OARs with proton therapy.

centers, the proton center capacity to treat children and the availability of expertise and support structures must be evaluated by the referral physicians.

## 6. Chemotherapy

Chemotherapy is integral part of treatment and in standard risk cases CSI doses can be reduced. Children less than 3 years, chemotherapy is recommended till the child will attain the age of 3 years. Drugs like carboplatin, cyclophosphamide and etoposide is recommended. There are various regimens recommended (Box 1). In a published database analysis of medulloblastoma children (n = 816) age 3–8 years who received adjuvant chemotherapy after surgery, overall rate of RT deferral after surgery was 15.1%. Their practice was associated was decreased overall survival in this pediatric population even in the well-established era of chemotherapy. [48] At present, recommendations of chemotherapy are:


A detailed discussion about the chemotherapy and late effects of radiochemotherapy, management of adverse effects are outside the scope of this chapter. It is recommended and important to have multidisciplinary follow-up with pediatric radiation oncologists and endocrinologists.

## 7. Follow up

In grown up children, sparing the anterior portion of the vertebral body results in

Volume and doses of radiation therapy Concurrent or adjuvant

CSI: 36Gy/ 20 fractions, 5 days a week Boost to posterior fossa: 19.8Gy/ 11

Gross metastatic deposits: Boost dose of

CSI: 23.4Gy/13 fractions, 5 days a week Boost to whole posterior fossa (or tumor bed): 30.6Gy/17 fractions, 5 times/week

CSI: 36Gy/20 fractions, 5 days a week Boost to posterior fossa: 19.8Gy/11 fractions,

Boost to whole posterior fossa (or tumor bed): 30.6Gy/17 fractions, 5 times/week

fractions, 5 times/week

Brain and Spinal Tumors - Primary and Secondary

5.4–9 Gy/3–5 fractions

Standard risk Children <18 year

Adults

Radiotherapy doses according to risk stratification.

5 times/week

Low risk CSI: 23.4Gy/13 fractions, 5 days a week

chemotherapy

chemotherapy

Children <18 year

chemotherapy

Concurrent carboplatin followed by adjuvant six cycles of systemic

Weekly vincristine followed by adjuvant six cycles of systemic

Reduced intensity chemotherapy

Consensus report from the Stockholm pediatric proton therapy conference showed that treatment of choice for medulloblastoma is proton therapy [45]. Based on the review of the existing theoretical and early clinical outcomes evidence, results showed that proton craniospinal irradiation provide similar control of tumor with potentially decreased doses to the normal structures thus reduces the risk of side effects when compared with photon existing data [46]. Spot-scanned intensitymodulated proton therapy (IMPT) is advantageous over the photon therapy in

Weight changes in medulloblastoma and adaptive proton therapy are coming up but at present there is scanty data available. Patient selection is of utmost important in proton therapy. Limitations of patients with their families to travel in these

CSI Schematic Model. (A) Photons are absorbed and secondary electrons have large range in mm resulting in doses beyond the target volume. (B) Advantage of stopping of protons is due to the Bragg peak curve resulting in

minimization of bone marrow dose (Figure 7).

Various risk stratification

High risk and very high risk disease

Table 3.

Figure 7.

146

lower doses to OARs with proton therapy.

terms of all radiobiological risk estimation [47].

Follow up counseling is mandatory prior to initiation of treatment. MRI brain may be performed every three months and MRI spine may be obtained every six months in standard risk category of standard risk patients for the initial two years. These two investigations can be performed every 6 months up to five years, and then repeated every year. In high-risk group, MRI of whole brain and spine may be repeated every three months for the initial two years. Thorough clinical examination with every visit is necessary. In case of pediatric or adolescence groups following radiotherapy, neuroendocrine follow-up with evaluation of serum hormonal levels should be performed every six months.

## Acknowledgements

Authors are grateful to Prof. Sunil Saini, Director Cancer Research Institute, Swami Rama Himalayan University for providing motivation and necessary facilities for writing this book chapter.

References

[1] Millard NE, De Braganca KC. Medulloblastoma. Journal of Child Neurology. 2016;31(12):1341-1353

[3] Adesina AM, Yachnis AT. Medulloblastoma Pathology. 2015

[5] Huang MA . Pediatric Medulloblastoma. 2017

Medulloblastoma, 2018

18(7):895-897

2004. p. 1035

1613-1637

149

[6] Lassaletta A, Ramaswamy V. Medulloblastoma in adults: They're not just big kids. Neuro-Oncology. 2016;

[7] Jallo GI, Osburn BR, Shimony N.

[8] Khanna V, Achey RL, Ostrom QT, Block-Beach H, Kruchko C, Barnholtz-Sloan JS. Incidence and survival trends for medulloblastomas in the United States from 2001 to 2013. Journal of Neuro-Oncology. 2017;135(3):433-441

[9] Wilne S, Collier J, Kennedy C, Jenkins A, Grout J, Mackie S, et al. Progression from first symptom to diagnosis in childhood brain tumors. European Journal of Pediatrics. 2012;171(1): 87-9310. DOI: 1007/s00431-011-1485-7

[10] Krishna V. The nervous system. In: Text Book of Pathology. Chennai, India: Orient Longman Private Limited;

Medulloblastoma: A comprehensive review with radiologic-pathologic correlation. Radiographics. 2003;23(6):

[11] Koeller KK, Rushing EJ.

[4] Gregory JJ. Overview of pediatric cancer. In: Pediatrics. Merck Manual; Global Medical Knowledge. 2015

[2] Nelson JS et al. Embryonal tumors of the central nervous system. In: Principles and Practice of Neuropathology. 2nd ed. Oxford University Press; 2003. p. 384

DOI: http://dx.doi.org/10.5772/intechopen.84344

Pediatric Medulloblastoma: A Radiation Oncologist Perspective

[12] Wu G-Y, Haopeng P, Ghimire P, Liu G. H magnetic resonance spectroscopy and diffusion weighted imaging findings of medulloblastoma in 3.0T MRI: A retrospective analysis of 17 cases. Neural Regeneration Research.

[13] Muzumdar D, Deshpande A, Kumar R, Sharma A, Goel N, Dange N, et al. Medulloblastoma in childhood—King Edward Memorial hospital surgical experience and review: Comparative analysis of the case series of 365 patients. Journal of Pediatric

Neurosciences. 2011;6(Supp. 1):S78-S85

[14] Spennato P, Ruggiero C, Cinalli G. Medulloblastoma—Surgery. In: Ozek MM, Cinalli G, Maixner W, Sainte-Rose C, editors. Posterior Fossa Tumors in Children. Switzerland: Springer; 2015.

[15] Meyers SP, Wildenhain SL, Chang JK, Bourekas EC, Beattie PF, Korones DN, et al. Postoperative evaluation for disseminated

[16] Harreld JH, Mohammed N,

Goldsberry G, Li X, Li Y, Boop F, et al. Postoperative intraspinal subdural collections after pediatric posterior fossa tumor resection: Incidence, imaging, and clinical features. AJNR. American Journal of Neuroradiology. 2015;36:

[17] Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathologica. 2016;

medulloblastoma involving the spine: Contrast-enhanced MRI findings, CSF cytologic analysis, timing of disease occurrence, and patient outcomes. AJNR. American Journal of Neuroradiology.

2012;7(32):2554-2559

pp. 313-332

2000;21:1757-1765

993-999

131:103-120

## Conflict of interest

The authors declare that this chapter was written in the absence of any commercial or financial relationships that could elucidate as a potential conflict of interest.

## Author details

Meenu Gupta\* and Mushtaq Ahmad Cancer Research Institute, Swami Rama Himalayan University, Dehradun, India

\*Address all correspondence to: meenugupta.786@rediffmail.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

Acknowledgements

Conflict of interest

interest.

Author details

148

Meenu Gupta\* and Mushtaq Ahmad

provided the original work is properly cited.

ties for writing this book chapter.

Brain and Spinal Tumors - Primary and Secondary

Authors are grateful to Prof. Sunil Saini, Director Cancer Research Institute, Swami Rama Himalayan University for providing motivation and necessary facili-

The authors declare that this chapter was written in the absence of any commercial or financial relationships that could elucidate as a potential conflict of

Cancer Research Institute, Swami Rama Himalayan University, Dehradun, India

© 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,

\*Address all correspondence to: meenugupta.786@rediffmail.com

[1] Millard NE, De Braganca KC. Medulloblastoma. Journal of Child Neurology. 2016;31(12):1341-1353

[2] Nelson JS et al. Embryonal tumors of the central nervous system. In: Principles and Practice of Neuropathology. 2nd ed. Oxford University Press; 2003. p. 384

[3] Adesina AM, Yachnis AT. Medulloblastoma Pathology. 2015

[4] Gregory JJ. Overview of pediatric cancer. In: Pediatrics. Merck Manual; Global Medical Knowledge. 2015

[5] Huang MA . Pediatric Medulloblastoma. 2017

[6] Lassaletta A, Ramaswamy V. Medulloblastoma in adults: They're not just big kids. Neuro-Oncology. 2016; 18(7):895-897

[7] Jallo GI, Osburn BR, Shimony N. Medulloblastoma, 2018

[8] Khanna V, Achey RL, Ostrom QT, Block-Beach H, Kruchko C, Barnholtz-Sloan JS. Incidence and survival trends for medulloblastomas in the United States from 2001 to 2013. Journal of Neuro-Oncology. 2017;135(3):433-441

[9] Wilne S, Collier J, Kennedy C, Jenkins A, Grout J, Mackie S, et al. Progression from first symptom to diagnosis in childhood brain tumors. European Journal of Pediatrics. 2012;171(1): 87-9310. DOI: 1007/s00431-011-1485-7

[10] Krishna V. The nervous system. In: Text Book of Pathology. Chennai, India: Orient Longman Private Limited; 2004. p. 1035

[11] Koeller KK, Rushing EJ. Medulloblastoma: A comprehensive review with radiologic-pathologic correlation. Radiographics. 2003;23(6): 1613-1637

[12] Wu G-Y, Haopeng P, Ghimire P, Liu G. H magnetic resonance spectroscopy and diffusion weighted imaging findings of medulloblastoma in 3.0T MRI: A retrospective analysis of 17 cases. Neural Regeneration Research. 2012;7(32):2554-2559

[13] Muzumdar D, Deshpande A, Kumar R, Sharma A, Goel N, Dange N, et al. Medulloblastoma in childhood—King Edward Memorial hospital surgical experience and review: Comparative analysis of the case series of 365 patients. Journal of Pediatric Neurosciences. 2011;6(Supp. 1):S78-S85

[14] Spennato P, Ruggiero C, Cinalli G. Medulloblastoma—Surgery. In: Ozek MM, Cinalli G, Maixner W, Sainte-Rose C, editors. Posterior Fossa Tumors in Children. Switzerland: Springer; 2015. pp. 313-332

[15] Meyers SP, Wildenhain SL, Chang JK, Bourekas EC, Beattie PF, Korones DN, et al. Postoperative evaluation for disseminated medulloblastoma involving the spine: Contrast-enhanced MRI findings, CSF cytologic analysis, timing of disease occurrence, and patient outcomes. AJNR. American Journal of Neuroradiology. 2000;21:1757-1765

[16] Harreld JH, Mohammed N, Goldsberry G, Li X, Li Y, Boop F, et al. Postoperative intraspinal subdural collections after pediatric posterior fossa tumor resection: Incidence, imaging, and clinical features. AJNR. American Journal of Neuroradiology. 2015;36: 993-999

[17] Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathologica. 2016; 131:103-120

[18] Sengupta S, Krummel DP, Pomeroy S. The evolution of medulloblastoma therapy to personalized medicine. F1000Research. 2017;6:490

[19] Kijima N, Kanemura Y. Molecular classification of medulloblastoma. Neurologia Medico-Chirurgica. 2016; 56(11):687-697

[20] Hayat MA, editor. Pediatric Cancer. Diagnosis, Therapy, and Prognosis. Vol. 42013. Springer. pp. 93-95

[21] DeSouza R-M, Jones BRT, Lowis SP, Kurian KM. Pediatric medulloblastoma —Update on molecular classification driving targeted therapies. Frontiers in Oncology. 2014;4:176

[22] Paterson E, Farr RF. Cerebellar medulloblastoma: Treatment by irradiation of the whole central nervous system. Acta Radiologica. 1953;39(4): 323-336

[23] Paulino AC. Radiotherapeutic management of medulloblastoma. Oncology. 1997;11:813-823

[24] Lannering B, Rutkowski S, Doz F, Pizer B, Gustafsson G, Navajas A, et al. Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: Results from the randomized multicenter HIT-SIOP PNET 4 trial. Journal of Clinical Oncology. 2012; 30(26):3187-3193

[25] Tai P, Koul R, Khanh V, Edwards T, Buwembo J, Teles AR, et al. A simplified supine technique expedites the delivery of effective craniospinal radiation to medulloblastoma—Comparison with other techniques in the literature. Cureus. 2015;7(12):e404

[26] Athiyaman H, Mayilvaganan A, Singh D. A simple planning technique of craniospinal irradiation in the eclipse treatment planning system. Journal of Medical Physics. 2014;39(4):251-258

[27] Parker WA, Freeman CR. A simple technique for craniospinal radiotherapy in the supine position. Radiotherapy and Oncology. 2006;78:217-222

Research and Therapeutics. 2017;13:

DOI: http://dx.doi.org/10.5772/intechopen.84344

Pediatric Medulloblastoma: A Radiation Oncologist Perspective

dose with reduced-dose neuraxis

2000;18:3004-3011

Cancer. 2015;62:553-564

Health. 2016;13(11):1057

2016;96(2):387-392

[45] Indelicato DJ, Merchant T, Laperriere N, Lassen Y, Vennarini S, Wolden S. Consensus report from the stockholm pediatric proton therapy conference. International Journal of Radiation Oncology, Biology, Physics.

[46] Mahajan A. Proton craniospinal radiation therapy: Rationale and clinical evidence. International Journal of Particle Therapy. 2014;1(2):399-407

[47] Brodin NP, Munck Af Rosenschöld P, Aznar MC, et al. Radiobiological risk

secondary cancer for proton and photon

[48] Kann BH, Park HS, Lester-Coll NH, Yeboa DN, Benitez V, Khanet AJ, et al. Postoperative radiotherapy patterns of care and survival implications for medulloblastoma in young children. JAMA Oncology. 2016;2(12):1574-1581

[49] Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. Journal

of Clinical Oncology. 2006;24:

4202-4208

estimates of adverse events and

radiation therapy of pediatric medulloblastoma. Acta Oncologica.

2011;50:806-816

irradiation. Journal of Clinical Oncology.

[43] Parkes J, Hendricks M, Ssenyonga P, Mugamba J, Molyneux E, Meeterenet A S-v, et al. Clinical practice guidelines SIOP PODC. Adapted treatment recommendations for standard-risk medulloblastoma in low and middle income settings. Pediatric Blood &

[44] Kutanzi KR, Lumen A, Koturbash I, Miousse IR. Pediatric exposures to ionizing radiation: Carcinogenic considerations. International Journal of Environmental Research and Public

[36] Gupta T, Sarkar C, et al. Indian society of neuro-oncology consensus guidelines for the contemporary management of medulloblastoma. Neurology India. 2017;65:315-332

[37] Parker W, Filion E, et al. Intensitymodulated radiotherapy for craniospinal

considerations, dose constraints, and competing risks. International Journal of Radiation Oncology • Biology • Physics.

[38] Sharma DS, Gupta T, Jalali R, Master Z, Phurailatpam RD, Sarin R. Highprecision radiotherapy for craniospinal irradiation: Evaluation of threedimensional conformal radiotherapy, intensity-modulated radiation therapy and helical tomotherapy. The British Journal of Radiology. 2009 Dec;82(984):

[39] Huang E, Teh BS, Strother DR, Davis QG, Chiu JK, Lu HH, et al. Intensitymodulated radiation therapy for pediatric medulloblastoma: Early report on the reduction of ototoxicity. International Journal of Radiation Oncology, Biology,

irradiation: Target volume

2007;69(1):251-257

1000-1009

Physics. 2002;52:599-605

9789080625679

2002;54(3):855-860

151

[40] Pierotti MA, van Harten W, editors. European Options and

[41] Abacioglu U, OmerUzel MS, SedatTurkan AO. Medulloblastoma in adults: Treatment results and prognostic

factors. International Journal of

Radiation Oncology • Biology • Physics.

[42] Thomas PR, Deutsch M, Kepner JL, et al. Low-stage medulloblastoma: Final analysis of trial comparing standard-

Recommendations for Cancer Diagnosis and Therapy. Vol. 12011. Brussels, Belgium: Organisation of European Cancer Institutes European Economic Interest Grouping c/o Fondation Universitaire (OECI-EEIG); ISBN:

1027-1031

[28] Taqaddas A. Oncological management of medulloblastoma and new viral therapeutic targets. International Journal of Medical and Health Sciences. 2015;9(1):27-30

[29] Ajithkumar T, Horan G, Padovani L, Thorp N, Timmermann B, Alapetite C, et al. SIOPE—Brain tumor group consensus guideline on craniospinal target volume delineation for highprecision radiotherapy. Radiotherapy & Oncology. 2018;128(2):192-197

[30] Noble DJ, Scoffings D, et al. Fast imaging employing steady-state acquisition (FIESTA) MRI to investigate cerebrospinal fluid (CSF) within dural reflections of posterior fossa cranial nerves. The British Journal of Radiology. 2016;89(1067):20160392

[31] Siddiqui JD, Loeffler JS, Murphy MA. Radiation optic neuropathy after proton beam therapy for optic nerve sheath meningioma. Journal of Neuro-Ophthalmology. 2013;33:165-168

[32] Ferguson I et al. Risk factors for radiation-induced optic neuropathy: A casecontrol study. Clinical & Experimental Ophthalmology. 2017;45: 592-597

[33] Jereb B, Reid A, Ahuja RK. Patterns of failure in patients with medulloblastoma. Cancer. 1982;50:2941-2947

[34] Donnal J, Halperin EC, Friedman HS, et al. Subfrontal recurrenceof medulloblastoma. Journal of Neurology Research. 1992;13:1617-1618

[35] Gupta M, Kant R, et al. A dosimetric comparison between three-dimensional conformal radiation therapy and intensity-modulated radiation therapy in the treatment of posterior fossa boost in medulloblastoma. Journal of Cancer

Pediatric Medulloblastoma: A Radiation Oncologist Perspective DOI: http://dx.doi.org/10.5772/intechopen.84344

Research and Therapeutics. 2017;13: 1027-1031

[18] Sengupta S, Krummel DP, Pomeroy S. The evolution of medulloblastoma therapy to personalized medicine. F1000Research. 2017;6:490

Brain and Spinal Tumors - Primary and Secondary

[27] Parker WA, Freeman CR. A simple technique for craniospinal radiotherapy in the supine position. Radiotherapy and

management of medulloblastoma and

[29] Ajithkumar T, Horan G, Padovani L, Thorp N, Timmermann B, Alapetite C, et al. SIOPE—Brain tumor group consensus guideline on craniospinal target volume delineation for highprecision radiotherapy. Radiotherapy &

Oncology. 2006;78:217-222

[28] Taqaddas A. Oncological

new viral therapeutic targets. International Journal of Medical and Health Sciences. 2015;9(1):27-30

Oncology. 2018;128(2):192-197

2016;89(1067):20160392

592-597

[30] Noble DJ, Scoffings D, et al. Fast imaging employing steady-state

[31] Siddiqui JD, Loeffler JS, Murphy MA. Radiation optic neuropathy after proton beam therapy for optic nerve sheath meningioma. Journal of Neuro-Ophthalmology. 2013;33:165-168

[32] Ferguson I et al. Risk factors for radiation-induced optic neuropathy: A casecontrol study. Clinical &

Experimental Ophthalmology. 2017;45:

[33] Jereb B, Reid A, Ahuja RK. Patterns of failure in patients with medulloblastoma.

[34] Donnal J, Halperin EC, Friedman HS, et al. Subfrontal recurrenceof medulloblastoma. Journal of Neurology

[35] Gupta M, Kant R, et al. A dosimetric comparison between three-dimensional conformal radiation therapy and

intensity-modulated radiation therapy in the treatment of posterior fossa boost in medulloblastoma. Journal of Cancer

Cancer. 1982;50:2941-2947

Research. 1992;13:1617-1618

acquisition (FIESTA) MRI to investigate cerebrospinal fluid (CSF) within dural reflections of posterior fossa cranial nerves. The British Journal of Radiology.

[19] Kijima N, Kanemura Y. Molecular classification of medulloblastoma. Neurologia Medico-Chirurgica. 2016;

[20] Hayat MA, editor. Pediatric Cancer. Diagnosis, Therapy, and Prognosis. Vol.

[21] DeSouza R-M, Jones BRT, Lowis SP, Kurian KM. Pediatric medulloblastoma —Update on molecular classification driving targeted therapies. Frontiers in

[22] Paterson E, Farr RF. Cerebellar medulloblastoma: Treatment by

[23] Paulino AC. Radiotherapeutic management of medulloblastoma.

[24] Lannering B, Rutkowski S, Doz F, Pizer B, Gustafsson G, Navajas A, et al. Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: Results from the randomized multicenter HIT-SIOP PNET 4 trial. Journal of Clinical Oncology. 2012;

[25] Tai P, Koul R, Khanh V, Edwards T,

medulloblastoma—Comparison with other techniques in the literature.

[26] Athiyaman H, Mayilvaganan A, Singh D. A simple planning technique of craniospinal irradiation in the eclipse treatment planning system. Journal of Medical Physics. 2014;39(4):251-258

Buwembo J, Teles AR, et al. A simplified supine technique expedites the delivery of effective

craniospinal radiation to

Cureus. 2015;7(12):e404

150

Oncology. 1997;11:813-823

30(26):3187-3193

irradiation of the whole central nervous system. Acta Radiologica. 1953;39(4):

56(11):687-697

42013. Springer. pp. 93-95

Oncology. 2014;4:176

323-336

[36] Gupta T, Sarkar C, et al. Indian society of neuro-oncology consensus guidelines for the contemporary management of medulloblastoma. Neurology India. 2017;65:315-332

[37] Parker W, Filion E, et al. Intensitymodulated radiotherapy for craniospinal irradiation: Target volume considerations, dose constraints, and competing risks. International Journal of Radiation Oncology • Biology • Physics. 2007;69(1):251-257

[38] Sharma DS, Gupta T, Jalali R, Master Z, Phurailatpam RD, Sarin R. Highprecision radiotherapy for craniospinal irradiation: Evaluation of threedimensional conformal radiotherapy, intensity-modulated radiation therapy and helical tomotherapy. The British Journal of Radiology. 2009 Dec;82(984): 1000-1009

[39] Huang E, Teh BS, Strother DR, Davis QG, Chiu JK, Lu HH, et al. Intensitymodulated radiation therapy for pediatric medulloblastoma: Early report on the reduction of ototoxicity. International Journal of Radiation Oncology, Biology, Physics. 2002;52:599-605

[40] Pierotti MA, van Harten W, editors. European Options and Recommendations for Cancer Diagnosis and Therapy. Vol. 12011. Brussels, Belgium: Organisation of European Cancer Institutes European Economic Interest Grouping c/o Fondation Universitaire (OECI-EEIG); ISBN: 9789080625679

[41] Abacioglu U, OmerUzel MS, SedatTurkan AO. Medulloblastoma in adults: Treatment results and prognostic factors. International Journal of Radiation Oncology • Biology • Physics. 2002;54(3):855-860

[42] Thomas PR, Deutsch M, Kepner JL, et al. Low-stage medulloblastoma: Final analysis of trial comparing standarddose with reduced-dose neuraxis irradiation. Journal of Clinical Oncology. 2000;18:3004-3011

[43] Parkes J, Hendricks M, Ssenyonga P, Mugamba J, Molyneux E, Meeterenet A S-v, et al. Clinical practice guidelines SIOP PODC. Adapted treatment recommendations for standard-risk medulloblastoma in low and middle income settings. Pediatric Blood & Cancer. 2015;62:553-564

[44] Kutanzi KR, Lumen A, Koturbash I, Miousse IR. Pediatric exposures to ionizing radiation: Carcinogenic considerations. International Journal of Environmental Research and Public Health. 2016;13(11):1057

[45] Indelicato DJ, Merchant T, Laperriere N, Lassen Y, Vennarini S, Wolden S. Consensus report from the stockholm pediatric proton therapy conference. International Journal of Radiation Oncology, Biology, Physics. 2016;96(2):387-392

[46] Mahajan A. Proton craniospinal radiation therapy: Rationale and clinical evidence. International Journal of Particle Therapy. 2014;1(2):399-407

[47] Brodin NP, Munck Af Rosenschöld P, Aznar MC, et al. Radiobiological risk estimates of adverse events and secondary cancer for proton and photon radiation therapy of pediatric medulloblastoma. Acta Oncologica. 2011;50:806-816

[48] Kann BH, Park HS, Lester-Coll NH, Yeboa DN, Benitez V, Khanet AJ, et al. Postoperative radiotherapy patterns of care and survival implications for medulloblastoma in young children. JAMA Oncology. 2016;2(12):1574-1581

[49] Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. Journal of Clinical Oncology. 2006;24: 4202-4208

Chapter 10

Abstract

treatment for GBM.

1. Introduction

153

and Michael E. Ivan

Laser Ablation for Gliomas

Alexa Semonche, Daniel Eichberg, Ashish Shah

Laser interstitial thermal therapy (LITT) is a novel minimally invasive neurosurgical procedure in which laser light is delivered through a stereotactically positioned probe to an intracranial lesion for controlled thermal ablation of the pathological tissue. LITT is considered for patients who are poor candidates for open surgical resection due to (1) location of lesion (e.g., deep-seated or near critical structures), (2) history of intracranial interventions or medical comorbidities that increase surgical risk, or (3) lesion refractoriness to prior conventional therapies. The use of LITT was initially limited by concerns over off-target thermal damage; however, recent advances in magnetic resonance imaging-based thermal imaging have enabled real-time monitoring of tissue ablation dynamics, thereby improving its safety profile. Accordingly, the past two decades have seen a rapid expansion in the use of LITT for a variety of intracranial pathologies, including neoplasms, radiation necrosis, and epilepsy. This chapter focuses on the novel application of LITT to both newly diagnosed and recurrent glioblastoma multiforme (GBM). We first review the technological developments that enabled the safe use of LITT for GBM. We then review recent evidence regarding the indications, outcomes, and limitations of LITT as a novel adjuvant

Keywords: LITT, laser, glioma, glioblastoma, astrocytoma, ablation

1.1 Glioblastoma multiforme: standard-of-care and prognosis

of 64 years at diagnosis [1]. Current standard-of-care guidelines for initial

For example, methylguanine methyltransferase (MGMT) promoter

Isocitrate dehydrogenase 1 (IDH) mutation-positive tumors, especially in

World Health Organization (WHO) grade IV glioma (glioblastoma multiforme) is the most common and most lethal malignant primary brain tumor. The incidence in the United States is estimated to be 3.12 per 100,000 persons with a median age

treatment for grade III or IV gliomas (high-grade gliomas (HGG)) are maximal safe surgical resection followed by adjuvant temozolomide chemotherapy and radiation [2]. Although standard-of-care treatment improves median survival from 3 months in untreated patients to 14.8 months, GBM remains a terminal diagnosis as tumors inevitably recur [2, 3]. There are few positive prognostic factors. In a minority of patients, certain tumor molecular phenotypes correlate with improved prognosis.

hypermethylation is associated with an increased median survival of 21.7 months.

## Chapter 10

## Laser Ablation for Gliomas

Alexa Semonche, Daniel Eichberg, Ashish Shah and Michael E. Ivan

## Abstract

Laser interstitial thermal therapy (LITT) is a novel minimally invasive neurosurgical procedure in which laser light is delivered through a stereotactically positioned probe to an intracranial lesion for controlled thermal ablation of the pathological tissue. LITT is considered for patients who are poor candidates for open surgical resection due to (1) location of lesion (e.g., deep-seated or near critical structures), (2) history of intracranial interventions or medical comorbidities that increase surgical risk, or (3) lesion refractoriness to prior conventional therapies. The use of LITT was initially limited by concerns over off-target thermal damage; however, recent advances in magnetic resonance imaging-based thermal imaging have enabled real-time monitoring of tissue ablation dynamics, thereby improving its safety profile. Accordingly, the past two decades have seen a rapid expansion in the use of LITT for a variety of intracranial pathologies, including neoplasms, radiation necrosis, and epilepsy. This chapter focuses on the novel application of LITT to both newly diagnosed and recurrent glioblastoma multiforme (GBM). We first review the technological developments that enabled the safe use of LITT for GBM. We then review recent evidence regarding the indications, outcomes, and limitations of LITT as a novel adjuvant treatment for GBM.

Keywords: LITT, laser, glioma, glioblastoma, astrocytoma, ablation

## 1. Introduction

### 1.1 Glioblastoma multiforme: standard-of-care and prognosis

World Health Organization (WHO) grade IV glioma (glioblastoma multiforme) is the most common and most lethal malignant primary brain tumor. The incidence in the United States is estimated to be 3.12 per 100,000 persons with a median age of 64 years at diagnosis [1]. Current standard-of-care guidelines for initial treatment for grade III or IV gliomas (high-grade gliomas (HGG)) are maximal safe surgical resection followed by adjuvant temozolomide chemotherapy and radiation [2]. Although standard-of-care treatment improves median survival from 3 months in untreated patients to 14.8 months, GBM remains a terminal diagnosis as tumors inevitably recur [2, 3]. There are few positive prognostic factors. In a minority of patients, certain tumor molecular phenotypes correlate with improved prognosis. For example, methylguanine methyltransferase (MGMT) promoter hypermethylation is associated with an increased median survival of 21.7 months. Isocitrate dehydrogenase 1 (IDH) mutation-positive tumors, especially in

combination with MGMT hypermethylation, also correlate with a survival benefit [4]. Other favorable prognostic factors include younger age at diagnosis, pretreatment functional status, and extent of surgical resection of the tumor mass [5]. increased intracranial pressure. Tissue charring at temperatures >90°C can also damage healthy brain and impair laser penetration to further target regions. Therefore, the ideal temperature range for thermal ablation is 50–90°C [19]. The first use of LITT in neurosurgery was reported in the early 1980s [20]; however, concerns were raised over how to limit thermal injury to pathological tissue only [21]. Although early LITT users could stereotactically position a laser optical fiber to the center of a lesion, they did not have an accurate method for measuring heat distribution throughout the target and to surrounding off-target areas. Two advances in LITT technology have improved its safety: (1) real-time magnetic resonance (MR) thermometry and (2) the development of commercially available LITT systems that successfully integrate MR thermometry data and enhanced control over laser energy delivery into a standard workflow.

Laser Ablation for Gliomas

DOI: http://dx.doi.org/10.5772/intechopen.86829

MR thermometry was introduced in the 1990s as a way to monitor real-time changes in tissue temperature on an MR imaging sequence [22, 23]. T2-weighted MRI images are taken intraoperatively; changes in tissue temperature affect the water proton resonance frequency signal in a linear relationship and can be mapped onto pixels of the MRI image. The result is a heat damage map that can be updated throughout the procedure and used to guide the boundaries of laser ablation [24]. The NeuroBlate laser ablation system (Monteris, Inc.) and the Visualase Thermal Therapy System (Medtronic, Inc.) received Food and Drug Administration (FDA) approval in 2007 and 2009, respectively. These commercial LITT platforms use MR thermometry software that allows the surgeon to define a maximum temperature threshold at the periphery of the target lesion; surpassing this threshold automatically triggers laser shutdown to protect off-target regions [24]. The Visualase and NeuroBlate LITT systems also improved procedure safety in designing a cooling sheath to surround the laser fiber along the length of laser

probe, thereby limiting thermal damage to the tip of the probe [18].

The LITT setup consists of four components: (1) laser energy source, (2) laser applicator probe, (3) cooling mechanism, and (4) computer workstation with software for processing real-time MRI thermometry data and controlling laser energy delivery. The patient is induced under general anesthesia or monitored anesthesia care (MAC). In the operating room, the laser trajectory from a skull entry point to the

target lesion is planned using standard neuronavigation (e.g., Stealth system, Medtronic Inc.) technology. The laser applicator probe is stereotactically positioned along this trajectory through a single burr hole at the entry point. The surgeon may opt to perform stereotactic needle biopsy prior to implantation of the applicator probe to obtain a histopathological diagnosis. The patient is then transferred to an MRI suite under anesthesia. Laser energy is delivered through the probe to the target lesion in controlled doses lasting several minutes each. Concurrent real-time MRI thermal imaging (MRTI) of the treatment region allows the user to adjust laser output parameters so that thermal ablation of the target is achieved while avoiding thermal damage to normal surrounding brain tissue. Following LITT treatment, the applicator probe is removed, and the small skin opening overlying the entry point is closed.

The NeuroBlate system consists of a 12-Watt (W) pulsed-output 1064 nm wavelength neodymium-doped yttrium aluminum garnet (Nd-YAG) laser with a

2.2 Overview of the LITT setup and workflow

2.3 LITT system platforms and surgical technique

2.3.1 LITT system platforms

155

#### 1.2 Rationale for use of LITT for glioblastoma

Recent studies have improved our understanding of how the extent of surgical resection impacts progression-free survival and overall survival for GBM patients [6, 7]. Although GBM is a diffusely infiltrative disease, gross total resection (GTR) is associated with increased progression-free survival and overall survival compared to subtotal resection (STR), which itself confers a survival benefit compared to biopsy alone [7]. Studies aiming to quantify a threshold extent of resection have concluded that a threshold at 78% resection of radiographic tumor is necessary to confer a survival benefit compared to radiation and chemotherapy alone [8–11]. Other recent studies have found an additional survival benefit from supra-total resection (i.e., resection beyond the contrast-enhancing tumor margins) to include any fluid-attenuated inversion recovery (FLAIR) abnormalities or a total right frontal or parietal lobectomy compared to GTR [12, 13]. These findings support the current standard-of-care guidelines for maximal safe surgical resection and reinforce the primary role of cytoreduction in GBM treatment.

However, some patients may not be able to undergo conventional open surgical resection. Factors contributing to this include medical comorbidities that increase surgical risk, low preoperative functional status, inability to tolerate general anesthesia, and history of radiation therapy or prior craniotomy that may impair wound healing and increase risk of postoperative neurological worsening [14]. Up to 40% of GBM tumors are considered surgically "unresectable" based on their location in deep or eloquent brain regions or adjacent to critical neurovascular structures [15]. Postoperative neurological deficits from injury to eloquent brain regions during open surgical resection are associated with reduced overall survival and functional status [16]. When open surgery is not an option, patients may simply receive a needle biopsy for diagnosis and chemoradiation. For these patients, laser interstitial thermal therapy is a minimally invasive alternative approach for cytoreductive intervention.

## 2. Laser interstitial thermal therapy: Principles and technological developments

#### 2.1 Technological principles

LITT is a minimally invasive neurosurgical procedure that delivers laser light to an intracranial target to thermally ablate pathological tissue [17]. Laser light is a form of non-ionizing radiation and is emitted from a power source as a coherent beam of electromagnetic radiation. Laser light is delivered intracranially through a fiber optic ensheathed in a rigid laser probe that can be stereotactically inserted along a linear trajectory from a single skull entry point to the lesion. The primary mechanism of thermal damage occurs when laser light is absorbed by tissue water and hemoglobin molecules, causing excitation and release of heat. In LITT, laser light in the near-infrared range (980–1064 nm) is used to maximize tissue penetrance (up to 10 mm). Tissue heating to at least 43°C for several minutes is sufficient to cause irreversible tissue damage; heating to 60°C rapidly induces protein denaturation and damage to DNA and lipid membranes, resulting in coagulative necrosis [18]. At 100°C, tissue vaporization occurs, which can result in

#### Laser Ablation for Gliomas DOI: http://dx.doi.org/10.5772/intechopen.86829

combination with MGMT hypermethylation, also correlate with a survival benefit [4]. Other favorable prognostic factors include younger age at diagnosis, pretreatment functional status, and extent of surgical resection of the tumor mass [5].

Recent studies have improved our understanding of how the extent of surgical resection impacts progression-free survival and overall survival for GBM patients [6, 7]. Although GBM is a diffusely infiltrative disease, gross total resection (GTR) is associated with increased progression-free survival and overall survival compared to subtotal resection (STR), which itself confers a survival benefit compared to biopsy alone [7]. Studies aiming to quantify a threshold extent of resection have concluded that a threshold at 78% resection of radiographic tumor is necessary to confer a survival benefit compared to radiation and chemotherapy alone [8–11]. Other recent studies have found an additional survival benefit from supra-total resection (i.e., resection beyond the contrast-enhancing tumor margins) to include any fluid-attenuated inversion recovery (FLAIR) abnormalities or a total right frontal or parietal lobectomy compared to GTR [12, 13]. These findings support the current standard-of-care guidelines for maximal safe surgical resection and rein-

However, some patients may not be able to undergo conventional open surgical resection. Factors contributing to this include medical comorbidities that increase surgical risk, low preoperative functional status, inability to tolerate general anesthesia, and history of radiation therapy or prior craniotomy that may impair wound healing and increase risk of postoperative neurological worsening [14]. Up to 40% of GBM tumors are considered surgically "unresectable" based on their location in deep or eloquent brain regions or adjacent to critical neurovascular structures [15]. Postoperative neurological deficits from injury to eloquent brain regions during open surgical resection are associated with reduced overall survival and functional status [16]. When open surgery is not an option, patients may simply receive a needle biopsy for diagnosis and chemoradiation. For these patients, laser interstitial thermal therapy is a minimally invasive alternative approach for cytoreductive

2. Laser interstitial thermal therapy: Principles and technological

LITT is a minimally invasive neurosurgical procedure that delivers laser light to an intracranial target to thermally ablate pathological tissue [17]. Laser light is a form of non-ionizing radiation and is emitted from a power source as a coherent beam of electromagnetic radiation. Laser light is delivered intracranially through a fiber optic ensheathed in a rigid laser probe that can be stereotactically inserted along a linear trajectory from a single skull entry point to the lesion. The primary mechanism of thermal damage occurs when laser light is absorbed by tissue water and hemoglobin molecules, causing excitation and release of heat. In LITT, laser light in the near-infrared range (980–1064 nm) is used to maximize tissue penetrance (up to 10 mm). Tissue heating to at least 43°C for several minutes is sufficient to cause irreversible tissue damage; heating to 60°C rapidly induces protein denaturation and damage to DNA and lipid membranes, resulting in coagulative necrosis [18]. At 100°C, tissue vaporization occurs, which can result in

1.2 Rationale for use of LITT for glioblastoma

Brain and Spinal Tumors - Primary and Secondary

force the primary role of cytoreduction in GBM treatment.

intervention.

154

developments

2.1 Technological principles

increased intracranial pressure. Tissue charring at temperatures >90°C can also damage healthy brain and impair laser penetration to further target regions. Therefore, the ideal temperature range for thermal ablation is 50–90°C [19].

The first use of LITT in neurosurgery was reported in the early 1980s [20]; however, concerns were raised over how to limit thermal injury to pathological tissue only [21]. Although early LITT users could stereotactically position a laser optical fiber to the center of a lesion, they did not have an accurate method for measuring heat distribution throughout the target and to surrounding off-target areas. Two advances in LITT technology have improved its safety: (1) real-time magnetic resonance (MR) thermometry and (2) the development of commercially available LITT systems that successfully integrate MR thermometry data and enhanced control over laser energy delivery into a standard workflow.

MR thermometry was introduced in the 1990s as a way to monitor real-time changes in tissue temperature on an MR imaging sequence [22, 23]. T2-weighted MRI images are taken intraoperatively; changes in tissue temperature affect the water proton resonance frequency signal in a linear relationship and can be mapped onto pixels of the MRI image. The result is a heat damage map that can be updated throughout the procedure and used to guide the boundaries of laser ablation [24].

The NeuroBlate laser ablation system (Monteris, Inc.) and the Visualase Thermal Therapy System (Medtronic, Inc.) received Food and Drug Administration (FDA) approval in 2007 and 2009, respectively. These commercial LITT platforms use MR thermometry software that allows the surgeon to define a maximum temperature threshold at the periphery of the target lesion; surpassing this threshold automatically triggers laser shutdown to protect off-target regions [24]. The Visualase and NeuroBlate LITT systems also improved procedure safety in designing a cooling sheath to surround the laser fiber along the length of laser probe, thereby limiting thermal damage to the tip of the probe [18].

## 2.2 Overview of the LITT setup and workflow

The LITT setup consists of four components: (1) laser energy source, (2) laser applicator probe, (3) cooling mechanism, and (4) computer workstation with software for processing real-time MRI thermometry data and controlling laser energy delivery. The patient is induced under general anesthesia or monitored anesthesia care (MAC). In the operating room, the laser trajectory from a skull entry point to the target lesion is planned using standard neuronavigation (e.g., Stealth system, Medtronic Inc.) technology. The laser applicator probe is stereotactically positioned along this trajectory through a single burr hole at the entry point. The surgeon may opt to perform stereotactic needle biopsy prior to implantation of the applicator probe to obtain a histopathological diagnosis. The patient is then transferred to an MRI suite under anesthesia. Laser energy is delivered through the probe to the target lesion in controlled doses lasting several minutes each. Concurrent real-time MRI thermal imaging (MRTI) of the treatment region allows the user to adjust laser output parameters so that thermal ablation of the target is achieved while avoiding thermal damage to normal surrounding brain tissue. Following LITT treatment, the applicator probe is removed, and the small skin opening overlying the entry point is closed.

#### 2.3 LITT system platforms and surgical technique

#### 2.3.1 LITT system platforms

The NeuroBlate system consists of a 12-Watt (W) pulsed-output 1064 nm wavelength neodymium-doped yttrium aluminum garnet (Nd-YAG) laser with a side-firing laser probe design, allowing some control over the direction of ablation. Temperature at the tip is controlled with a C02 gas cooling mechanism with a builtin thermocouple for feedback control. The Visualase system consists of a 15 W 980 nm diode laser with diffusing-tip probe design. Within the probe, the laser fiber optic is ensheathed within catheter circulating cooled saline. Both systems have a computer workstation with software for MR thermal imaging analysis and control over laser treatment parameters [25]. The 1064 nm wavelength laser used in the NeuroBlate system allows for deeper tissue penetration and potentially larger ablation zone, while the Visualase 980 nm wavelength laser produces more efficient heating [9].

#### 2.3.2 Surgical procedure

After the patient is induced under anesthesia, stereotactic registration is performed to plan laser probe trajectory. If a stereotactic headframe is used to set the laser probe trajectory, then a preoperative T1-weighted MRI with contrast and neuronavigation technology is used to plan the trajectory. If the surgeon is using a frameless setup for registration, then an initial computed-tomography (CT) head with fiducial markers is obtained; this is merged with preoperative T1-weighted MRI with contrast studies, and then registration proceeds using neuronavigation. Once registration is complete, a linear trajectory is planned connecting a single entry site at the skull to the lesion that avoids critical brain structures. A trajectory that is orthogonal to the skull surface in all three dimensional planes helps to prevent skiving during drilling and catheter placement and should be utilized. After image registration, the entry point is found with the navigation wand and marked. Local anesthetic is infiltrated at the scalp over the entry site. A precision aiming device and Stealth navigation wand are aligned along the planned trajectory. A 4-mm incision is made to bring the navigation wand tip onto the skull surface entry point. A small burr hole is made with a 3.2-mm drill bit. After the dura is punctured, a reducing cannula is used to pass a rigid stylet, which maintains alignment during placement of the plastic bone anchor. The plastic bone anchor is screwed into the skull with the rigid stylet as a guide. The laser probe is placed into the cooling catheter and fixed in place (Figure 1). The patient is then transported under sterile draping and with continued general anesthesia to the MRI suite, where a T2-weighted MRI imaging is then performed to confirm placement of the laser probe in the lesion.

The LITT system software is used to set maximum temperature thresholds of 90°C in the immediate ablation zone around the laser probe tip and 50°C at the target periphery to ensure tissue ablation throughout the target zone (Figure 2A–D). Additional maximum temperature thresholds are set in the normal parenchyma surrounding the lesion that, if reached, trigger automatic shutoff to avoid off-target tissue damage [19]. Under real-time MR thermography guidance, a 30–60-second, 3–4 W-test dose is administered to localize the distal end of the laser probe. Once localization of the laser probe to the target is confirmed, the lesion is treated with 10–15 W doses of laser light in 1–3 minute intervals. Ablation is considered complete when the region of tissue reaching 50°C is covered (Figure 2E). After ablation is complete, the LITT apparatus is removed through the burr hole craniotomy, and the skin is closed. Typical length of hospital stay is under 48 hours [19, 24, 26, 27].

Postoperative MRI imaging is typically obtained on the first day following LITT. On T1-weighted MRI with contrast, the thermal ablation zone has a thin enhancing rim with potential surrounding edema and enhancing residual blood products and protein coagulation [19]. Residual tumor remaining after subtotal ablation can be

detected on this first postoperative scan. The extent of ablation can be determined using volumetric analysis volume of the ablation zone postoperatively to the volume

Representative results of MR thermometry, which acquires real-time temperature data for each pixel of an M2 weighted MRI image. Representative preoperative sagittal (A), axial (B), and coronal (C) T1-weighted MRI with contrast images are suggestive of high-grade glioma. In planning a course of LITT, markers for temperature thresholds to achieve ablation while avoiding off-target damage or tissue vaporization are set by the user (D). During LITT, a damage zone of tissue achieving temperatures sufficient for ablation is represented by orange

of the lesion on the preoperative MRI obtained for surgical planning [28].

Intraoperative setup for laser interstitial thermal therapy. The laser probe trajectory is planned under neuronavigation. The skin overlying the skull entry point is incised, a small burr hole is drilled, and a small incision in the dura is made. A cannula is inserted and used to guide the rigid stylet and bone anchor in the

Figure 1.

Laser Ablation for Gliomas

DOI: http://dx.doi.org/10.5772/intechopen.86829

Figure 2.

pixels (E).

157

correct orientation along the planned trajectory.

Laser Ablation for Gliomas DOI: http://dx.doi.org/10.5772/intechopen.86829

#### Figure 1.

side-firing laser probe design, allowing some control over the direction of ablation. Temperature at the tip is controlled with a C02 gas cooling mechanism with a builtin thermocouple for feedback control. The Visualase system consists of a 15 W 980 nm diode laser with diffusing-tip probe design. Within the probe, the laser fiber optic is ensheathed within catheter circulating cooled saline. Both systems have a computer workstation with software for MR thermal imaging analysis and control over laser treatment parameters [25]. The 1064 nm wavelength laser used in the NeuroBlate system allows for deeper tissue penetration and potentially larger ablation zone, while the Visualase 980 nm wavelength laser produces more efficient

After the patient is induced under anesthesia, stereotactic registration is performed to plan laser probe trajectory. If a stereotactic headframe is used to set the laser probe trajectory, then a preoperative T1-weighted MRI with contrast and neuronavigation technology is used to plan the trajectory. If the surgeon is using a frameless setup for registration, then an initial computed-tomography (CT) head with fiducial markers is obtained; this is merged with preoperative T1-weighted MRI with contrast studies, and then registration proceeds using neuronavigation. Once registration is complete, a linear trajectory is planned connecting a single entry site at the skull to the lesion that avoids critical brain structures. A trajectory that is orthogonal to the skull surface in all three dimensional planes helps to prevent skiving during drilling and catheter placement and should be utilized. After image registration, the entry point is found with the navigation wand and marked. Local anesthetic is infiltrated at the scalp over the entry site. A precision aiming device and Stealth navigation wand are aligned along the planned trajectory. A 4-mm incision is made to bring the navigation wand tip onto the skull surface entry point. A small burr hole is made with a 3.2-mm drill bit. After the dura is punctured, a reducing cannula is used to pass a rigid stylet, which maintains alignment during placement of the plastic bone anchor. The plastic bone anchor is screwed into the skull with the rigid stylet as a guide. The laser probe is placed into the cooling catheter and fixed in place (Figure 1). The patient is then transported under sterile draping and with continued general anesthesia to the MRI suite, where a T2-weighted MRI imaging is then performed to confirm placement of the laser

The LITT system software is used to set maximum temperature thresholds of 90°C in the immediate ablation zone around the laser probe tip and 50°C at the

(Figure 2A–D). Additional maximum temperature thresholds are set in the normal parenchyma surrounding the lesion that, if reached, trigger automatic shutoff to avoid off-target tissue damage [19]. Under real-time MR thermography guidance, a 30–60-second, 3–4 W-test dose is administered to localize the distal end of the laser probe. Once localization of the laser probe to the target is confirmed, the lesion is treated with 10–15 W doses of laser light in 1–3 minute intervals. Ablation is considered complete when the region of tissue reaching 50°C is covered

(Figure 2E). After ablation is complete, the LITT apparatus is removed through the burr hole craniotomy, and the skin is closed. Typical length of hospital stay is under

Postoperative MRI imaging is typically obtained on the first day following LITT. On T1-weighted MRI with contrast, the thermal ablation zone has a thin enhancing rim with potential surrounding edema and enhancing residual blood products and protein coagulation [19]. Residual tumor remaining after subtotal ablation can be

target periphery to ensure tissue ablation throughout the target zone

heating [9].

2.3.2 Surgical procedure

Brain and Spinal Tumors - Primary and Secondary

probe in the lesion.

48 hours [19, 24, 26, 27].

156

Intraoperative setup for laser interstitial thermal therapy. The laser probe trajectory is planned under neuronavigation. The skin overlying the skull entry point is incised, a small burr hole is drilled, and a small incision in the dura is made. A cannula is inserted and used to guide the rigid stylet and bone anchor in the correct orientation along the planned trajectory.

#### Figure 2.

Representative results of MR thermometry, which acquires real-time temperature data for each pixel of an M2 weighted MRI image. Representative preoperative sagittal (A), axial (B), and coronal (C) T1-weighted MRI with contrast images are suggestive of high-grade glioma. In planning a course of LITT, markers for temperature thresholds to achieve ablation while avoiding off-target damage or tissue vaporization are set by the user (D). During LITT, a damage zone of tissue achieving temperatures sufficient for ablation is represented by orange pixels (E).

detected on this first postoperative scan. The extent of ablation can be determined using volumetric analysis volume of the ablation zone postoperatively to the volume of the lesion on the preoperative MRI obtained for surgical planning [28].

Additional follow-up MRI studies are obtained 1–3 months postoperatively and then at longer intervals depending on clinical status, pathology, and radiology findings.

for recurrent GBM. Case 2 demonstrates the use of LITT in treating primary GBM and the utility of performing stereotactic needle biopsy during the same operative setting to yield diagnostic information. In Case 3, we provide an example of subtotal

A 55-year-old gentleman with a 1-year history of GBM presented with focal nodular enhancement in the right temporal lobe on surveillance MRI. One year prior, he underwent surgical resection followed by temozolomide chemotherapy and radiation. Upon presentation to our surgical neuro-oncology service, the patient was asymptomatic; neurological exam was non-focal. Because of the surgeon's judgment that LITT would be able to achieve gross total ablation, the small size of the lesion, and the patient's history of treatment failure with surgical resection and chemoradiation, the patient was consented for LITT. After the stereotactic placement of the Visualase laser probe and confirmation of its location on intraoperative MRI imaging (Figure 3A), LITT was performed according to the following treat-

A 55-year-old gentleman presenting with asymptomatic GBM recurrence. Intraoperative T2-weighted sagittal MRI showing stereotactic placement of laser probe at target lesion (A). Postoperative day 1 of T1-weighted axial MRI with contrast demonstrates gross total lesion ablation; hyperintense signal most likely represents blood products (B) instead of residual tumor, as the same region does not enhance on T2-weighted MRI (C). At 22 months follow-up,T1-weighted axial MRI imaging with contrast showed the patient was recurrence-free (D).

ablation of a recurrent GBM tumor.

DOI: http://dx.doi.org/10.5772/intechopen.86829

Laser Ablation for Gliomas

3.3.1 Case 1

ment parameters:

Figure 3.

159

## 3. Patient selection

## 3.1 Indications

The development of commercially available stereotactic LITT systems that allow highly controlled delivery of laser light and real-time MRTI monitoring has enabled the routine use of the LITT. Currently, LITT is a treatment option for a variety of intracranial pathologies, including neoplasms (e.g., dural-based lesions, gliomas, metastases), epileptogenic foci (e.g., medial temporal sclerosis, focal cortical dysplasia), radiation necrosis, and chronic pain syndromes. The application of LITT to both newly diagnosed and recurrent gliomas has developed over the past decade; reports from initial institutional experiences demonstrate that LITT can be safely used for both supratentorial and infratentorial gliomas [28].

## 3.2 Criteria for patient selection

Identifying suitable candidates for LITT is important to ensure procedural safety and to optimize target lesion ablation. We propose that LITT is a viable alternative to open surgical resection in patients who meet the following criteria:


Therefore, LITT offers a minimally invasive cytoreductive therapy for patients with surgically inaccessible or treatment refractory tumors who would not benefit more from open surgical resection.

## 3.3 Illustrative case series

Here we present three cases of GBM tumors treated with LITT at our institution (University of Miami, Miller School of Medicine). Case 1 illustrates the use of LITT

### Laser Ablation for Gliomas DOI: http://dx.doi.org/10.5772/intechopen.86829

for recurrent GBM. Case 2 demonstrates the use of LITT in treating primary GBM and the utility of performing stereotactic needle biopsy during the same operative setting to yield diagnostic information. In Case 3, we provide an example of subtotal ablation of a recurrent GBM tumor.

## 3.3.1 Case 1

Additional follow-up MRI studies are obtained 1–3 months postoperatively and then at longer intervals depending on clinical status, pathology, and radiology findings.

The development of commercially available stereotactic LITT systems that allow highly controlled delivery of laser light and real-time MRTI monitoring has enabled the routine use of the LITT. Currently, LITT is a treatment option for a variety of intracranial pathologies, including neoplasms (e.g., dural-based lesions, gliomas, metastases), epileptogenic foci (e.g., medial temporal sclerosis, focal cortical dysplasia), radiation necrosis, and chronic pain syndromes. The application of LITT to both newly diagnosed and recurrent gliomas has developed over the past decade; reports from initial institutional experiences demonstrate that LITT can be safely

Identifying suitable candidates for LITT is important to ensure procedural safety and to optimize target lesion ablation. We propose that LITT is a viable alternative

1. Lesion size of <3 cm diameter in any dimension. This size restriction reduces

2. The surgeon can reasonably predict to achieve an extent of ablation of at least 80%. This threshold is generalized from previous studies of the extent of tumor resection necessary to confer a significant survival benefit in open surgical

splenium, etc., in eloquent motor or speech areas or near critical neurovascular

4.Treatment refractory lesions (i.e., failure of previous craniotomy or radiation).

Therefore, LITT offers a minimally invasive cytoreductive therapy for patients with surgically inaccessible or treatment refractory tumors who would not benefit

Here we present three cases of GBM tumors treated with LITT at our institution (University of Miami, Miller School of Medicine). Case 1 illustrates the use of LITT

5. Patients with medical comorbidities, low preoperative functional status, or history of previous craniotomy/radiation therapy who are unable to tolerate prolonged anesthesia and blood loss or who are at high risk of surgical morbidity and impaired wound healing. Of note, patients should still have a preoperative functional status appropriate for a minimally invasive surgical procedure under anesthesia; in our institutional experience, patients are eligible if they have a Karnofsky Performance Score (KPS) of at least 70.

3. Lesions that are inaccessible via conventional open surgery (e.g., lesions located adjacent to deep structures such as the basal ganglia, thalamus,

used for both supratentorial and infratentorial gliomas [28].

the risk of damage to critical brain regions.

to open surgical resection in patients who meet the following criteria:

3. Patient selection

Brain and Spinal Tumors - Primary and Secondary

3.2 Criteria for patient selection

resection [8–11].

structures).

more from open surgical resection.

3.3 Illustrative case series

158

3.1 Indications

A 55-year-old gentleman with a 1-year history of GBM presented with focal nodular enhancement in the right temporal lobe on surveillance MRI. One year prior, he underwent surgical resection followed by temozolomide chemotherapy and radiation. Upon presentation to our surgical neuro-oncology service, the patient was asymptomatic; neurological exam was non-focal. Because of the surgeon's judgment that LITT would be able to achieve gross total ablation, the small size of the lesion, and the patient's history of treatment failure with surgical resection and chemoradiation, the patient was consented for LITT. After the stereotactic placement of the Visualase laser probe and confirmation of its location on intraoperative MRI imaging (Figure 3A), LITT was performed according to the following treatment parameters:

#### Figure 3.

A 55-year-old gentleman presenting with asymptomatic GBM recurrence. Intraoperative T2-weighted sagittal MRI showing stereotactic placement of laser probe at target lesion (A). Postoperative day 1 of T1-weighted axial MRI with contrast demonstrates gross total lesion ablation; hyperintense signal most likely represents blood products (B) instead of residual tumor, as the same region does not enhance on T2-weighted MRI (C). At 22 months follow-up,T1-weighted axial MRI imaging with contrast showed the patient was recurrence-free (D).

1. Test dose at 4 W for 7 seconds. Concurrent real-time MRI thermometry data confirmed total coverage of the target lesion.

Neurological exam was positive for 4/5 strength in the right hand, but was otherwise non-focal. MRI studies re-demonstrated the recurrence and extensive surrounding edema (Figure 5A, B). Because the lesion was small (2.0 cm maximum diameter) and failed both prior surgical resection and radiosurgery, the patient was consented for LITT. The patient was induced under general anesthesia, and a laser probe entry site and trajectory angle to the target lesion were planned using preoperative MRI imaging and Stealth neuronavigation (Medtronic, Inc.). The Visualase thermal therapy system laser probe was inserted stereotactically along the planned trajectory as described above (Figure 5C). The ablation procedure began with a test dose of laser energy at 3 W (20% of maximum power) for 3 minutes. Concurrent real-time MRI thermometry data was used to confirm target lesion coverage by the developing ablation zone. Next laser power output was increased to 7.5 W (50% maximum power) for 3 minutes, with successive 3-minute doses at 3 W stepwise increases in power. Once target area coverage was maximized and ablation temperature threshold reached (without reaching the maximum temperature threshold in off-target zones), the laser power was increased to 90% maximum power output for maximal ablation in 3-minute intervals. The final ablation zone was confirmed with

There were no complications. The patient was discharged the following day on

recurrence at 9-week post-LITT (Figure 5E). The patient died 10 months following

We present this case to illustrate how a subtotal ablation <80% may not be

A 58-year-old female with left frontoparietal ring-enhancing lesion T1-weighted axial MRI with contrast suspicious for tumor recurrence (A) with surrounding peripheral edema on T2-weighted FLAIR sequence (B). Intraoperative sagittal T2-weighted MRI showing correct positioning of the laser probe to the lesion (C). Postoperative day 1 of axial T1-weighted MRI (D) demonstrates subtotal (70%) thermal ablation of the lesion. Follow-up T1-weighted MRI with contrast approximately 9-week post-LITT demonstrates tumor

a course of dexamethasone with steroid taper over 2 weeks. T1-weighted MRI with contrast on postoperative day 1 showed subtotal ablation of 70% of the pre-treatment volume (Figure 5D). Follow-up MRI imaging showed tumor

MRI thermometry.

Laser Ablation for Gliomas

DOI: http://dx.doi.org/10.5772/intechopen.86829

the procedure.

Figure 5.

progression (E).

161

sufficient to confer a clinical benefit.

2. Ablation dose at 10 W laser power for 3 minutes. Because MRI thermometry data confirmed target area ablation and ablation temperature threshold was reached (without reaching the maximum temperature threshold in off-target zones), the treatment was considered complete.

T1-weighted MRI on postoperative day 1 showed gross total (100%) lesion ablation (Figure 3B and C). The hyperintense signal in the tumor region represented blood products. On follow-up, the patient remained recurrence-free for over 2 years (26 months) (Figure 3D). The patient's family reported his death 3 months following tumor recurrence.

## 3.3.2 Case 2

A 60-year-old gentleman with progressive gait instability and confusion for 2 weeks and worsening headache for 2 days presented to the emergency department. MRI demonstrated a deep-seated left mesial temporal lobe lesion (Figure 4A). Due to the location of the lesion and progression of his symptoms, the patient was consented for stereotactic needle biopsy and LITT. In the operating room, a trajectory for the stereotactic biopsy needle and laser probe was planned, taking care to avoid critical cortical structures, ventricles, tentorium, arteries, and veins, targeting the center of the lesion volume (Figure 4B). To perform stereotactic needle biopsy, a preoperative and intraoperative computed-tomography scan was obtained using an O-Arm (Medtronic) to register and confirm intralesional biopsy. Two frozen cores of tissue were sent for pathological analysis, which confirmed the presence of necrotic brain tissue. Following biopsy, the laser probe was targeted to the lesion using neuronavigation with preoperative MRI registration. Follow-up T1-weighted MRI with contrast demonstrated gross total (100%) ablation (Figure 4C). At 1.4-year follow-up, the patient remains recurrence-free.

#### 3.3.3 Case 3

A 58-year-old female with history of GBM initially diagnosed 2 years prior presented with focal recurrence in the left frontoparietal lobe on MRI imaging. The recurrence had recently been treated with stereotactic radiosurgery, after which the patient noticed new-onset right-hand weakness that did not improve with steroids.

#### Figure 4.

A 60-year-old gentleman found to have a new, deep-seated lesion on T1-weighted coronal MRI with contrast suspicious for glioma (A). Intraoperative T2-weighted sagittal MRI shows stereotactic positioning of the laser probe to access the lesion while avoiding critical brain structures (B). Postoperative T1-weighted sagittal MRI with contrast demonstrates gross total ablation of the lesion (C).

#### Laser Ablation for Gliomas DOI: http://dx.doi.org/10.5772/intechopen.86829

1. Test dose at 4 W for 7 seconds. Concurrent real-time MRI thermometry data

2. Ablation dose at 10 W laser power for 3 minutes. Because MRI thermometry data confirmed target area ablation and ablation temperature threshold was reached (without reaching the maximum temperature threshold in off-target

T1-weighted MRI on postoperative day 1 showed gross total (100%) lesion

represented blood products. On follow-up, the patient remained recurrence-free for over 2 years (26 months) (Figure 3D). The patient's family reported his death

A 60-year-old gentleman with progressive gait instability and confusion for 2 weeks and worsening headache for 2 days presented to the emergency depart-

(Figure 4A). Due to the location of the lesion and progression of his symptoms, the patient was consented for stereotactic needle biopsy and LITT. In the operating room, a trajectory for the stereotactic biopsy needle and laser probe was planned, taking care to avoid critical cortical structures, ventricles, tentorium, arteries, and veins, targeting the center of the lesion volume (Figure 4B). To perform stereotactic needle biopsy, a preoperative and intraoperative computed-tomography scan was obtained using an O-Arm (Medtronic) to register and confirm intralesional biopsy. Two frozen cores of tissue were sent for pathological analysis, which confirmed the presence of necrotic brain tissue. Following biopsy, the laser probe was targeted to the lesion using neuronavigation with preoperative MRI registration. Follow-up T1-weighted MRI with contrast demonstrated gross total (100%) ablation (Figure 4C). At 1.4-year follow-up, the patient remains recurrence-free.

A 58-year-old female with history of GBM initially diagnosed 2 years prior presented with focal recurrence in the left frontoparietal lobe on MRI imaging. The recurrence had recently been treated with stereotactic radiosurgery, after which the patient noticed new-onset right-hand weakness that did not improve with steroids.

A 60-year-old gentleman found to have a new, deep-seated lesion on T1-weighted coronal MRI with contrast suspicious for glioma (A). Intraoperative T2-weighted sagittal MRI shows stereotactic positioning of the laser probe to access the lesion while avoiding critical brain structures (B). Postoperative T1-weighted sagittal MRI

with contrast demonstrates gross total ablation of the lesion (C).

ablation (Figure 3B and C). The hyperintense signal in the tumor region

ment. MRI demonstrated a deep-seated left mesial temporal lobe lesion

confirmed total coverage of the target lesion.

Brain and Spinal Tumors - Primary and Secondary

zones), the treatment was considered complete.

3 months following tumor recurrence.

3.3.2 Case 2

3.3.3 Case 3

Figure 4.

160

Neurological exam was positive for 4/5 strength in the right hand, but was otherwise non-focal. MRI studies re-demonstrated the recurrence and extensive surrounding edema (Figure 5A, B). Because the lesion was small (2.0 cm maximum diameter) and failed both prior surgical resection and radiosurgery, the patient was consented for LITT. The patient was induced under general anesthesia, and a laser probe entry site and trajectory angle to the target lesion were planned using preoperative MRI imaging and Stealth neuronavigation (Medtronic, Inc.). The Visualase thermal therapy system laser probe was inserted stereotactically along the planned trajectory as described above (Figure 5C). The ablation procedure began with a test dose of laser energy at 3 W (20% of maximum power) for 3 minutes. Concurrent real-time MRI thermometry data was used to confirm target lesion coverage by the developing ablation zone. Next laser power output was increased to 7.5 W (50% maximum power) for 3 minutes, with successive 3-minute doses at 3 W stepwise increases in power. Once target area coverage was maximized and ablation temperature threshold reached (without reaching the maximum temperature threshold in off-target zones), the laser power was increased to 90% maximum power output for maximal ablation in 3-minute intervals. The final ablation zone was confirmed with MRI thermometry.

There were no complications. The patient was discharged the following day on a course of dexamethasone with steroid taper over 2 weeks. T1-weighted MRI with contrast on postoperative day 1 showed subtotal ablation of 70% of the pre-treatment volume (Figure 5D). Follow-up MRI imaging showed tumor recurrence at 9-week post-LITT (Figure 5E). The patient died 10 months following the procedure.

We present this case to illustrate how a subtotal ablation <80% may not be sufficient to confer a clinical benefit.

#### Figure 5.

A 58-year-old female with left frontoparietal ring-enhancing lesion T1-weighted axial MRI with contrast suspicious for tumor recurrence (A) with surrounding peripheral edema on T2-weighted FLAIR sequence (B). Intraoperative sagittal T2-weighted MRI showing correct positioning of the laser probe to the lesion (C). Postoperative day 1 of axial T1-weighted MRI (D) demonstrates subtotal (70%) thermal ablation of the lesion. Follow-up T1-weighted MRI with contrast approximately 9-week post-LITT demonstrates tumor progression (E).

## 4. Clinical outcomes

The first case series reporting the use of LITT in gliomas were published in 1990 by Sugiyama et al., which described the successful total ablation of five deep-seated gliomas [37]. The advent of MRI thermography and the Visualase and NeuroBlate systems enabled institutional centers to publish data on larger case series over the past decade. These initial experiences provide valuable evidence supporting the safety and efficacy of LITT in select patient. In Table 1 we present a comprehensive review of the literature of studies evaluating clinical outcomes in patients treated with LITT for either newly diagnosed or recurrent GBM tumors. To accurately represent the current use of LITT, only studies that included the use of real-time MR thermography are included in our review.

Reference #

Laser Ablation for Gliomas

Schwartzmaier et al. 2005 [29]

Schwartzmaier et al. 2006 [30]

Carpentier et al. 2012 [26]

Jethwa et al 2012 [19]

Hawasli et al., 2013 [31]

Sloan et al. 2013 [27]

Mohammadi et al. 2014 [32]

Thomas et al. 2016 [33]

163

Cases

DOI: http://dx.doi.org/10.5772/intechopen.86829

Newlydiagnosed or recurrent GBM lesions

2 Recurrent 47 M

4 Recurrent 40-58

10 Recurrent Media n 54

4 Newlydiagnosed

6 Newlydiagnosed

24 Recurrent (14) and new (10) lesions

21 Recurrent (13) and new (8) lesions

16 Recurrent Median age 62,

67 M

range 44-69, 10 men, 6 women

years, 3 men, 1 woman

Media n 60 years, range 56-81

Media n 50 years, range 34-78, 6 men, 2 women

years, range 34-69. 8 men, 2 women

Media n age 56 (range 19-79), 38% female

Mean age 49 years

Age, Gender Location of lesion LITT

1 Temporal 1 Parietooccipital

3 Frontal 1 Frontoparietal 1 Frontotemporal 1 Temporal 1 Parietal 3 Parietooccipital 1 Corpus callosum 1 Parasagittal

1 temporo-polar 1 corpus callosum 1 frontal 1 temporal

right frontal right frontal left temporal right midbrain

thalamus left thalamus basal ganglia left thalamus right corpus callosum thalamus

2 temporal 1 temporoparietal 1 temporooccipital 3 parietal 3 frontal

15 tumors in frontal lobe, 7 in thalamic region, 5 parietal, 5 temporal, 2 insular, 1 corpus callosum.

8 in eloquent regions (62%): 3 in motor cortex, 3 in speech, 1 temporal, 2 splenium, 2 cingulate, 2 insular

system used, Extent of ablation

1064 nm laser, STA

1064 nm laser; NR

Visualase; SupA of 1 mm diameter or more

Visualase, NR

Neuroblate; median 90.3% ablation

Neuroblate; Median ablation volume at yellow line: 98%, at blue line: 91% (includes non-GBM tumors included in study)

NeuroBlate; NR

Mean/median Recurrencefree survival; Overall survival

1 recurrence; 13-16 months

6.9 months; NR

1.25 months; 10 months

NR; NR

Recurrence in 3 of 6 patients at median 3.2 months (range 2.5-15 months); 3 of 6 patients alive at last follow-up, 3 of 6 patients died at median 1.7 months

NR 10.5 months;

5.1 months; 68% survival at 1 year

> 5 months; 7 months

Abbreviations: M, male; F, female; NR, not reported; LITT, laser interstitial thermal therapy; STA, subtotal ablation; SupA, supra-ablation

## 5. Discussion

#### 5.1 Current role of LITT in neurosurgery

The use of laser-based ablation technology in neurosurgery began with the treatment of movement disorders, chronic pain syndromes, and epilepsy. Technological advances over the past two decades in laser interstitial thermal therapy delivery platforms and real-time MR thermal imaging of tissue ablation dynamics have made LITT a viable minimally invasive therapy for a variety of intracranial and spinal lesions, including metastases, epileptogenic foci, radiation necrosis, dural-based lesions, and gliomas.

The advantage of LITT in treating gliomas includes:


4. Clinical outcomes

5. Discussion

MR thermography are included in our review.

Brain and Spinal Tumors - Primary and Secondary

5.1 Current role of LITT in neurosurgery

dural-based lesions, and gliomas.

critical structures.

ionizing radiation [18].

162

thermal therapy; STA, subtotal ablation; SupA, supra-ablation

The advantage of LITT in treating gliomas includes:

The first case series reporting the use of LITT in gliomas were published in 1990 by Sugiyama et al., which described the successful total ablation of five deep-seated gliomas [37]. The advent of MRI thermography and the Visualase and NeuroBlate systems enabled institutional centers to publish data on larger case series over the past decade. These initial experiences provide valuable evidence supporting the safety and efficacy of LITT in select patient. In Table 1 we present a comprehensive review of the literature of studies evaluating clinical outcomes in patients treated with LITT for either newly diagnosed or recurrent GBM tumors. To accurately represent the current use of LITT, only studies that included the use of real-time

Abbreviations: M, male; F, female; NR, not reported; LITT, laser interstitial

The use of laser-based ablation technology in neurosurgery began with the treatment of movement disorders, chronic pain syndromes, and epilepsy. Technological advances over the past two decades in laser interstitial thermal therapy delivery platforms and real-time MR thermal imaging of tissue ablation dynamics have made LITT a viable minimally invasive therapy for a variety of intracranial and spinal lesions, including metastases, epileptogenic foci, radiation necrosis,

1. Achieving cytoreduction in poor open surgical candidates: because laser light is delivered through a 1–3-mm diameter laser probe inserted through a single burr hole and dural opening, LITT reduces the risk of morbidity associated with craniotomy for surgical resection. This is especially relevant in GBM patients as the risk of neurological morbidity and poor wound healing or infection increases with repeat craniotomies and radiation therapy. The ability to tightly control the ablation zone using real-time MR thermography means that LITT is well suited for treatment of lesions in deep-seated locations or near

2. Shorter procedure time and quicker recovery: the small incision required may result in fewer wound-healing complications, particularly in patients with impaired wound healing due to prior craniotomies or radiation therapy. Finally, a minimally invasive approach enables a quicker recovery and transition to continue chemotherapy or initiate another adjuvant therapy [26, 39].

3. The use of non-ionizing radiation: unlike ionizing radiation therapy, LITT thermal therapy can be used repeatedly without the risk of radiation necrosis [9]. Moreover, LITT can be used as a salvage therapy in treatment refractory tumors and may avoid increased risk of secondary malignancy-associated

4.Treatment of lesions that are inaccessible via open surgery: gliomas located in deep or eloquent regions of the brain (e.g., insula, thalamus, corpus callosum)



hemorrhage may be reduced by obtaining a computed-tomography angiography (CTA) showing the location of critical vessels to avoid during

2. Transient neurological deficit: neurological deficits such as weakness,

hemianopsia, seizures, and dysphagia are often attributed to direct thermal injury to functional brain areas or cerebral edema. Estimates of transient neurological deficits have been reported to occur in 13–15% of patients [19, 40]. Permanent neurological morbidity is less common (5.6% of cases according to a recent literature review) [40]. Cerebral edema is frequently observed in the immediate postoperative period following LITT. A recent volumetric and timecourse analysis found that edema volume has been shown to increase on average 41.5% immediately postoperatively, followed by a gradual decline resulting on average an 80.9% decrease in preoperative edema volume [28]. Although cerebral edema is common, it is unlikely to cause permanent

neurological deficits and may be controlled with a course of steroids. Treatment of large (>3cm) lesions, use of multiple laser probes, or use of multiple laser trajectories is associated with a higher risk of significant cerebral edema [41].

Less common (<5% of all cases) complications include permanent neurological deficit, infection (e.g., ventriculitis, meningitis, or brain abscess), deep venous thrombosis, diabetes insipidus, hyponatremia, and intracranial hypertension. There is one reported case of gliosarcoma tumor seeding along the laser probe tract [27]. Finally, there are only two recorded deaths attributed to LITT in the literature, from

Our discussion of patient selection also reveals specific limitations of LITT. Multiple reviews cite a lesion size limit of 3 cm to reduce the chance of intracranial hypertension secondary to edema [18, 31]. As discussed previously, preoperative functional status, lesion accessibility by a laser trajectory, and anticipated extent of

In discussing complication rates, it is important to emphasize that LITT is a novel procedure, and so practitioners and institutions operate with a learning curve [18]. Recently, more institutional case series have proposed modifications to improve safety, for example, staging the treatment of larger (>3 cm) lesions to over multiple procedures to avoid morbidity or employing algorithms to optimize laser

Along with further improvements in procedural safety, the future of LITT may lie in combination therapies to enhance tumor control and overall survival. Previous studies have shown that LITT induces a temporary increase in blood-brain barrier (BBB) permeability, which may offer a window of opportunity to deliver adjuvant chemotherapy more effectively [42, 43]. Another line of investigation is the use of gold nanoparticles, which may enhance tissue energy absorption and increase

Finally, future investigations will require prospective and randomized-controlled

LITT is a novel adjuvant therapy for treatment of a wide variety of intracranial

pathologies. In this chapter we review the evidence supporting the safety and

trials to evaluate the clinical outcomes of LITT compared to other therapies.

ablation are also factors that limit the use of LITT to particular lesions.

postoperative meningitis and intracranial hemorrhage [32].

laser trajectory planning.

DOI: http://dx.doi.org/10.5772/intechopen.86829

Laser Ablation for Gliomas

5.3 Future directions

trajectory planning [42].

ablation efficacy [45].

6. Conclusion

165

Abbreviations: M, male; F, female; NR, not reported; LITT, laser interstitial thermal therapy; STA, subtotal ablation; SupA, supra-ablation.

#### Table 1.

Literature review of case series describing LITT for GBM (adapted from: [9, 38]).

may increase open surgical risk to a degree that patients only receive stereotactic needle biopsy and adjuvant chemoradiation, thus losing the survival benefit associated with aggressive cytoreduction. Because LITT is delivered through a thin laser probe, lesions that are typically considered "surgically inaccessible" can now be treated with reduced risk of neurological morbidity [39].

The use of LITT for gliomas was initially limited to treating recurrences that failed conventional first-line therapies (i.e., surgical resection and adjuvant chemoradiation). Recently, LITT has been applied as a primary treatment for newly-diagnosed gliomas. Preliminary institutional experiences report local control and overall survival times of several months—over 1 year.

Patient selection is of critical importance in ensuring safe and effective use of LITT. To summarize, lesions should be <3 cm in diameter, in a region that can be accessed via a linear laser catheter trajectory without injury to critical structures and in patients who are able to tolerate a minimally invasive surgical procedure under anesthesia. In addition, the lesion should have identifiable margins such that at least 80% of the target area can be feasibly ablated with a roughly spherical ablation zone.

#### 5.2 Limitations of LITT

The increasing use of LITT has revealed it to be an overall safe, well-tolerated procedure. The most common adverse events associated with the procedure include:

1. Intracranial hemorrhage: despite the use of neuronavigation and stereotaxy for trajectory planning, the laser probe may be malpositioned, resulting in injury to vessels and bleeding [40]. Estimates of overall rates of accurate implantation range from 85.7 to over 95%, with only three reported cases of resulting intracranial hemorrhage resulting from malpositioning [19, 40]. The risk of

hemorrhage may be reduced by obtaining a computed-tomography angiography (CTA) showing the location of critical vessels to avoid during laser trajectory planning.

2. Transient neurological deficit: neurological deficits such as weakness, hemianopsia, seizures, and dysphagia are often attributed to direct thermal injury to functional brain areas or cerebral edema. Estimates of transient neurological deficits have been reported to occur in 13–15% of patients [19, 40]. Permanent neurological morbidity is less common (5.6% of cases according to a recent literature review) [40]. Cerebral edema is frequently observed in the immediate postoperative period following LITT. A recent volumetric and timecourse analysis found that edema volume has been shown to increase on average 41.5% immediately postoperatively, followed by a gradual decline resulting on average an 80.9% decrease in preoperative edema volume [28]. Although cerebral edema is common, it is unlikely to cause permanent neurological deficits and may be controlled with a course of steroids. Treatment of large (>3cm) lesions, use of multiple laser probes, or use of multiple laser trajectories is associated with a higher risk of significant cerebral edema [41].

Less common (<5% of all cases) complications include permanent neurological deficit, infection (e.g., ventriculitis, meningitis, or brain abscess), deep venous thrombosis, diabetes insipidus, hyponatremia, and intracranial hypertension. There is one reported case of gliosarcoma tumor seeding along the laser probe tract [27]. Finally, there are only two recorded deaths attributed to LITT in the literature, from postoperative meningitis and intracranial hemorrhage [32].

Our discussion of patient selection also reveals specific limitations of LITT. Multiple reviews cite a lesion size limit of 3 cm to reduce the chance of intracranial hypertension secondary to edema [18, 31]. As discussed previously, preoperative functional status, lesion accessibility by a laser trajectory, and anticipated extent of ablation are also factors that limit the use of LITT to particular lesions.

### 5.3 Future directions

may increase open surgical risk to a degree that patients only receive stereotactic needle biopsy and adjuvant chemoradiation, thus losing the survival benefit associated with aggressive cytoreduction. Because LITT is delivered through a thin laser probe, lesions that are typically considered "surgically inaccessible"

Abbreviations: M, male; F, female; NR, not reported; LITT, laser interstitial thermal therapy; STA, subtotal ablation;

Age, Gender Location of lesion LITT

1 splenium 1 orbitofrontal 1 parieto- occipital 1 post. Cingulate 1. precuneus 1 Genu

14 frontal 8 temporal 9 parietal 1 occipital 4 pareito-occipital 4 temporo-parietal 8 corpus callosum 2 insular 8 thalamic

Mean age 47 94% 11.5 months;

system used, Extent of ablation

Visualase; mean 98.5%

Neuroblate; 93.2% (yellow boundary), 88.0% (blue boundary)

Mean/median Recurrencefree survival; Overall survival

14.3 months; 6 of 7 patients alive at last follow-up, 1 death at 14 months

NR

6.6 months; 11.5 months

can now be treated with reduced risk of neurological morbidity [39].

failed conventional first-line therapies (i.e., surgical resection and adjuvant chemoradiation). Recently, LITT has been applied as a primary treatment for newly-diagnosed gliomas. Preliminary institutional experiences report local control

and overall survival times of several months—over 1 year.

Literature review of case series describing LITT for GBM (adapted from: [9, 38]).

zone.

164

5.2 Limitations of LITT

Reference #

Shah et al., 2016 [34]

Schroeder et al. 2014 [35]

Kamath et al. 2019 [36]

SupA, supra-ablation.

Table 1.

Cases

Newlydiagnosed or recurrent GBM lesions

Brain and Spinal Tumors - Primary and Secondary

7 Newlydiagnosed

5 Newlydiagnosed

54 Recurrent (41) and Newlydiagnosed (17)

Mean age 59, 3 male, 4 female

Mean age 59 years

The use of LITT for gliomas was initially limited to treating recurrences that

Patient selection is of critical importance in ensuring safe and effective use of LITT. To summarize, lesions should be <3 cm in diameter, in a region that can be accessed via a linear laser catheter trajectory without injury to critical structures and in patients who are able to tolerate a minimally invasive surgical procedure under anesthesia. In addition, the lesion should have identifiable margins such that at least 80% of the target area can be feasibly ablated with a roughly spherical ablation

The increasing use of LITT has revealed it to be an overall safe, well-tolerated procedure. The most common adverse events associated with the procedure include:

1. Intracranial hemorrhage: despite the use of neuronavigation and stereotaxy for trajectory planning, the laser probe may be malpositioned, resulting in injury to vessels and bleeding [40]. Estimates of overall rates of accurate implantation range from 85.7 to over 95%, with only three reported cases of resulting intracranial hemorrhage resulting from malpositioning [19, 40]. The risk of

In discussing complication rates, it is important to emphasize that LITT is a novel procedure, and so practitioners and institutions operate with a learning curve [18]. Recently, more institutional case series have proposed modifications to improve safety, for example, staging the treatment of larger (>3 cm) lesions to over multiple procedures to avoid morbidity or employing algorithms to optimize laser trajectory planning [42].

Along with further improvements in procedural safety, the future of LITT may lie in combination therapies to enhance tumor control and overall survival. Previous studies have shown that LITT induces a temporary increase in blood-brain barrier (BBB) permeability, which may offer a window of opportunity to deliver adjuvant chemotherapy more effectively [42, 43]. Another line of investigation is the use of gold nanoparticles, which may enhance tissue energy absorption and increase ablation efficacy [45].

Finally, future investigations will require prospective and randomized-controlled trials to evaluate the clinical outcomes of LITT compared to other therapies.

## 6. Conclusion

LITT is a novel adjuvant therapy for treatment of a wide variety of intracranial pathologies. In this chapter we review the evidence supporting the safety and

efficacy of LITT as a primary or adjuvant treatment for glioblastoma. Thus far, LITT is a safe, minimally invasive approach to cytoreduction in patients with gliomas that are poor open surgical candidates.

References

10.1093/neuonc/not151

Laser Ablation for Gliomas

den Bent MJ, 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. DOI: 10.1016/ S1470-2045(09)70025-7

[3] Johnson DR, O'Neill BP.

10.1007/s11060-011-0749-4

S1152851703000620

JNS10998

167

et al. IDH mutation and MGMT promoter methylation in glioblastoma: Results of a prospective registry. Oncotarget. 2015;6(38):40896-40906. DOI: 10.18632/oncotarget.5683

Glioblastoma survival in the United States before and during the

temozolomide era. Journal of Neuro-Oncology. 2012;107(2):359-364. DOI:

[4] Yang P, Zhang W, Wang Y, Peng X,

[5] Lamborn KR, Chang SM, Prados MD. Prognostic factors for survival of patients with glioblastoma: Recursive partitioning analysis. Neuro-Oncology. 2004;6(3):227-235. DOI: 10.1215/

[6] Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. Journal of Neurosurgery. 2011;115(1):3-8. DOI: 10.3171/2011.2.

[7] Brown TJ, Brennan MC, Li M, Church EW, et al. Association of extent

glioblastoma: A systematic review and meta-analysis. JAMA Oncology. 2016;

of resection with survival in

2(11):14560-11469

[1] Ostrom QT, Gittleman H, Farah P, Ondracek A, et al. CBTRUS statistical United States in 2006–2010. Neuro-Oncology. 2013;15 Suppl 2:ii1-i56. DOI:

DOI: http://dx.doi.org/10.5772/intechopen.86829

[8] Chaudhry NS, Shah AH, Ferraro N, Snelling BM, Bregy A, Madhavan K, et al. Predictors of long-term survival in patients with glioblastoma multiforme: Advancements from the last quarter century. Cancer Investigation. 2013; 31(5):287-308. DOI: 10.3109/07357907.

[9] Ivan ME, Mohammadi AM, De Deugd N, Reyes J, et al. Laser ablation of newly diagnosed malignant gliomas: A meta-analysis. Neurosurgery. 2016;79 (Suppl 1):S17-S23. DOI: 10.1227/ NEU.0000000000001446

[10] Oppenlander ME. An extent of resection threshold for recurrent

[11] Laws ER, Parney IF, Huang W, Anderson F, et al. Glioma outcomes I: Survival following surgery and prognostic factors for recently

diagnosed malignant glioma: Data from the glioma outcomes project. Journal of Neurosurgery. 2003;99(3):467-473. DOI: 10.3171/jns.2003.99.3.0467

[12] Roh TH, Kang SG, Moon JH, Sung KS, et al. Survival benefit of lobectomy over gross-total resection without lobectomy in cases of glioblastoma in the noneloquent area: A retrospective study. Journal of Neurosurgery. 2019;1: 1-7. DOI: 10.3171/2018.12.JNS182558

[13] Pessina F, Navarria P, Cozzi L, Ascolese AM, Simonelli M, Santoro A, et al. Noninvasive MRI thermometry with the proton resonance frequency method: Study of susceptibility effects. Magnetic Resonance in Medicine. 1995;

[14] Chang SM, Parney IF, McDermott M, Barker FG 2nd, Schmidt MH, Huang W, et al. Perioperative complications and

34:359-367

2014;120(4):846-853

glioblastoma and its risk for neurological morbidity. Journal of Neurosurgery.

2013.789899

[2] Stupp R, Hegi ME, Mason WP, Van

## Acknowledgements

The authors have no source of financial support to report.

## Conflict of interest

Michael Ivan is a consultant for Medtronic. The other authors have no financial, personal, or institutional interests in any of the materials, devices, or drugs described in this article. Laser ablation is the only Food and Drug Administrationapproved procedure for the ablation of soft tissue.

## Author details

Alexa Semonche, Daniel Eichberg, Ashish Shah and Michael E. Ivan\* Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, United States

\*Address all correspondence to: mivan@med.miami.edu

© 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

efficacy of LITT as a primary or adjuvant treatment for glioblastoma. Thus far, LITT is a safe, minimally invasive approach to cytoreduction in patients with

Michael Ivan is a consultant for Medtronic. The other authors have no financial,

personal, or institutional interests in any of the materials, devices, or drugs described in this article. Laser ablation is the only Food and Drug Administration-

Alexa Semonche, Daniel Eichberg, Ashish Shah and Michael E. Ivan\* Department of Neurological Surgery, University of Miami Miller School of

© 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,

\*Address all correspondence to: mivan@med.miami.edu

The authors have no source of financial support to report.

gliomas that are poor open surgical candidates.

Brain and Spinal Tumors - Primary and Secondary

approved procedure for the ablation of soft tissue.

Acknowledgements

Conflict of interest

Author details

166

Medicine, Miami, United States

provided the original work is properly cited.

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[2] Stupp R, Hegi ME, Mason WP, Van den Bent MJ, 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. DOI: 10.1016/ S1470-2045(09)70025-7

[3] Johnson DR, O'Neill BP. Glioblastoma survival in the United States before and during the temozolomide era. Journal of Neuro-Oncology. 2012;107(2):359-364. DOI: 10.1007/s11060-011-0749-4

[4] Yang P, Zhang W, Wang Y, Peng X, et al. IDH mutation and MGMT promoter methylation in glioblastoma: Results of a prospective registry. Oncotarget. 2015;6(38):40896-40906. DOI: 10.18632/oncotarget.5683

[5] Lamborn KR, Chang SM, Prados MD. Prognostic factors for survival of patients with glioblastoma: Recursive partitioning analysis. Neuro-Oncology. 2004;6(3):227-235. DOI: 10.1215/ S1152851703000620

[6] Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. Journal of Neurosurgery. 2011;115(1):3-8. DOI: 10.3171/2011.2. JNS10998

[7] Brown TJ, Brennan MC, Li M, Church EW, et al. Association of extent of resection with survival in glioblastoma: A systematic review and meta-analysis. JAMA Oncology. 2016; 2(11):14560-11469

[8] Chaudhry NS, Shah AH, Ferraro N, Snelling BM, Bregy A, Madhavan K, et al. Predictors of long-term survival in patients with glioblastoma multiforme: Advancements from the last quarter century. Cancer Investigation. 2013; 31(5):287-308. DOI: 10.3109/07357907. 2013.789899

[9] Ivan ME, Mohammadi AM, De Deugd N, Reyes J, et al. Laser ablation of newly diagnosed malignant gliomas: A meta-analysis. Neurosurgery. 2016;79 (Suppl 1):S17-S23. DOI: 10.1227/ NEU.0000000000001446

[10] Oppenlander ME. An extent of resection threshold for recurrent glioblastoma and its risk for neurological morbidity. Journal of Neurosurgery. 2014;120(4):846-853

[11] Laws ER, Parney IF, Huang W, Anderson F, et al. Glioma outcomes I: Survival following surgery and prognostic factors for recently diagnosed malignant glioma: Data from the glioma outcomes project. Journal of Neurosurgery. 2003;99(3):467-473. DOI: 10.3171/jns.2003.99.3.0467

[12] Roh TH, Kang SG, Moon JH, Sung KS, et al. Survival benefit of lobectomy over gross-total resection without lobectomy in cases of glioblastoma in the noneloquent area: A retrospective study. Journal of Neurosurgery. 2019;1: 1-7. DOI: 10.3171/2018.12.JNS182558

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Section 6

Chemo/Immunotherapies

for CNS Tumors

## Section 6
