**3. Where we are and where we are going**

survival rates were 87.4 (SE 8.4) and 58.8% (SE 11.9), respectively, with the extent of resection

Also in 2006, Mauffrey reported on his retrospectively reviewed series of 27 paediatric patients admitted to hospital in Turin, Italy with a diagnosis of brainstem glioma [20]. Thirteen patients had a diffuse pontine tumour on MRI scan, while fourteen had other brainstem gliomas. Those in the first group had a shorter mean duration of symptoms prior to diagnosis (2.6 vs. 10.6 months), never demonstrated gadolinium enhancement of their tumour on MRI (vs. 78.6% in the other group), and were much more likely to have symptoms or findings indicating cranial nerve involvement (77.0 vs. 28.5%). None of the 13 with diffuse gliomas underwent radical surgery, whereas it was the treatment of choice in the remaining 14. Two-year survival rates were 25% and 90%, respectively, and 60% of the latter remained alive at five years [20].

In 2008, Teo and Siu [63] reported on their results with 34 consecutive patients between 3 and 16 years of age who underwent endoscope-assisted microsurgery for focal brainstem gliomas with the intent of radial resection between 1999 and 2005. More than 90% tumour resection was achieved in 31patients, while >50% was attained in the remainder. There was no perioperative mortality and the average follow-up was 46 months. Twenty-three patients (74%) harboured low-grade and 11 (26%) high-grade gliomas. Kaplan-Meier survival analysis revealed marked differences in the 5-year survival rates between the two groups (100% vs. 33%). Multivariate analysis demonstrated that the degree of tumour resection was not

Two papers published over the past couple of years are those by Fried et al. [72], based at The Hospital for Sick Children in Toronto Canada, and Klimo et al., based at George Washington University in Washington, DC [23]. The latter study, like all those described previously, was relatively small, with just 52 patients (32 boys), all with radiographically-confirmed, low-grade focal brainstem gliomas seen from 1986 to 2010. The median duration of follow-up was 10.0 years, and the median age at diagnosis 6.5 years (range 1-17 years). Tumors were located in the midbrain (n=22, 42%), pons (n=15, 29%), and medulla (n=15, 29%). Surgical extirpation was the primary treatment in 25 patients (48%). Five-and 10-year event-free survival and overall survival rates were 59% and 98%, and 52% and 90%, respectively. Surprisingly, children with intrinsic tumors trended towards slightly higher event-free survival at 5 years than those with exophytic tumors (p=0.054), but not at 10 years (p=0.147). No other variables were predictive

The retrospective study by Fried et al. is by far the largest to date, assessing a total of 223 children with brainstem tumours (12% of all CNS tumours seen) followed at The Hospital for Sick Children in Toronto over the preceding 25 years [72]. Ninety-five of these tumours were diffuse and an additional 17 were high-grade astrocytomas (grade III or IV). The investigators made several novel observations. First, whereas 75% of tumors involving the pons were highgrade, 98% of tumours lacking pontine involvement were low-grade (p = 0.0001). Second, residual tumour after surgery, even when visualized, did not adversely alter either progres‐ sion-free survival or overall survival. And, among those requiring further treatment, 5-year progression-free and overall survival were comparable between those receiving chemotherapy (53 and 93%) and those administered radiotherapy (66 and 83%) (p = 0.26 and 0.30, respective‐

identified as the best predictor of survival (p=0.012) [77].

42 Tumors of the Central Nervous System – Primary and Secondary

associated with poor outcome at 6 months.

of event-free survival [23].

Clearly, the past forty years have brought about substantial changes in the way brainstem tumours are both perceived and managed. No longer is the term 'brainstem glioma' used to lump all brainstem lesions together as homogenous, untreatable and ultimately fatal. Now, either three or four heterogeneous classes of tumour are described, and all but one is considered to be an indication for aggressive, often surgical treatment. Some investigators sub-classify lesions further, related to their anatomical location (e.g., midbrain, pons, medulla). In essence, though, irrespective of the number of tumour types proposed, all categorization systems ultimately separate diffuse intrinsic lesions from all others.

Current diagnosis largely depends on the use of patient histories and physical findings, especially paying attention to the duration of symptoms prior to diagnosis and the type(s) of neurological deficits identified (e.g., ocular palsies), followed by magnetic resonance imaging, both with and without contrast. Lesions that are intrinsic and diffuse, and lesions that involve the pons are generally considered to be a contraindication to surgery, though many clinicians are now biopsying them to determine if they are high-or low-grade to estimate course and likely survival time [81]. Conversely, lesions that are focal, cystic, and extraphytic are usually considered treatable, with surgery to remove as much of the tumour as possible often consid‐ ered the treatment of choice. Table 4, utilizing the most recently proposed classification system of Ramos et al. [61], summarizes current general practices. Following the 2013 publication of guidelines promoting the biopsy of diffuse intrinsic brainstem lesions to aid in the develop‐ ment of targeted therapies [82], stereotactic biopsies must now be at least considered standard of care for these patients. Radiation therapy, sometimes combined with chemotherapy, appears to induce brief clinical remissions in patients with diffuse tumours for whom surgery is not indicated, and may prolong survival slightly [83]. With other tumours, surgery often plays the major role; though some patients merely require monitoring and others respond well to radiation or conservative measures like CSF shunting alone.

There remains no consensus, however, as to how to best categorize lesions; and the lion's share of brainstem tumours continue to be considered untreatable and to have a dismal prognosis. Consequently, three major challenges that remain are (1) coming to some consensus as to classifying lesions, so as to best predict their course, likely response to treatment and, hence, when and how best to treat them; (2) developing more effective non-surgical treatments to treat the intrinsic diffuse tumours for which all current treatments, including surgery, have been ineffective and the prognosis remains abysmal; and (3) optimizing quality of life in these children and their families, irrespective of long-term prognosis. With a view to these three main objectives, we now briefly explore current and future directions in the detection, diagnosis and classification of brainstem tumours, and in their non-operative and operative

Paediatric Brainstem Cancers — Where We Have Been; Where We Are; Where We Are Going

http://dx.doi.org/10.5772/58297

45

In few fields have there been as many and as dramatic advances as in the field of diagnostic imaging, and this appears to be having a significant impact upon how brain and brainstem tumours are now detected and diagnosed. Increasing recognition that not all brainstem tumours are a diverse collection of pathological entities with distinct courses and responses to treatment, has led to attempts to distinguish between them using advanced imaging. Typically, for example, diffuse intrinsic fibrillary astrocytomas appear hypo-intense on T1-weighted images, while heterogeneously hyper-intense on T2-weighted images; they also exhibit indistinct margins that reflect the tumour's highly infiltrative nature [61]. Beyond distinctions made using different MR sequences, various contrasts are now being used to try to detect lesions that otherwise might be missed [84] and to delineate low-from high-grade lesions [19; 45;56;64;76]. For example, dorsal exophytic tumours often are low-grade pilocytic astrocyto‐ mas that, like high-grade fibrillary astrocytomas, may be hypo-intense on T1-weighted images and hyper-intense on T2-weighted images; however, they classically appear well-demarcated. Moreover, after gadolinium infusion, a cystic component often is identified, as only the solid portion of the tumour is enhanced, revealing a hypo-intense centre [61;85;86]. More recent advances in MR scanning — like MR spectroscopy, MR perfusion, and diffusion tensor imaging (DTI) — are also being utilized to further establish the histopathologic diagnosis of brainstem lesions [18;61]. An additional advantage of these newer MR technologies is that they are better at monitoring for disease recurrence or progression after treatment, since radiationinduced necrosis may be mistaken for tumour re-growth with traditional MRI [87-90]. In addition, functional scans — like functional MRI (fMRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) — are emerging as additional imaging tools to identify and characterize lesions in the brain, brainstem and spinal cord [19;91-95]. Further development of these tools may aid in further delineating the various brainstem tumours, even obviating the need for tissue in those patients for whom biopsies

This being said, among the most major imaging advances related to brainstem tumours relates to stereotactic biopsies. A *stereotactic biopsy* utilizes a computer and images performed in at least two planes, first to localize a target lesion, like a tumour, in three-dimensional space; then

management.

pose undue risk.

**3.1. Enhanced diagnostics and classification**


**Table 4.** Current Management of Paediatric Brainstem Tumours

There remains no consensus, however, as to how to best categorize lesions; and the lion's share of brainstem tumours continue to be considered untreatable and to have a dismal prognosis. Consequently, three major challenges that remain are (1) coming to some consensus as to classifying lesions, so as to best predict their course, likely response to treatment and, hence, when and how best to treat them; (2) developing more effective non-surgical treatments to treat the intrinsic diffuse tumours for which all current treatments, including surgery, have been ineffective and the prognosis remains abysmal; and (3) optimizing quality of life in these children and their families, irrespective of long-term prognosis. With a view to these three main objectives, we now briefly explore current and future directions in the detection, diagnosis and classification of brainstem tumours, and in their non-operative and operative management.

#### **3.1. Enhanced diagnostics and classification**

Current diagnosis largely depends on the use of patient histories and physical findings, especially paying attention to the duration of symptoms prior to diagnosis and the type(s) of neurological deficits identified (e.g., ocular palsies), followed by magnetic resonance imaging, both with and without contrast. Lesions that are intrinsic and diffuse, and lesions that involve the pons are generally considered to be a contraindication to surgery, though many clinicians are now biopsying them to determine if they are high-or low-grade to estimate course and likely survival time [81]. Conversely, lesions that are focal, cystic, and extraphytic are usually considered treatable, with surgery to remove as much of the tumour as possible often consid‐ ered the treatment of choice. Table 4, utilizing the most recently proposed classification system of Ramos et al. [61], summarizes current general practices. Following the 2013 publication of guidelines promoting the biopsy of diffuse intrinsic brainstem lesions to aid in the develop‐ ment of targeted therapies [82], stereotactic biopsies must now be at least considered standard of care for these patients. Radiation therapy, sometimes combined with chemotherapy, appears to induce brief clinical remissions in patients with diffuse tumours for whom surgery is not indicated, and may prolong survival slightly [83]. With other tumours, surgery often plays the major role; though some patients merely require monitoring and others respond well

to radiation or conservative measures like CSF shunting alone.

**location Usual histology Biopsy Surgery**

Brainstem gangliocytomas often possible

in medulla or gangliocytomas possible in ~75% of

fibrillary astrocytomas

ventricle other low-grade

Diffuse Intrinsic or Pons grade III-IV gliomas Yes No Yes +/- 10%

glioma resection is possible

Focal Tectal Tectum low-grade gliomas Yes Shunt placement Yes Usually not ~ 100%

**Radiatio n**

astrocytomas Yes Complete resection +/- +/- ≥ 90%

astrocytomas Yes Usually only partial +/- +/- ≥ 90%

astrocytomas Yes Complete resection +/- +/- ~ 100%

pts

Resection often unnecessary

**Chemothera py**

**2-year survival**

**Tumour type Typical**

Focal Medulla pilocystic

44 Tumors of the Central Nervous System – Primary and Secondary

Dorsal Exophytic Mostly in 4th pilocystic

Cervicomedullary Epicentre either pilocystic

cervical spine

**Table 4.** Current Management of Paediatric Brainstem Tumours

Diffusely Infiltrative In few fields have there been as many and as dramatic advances as in the field of diagnostic imaging, and this appears to be having a significant impact upon how brain and brainstem tumours are now detected and diagnosed. Increasing recognition that not all brainstem tumours are a diverse collection of pathological entities with distinct courses and responses to treatment, has led to attempts to distinguish between them using advanced imaging. Typically, for example, diffuse intrinsic fibrillary astrocytomas appear hypo-intense on T1-weighted images, while heterogeneously hyper-intense on T2-weighted images; they also exhibit indistinct margins that reflect the tumour's highly infiltrative nature [61]. Beyond distinctions made using different MR sequences, various contrasts are now being used to try to detect lesions that otherwise might be missed [84] and to delineate low-from high-grade lesions [19; 45;56;64;76]. For example, dorsal exophytic tumours often are low-grade pilocytic astrocyto‐ mas that, like high-grade fibrillary astrocytomas, may be hypo-intense on T1-weighted images and hyper-intense on T2-weighted images; however, they classically appear well-demarcated. Moreover, after gadolinium infusion, a cystic component often is identified, as only the solid portion of the tumour is enhanced, revealing a hypo-intense centre [61;85;86]. More recent advances in MR scanning — like MR spectroscopy, MR perfusion, and diffusion tensor imaging (DTI) — are also being utilized to further establish the histopathologic diagnosis of brainstem lesions [18;61]. An additional advantage of these newer MR technologies is that they are better at monitoring for disease recurrence or progression after treatment, since radiationinduced necrosis may be mistaken for tumour re-growth with traditional MRI [87-90]. In addition, functional scans — like functional MRI (fMRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) — are emerging as additional imaging tools to identify and characterize lesions in the brain, brainstem and spinal cord [19;91-95]. Further development of these tools may aid in further delineating the various brainstem tumours, even obviating the need for tissue in those patients for whom biopsies pose undue risk.

This being said, among the most major imaging advances related to brainstem tumours relates to stereotactic biopsies. A *stereotactic biopsy* utilizes a computer and images performed in at least two planes, first to localize a target lesion, like a tumour, in three-dimensional space; then to determine its depth; and finally to guide the removal of tissue for pathological examination. Stereotactic biopsies rely on the underlying principle of *parallax*, a process that initially was used in astrology to estimate distances between stars [96]. *Parallax* is the concept of using multiple site lines to visualize the same object relative to objects of known position in front of and behind it. Since objects closer to the observer tend to move more than objects that are more distant when the point of observation changes, measuring the degree of movement of the target lesion relative to reference points, combined with recording the change in viewing angle, permits one to estimate the depth or "Z-dimension" of the target lesion [97]. Long used to aid in the biopsy of breast lesions [98], CT-guided stereotactic biopsies have been used for the diagnosis of brain lesions since the nineteen seventies [99;100], but not with brainstem lesions until more recently. Just this year, Cage et al. reported on their results specifically biopsying diffuse brainstem tumours; they also extensively reviewed the literature [81]. In their own series, nine children with pontine lesions were biopsied, with successful tissue collection achieved in all cases. Among these lesions, four were found to be low-grade (grade I or II) astrocytomas, and five high-grade (grade III or IV) gliomas, demonstrating heterogeneity even among diffuse pontine lesions. Moreover, only one patient experienced any post-operative complication – transient seizures and hydrocephalus. In their review of the literature, the same authors identified twenty case series besides their own, ranging in size from a single paediatric patient [101] to 52 children [102]. In this latter series, among 52 paediatric brainstem biopsies, only five patients experienced any post-operative morbidity, in four instances transient; and there were no deaths. Biopsy was felt to alter management in 18% of the cases. In another one of the larger series, Kondziolka and Lunsford reported on their use of CT-guided stereotactic biopsies in 40 consecutive patients seen over a 13-year interval [103]. Of this number, 20 patients had midbrain lesions (n=20), 18 pontine lesions, and two medullary lesions. Midline lesions were approached via a coronal, trans-thalamic trajectory; lateral brain stem lesions usually were approached via a trans-cerebellar route. A histologic diagnosis was achieved in 38 patients (95%), and no post-biopsy haemorrhages were noted on CT performed immediately after the procedure. Only one patient (2.5%) experienced a complication, which was transient diplopia. Altogether across the twenty-one papers Cage et al. reviewed, there were 294 documented brainstem biopsies in paediatric patients, among whom there were 16 cases of an intra-operative complication (5.4%); 42 cases of increased post-operative morbidity (14.3%) that was transient in the vast majority of cases; 29 inconclusive biopsies (9.9%); and two procedure-related deaths (0.7%) [102]. The authors concluded that brainstem biopsies are safer than widely perceived and that, when used judiciously, might be both safe and of advantage in terms of determining treatment. Stereotactic biopsies have been demonstrated to be superior to MRI alone in accurately diagnosing brainstem lesions [104].

targets and optimized ways to cross the blood-brain barrier. In fact, one key rationale behind obtaining tissue in patients with diffuse pontine lesions stems from recent work to further classify lesions based upon a number of identifiable genetic and molecular alterations that may

Paediatric Brainstem Cancers — Where We Have Been; Where We Are; Where We Are Going

http://dx.doi.org/10.5772/58297

47

Until the last couple of years, the biology of diffuse intrinsic brainstem tumours was entirely unknown. However, tissue analysis has now identified a number of identifiable genetic and molecular alterations — like amplification of receptor tyrosine kinases and cell-cycle regula‐ tory genes, and alterations in membrane proteins and the Hedgehog (Hh) signaling pathway [79;105-109] — that could serve as therapeutic targets. Much of this research is being aided by the development of human glioma cell lines that can be studied in the lab [110]. One particular membrane protein that has garnered considerable recent interest is B7-H3 (also called CD276), a type I trans-membrane glycoprotein that is part of the B7-CD28 family [111]. This glycopro‐ tein is known to interact with host defenses in certain cancers, being recognized by the monoclonal antibody 8H9 [112] that binds to a vast array of different tumours. Among primary brain tumors, for example, it bound to 15 of 17 glioblastomas, three of four mixed gliomas, and six of eight astrocytomas, among others; however, it did not bind to normal neurons or glial cells [113]. Moreover, extremely favourable results were observed in a study in which 21 children with recurrent stage IV neuroblastoma — like gliomas, a neuroectodermal tumor were administered compartmental intra-thecal antibody-based radio-immunotherapy [114]. The therapy consisted of 131I-monoclonal antibodies targeting B7-H3. Among the 21 children treated, 17 (81%) remained alive between seven and 74 months later (median 33 months), significantly longer than the expected, post-disease-recurrence median survival of six months. For all these reasons, the potential is there for B7-H3 to be a future therapeutic target for diffuse intrinsic brainstem gliomas. Considerable interest also has focussed on the epidermal growth factor receptor (EGFR), which has been the target of several chemotherapeutic drugs currently undergoing early phase trials, like gefitinib and erlotinib [115-117]. Another drug currently undergoing early phase testing is vandetanib, a tyrosine kinase inhibitor of both the EGFR and vascular endothelial growth factor receptor (VEGFR) [118]. To date, one-year survival rates have ranged from 38 to 56% [115-118], not significantly better than the median survival of 9 to

Promising results were observed when data were combined across four phase II trials [119] in which 18 mostly paediatric (age range 2 – 42 years, median=10) patients with brainstem gliomas were treated with anti-neoplaston A10 (A10I) and AS2-1 injections over a median of five months [120]. Fourteen of the 18 patients had diffuse intrinsic tumors; four were glioblas‐ tomas and 14 anaplastic gliomas. Prior to treatment, twelve patients had suffered a relapse and six had never received either radiation or chemotherapy. Contrary to the expected 2-year survival rate of roughly 10%, 39% remained alive at two years, and 22% at five years, including one patient with an anaplastic astrocytoma who remained alive for 17 years and another with a glioblastoma for more than five years. The only adverse event was a single case of reversible

Another potential boon to the treatment of all CNS malignancies may be the development of nanotherapeutic approaches, which include an entire new generation of novel targeted-

render these tumors susceptible to targeted therapies [79-81].

12 months reported elsewhere [79].

anaemia.

#### **3.2. Enhanced non-operative management**

Many have argued against biopsying diffuse intrinsic brainstem lesions, since they cannot be surgically removed or even de-bulked without causing unacceptable neurological deficits because of their location and infiltrating nature, and given the lack of enduring response that the vast majority of patients demonstrate to traditional chemotherapy and radiation. But this pessimistic outlook may be changing, given emerging knowledge about potential therapeutic targets and optimized ways to cross the blood-brain barrier. In fact, one key rationale behind obtaining tissue in patients with diffuse pontine lesions stems from recent work to further classify lesions based upon a number of identifiable genetic and molecular alterations that may render these tumors susceptible to targeted therapies [79-81].

to determine its depth; and finally to guide the removal of tissue for pathological examination. Stereotactic biopsies rely on the underlying principle of *parallax*, a process that initially was used in astrology to estimate distances between stars [96]. *Parallax* is the concept of using multiple site lines to visualize the same object relative to objects of known position in front of and behind it. Since objects closer to the observer tend to move more than objects that are more distant when the point of observation changes, measuring the degree of movement of the target lesion relative to reference points, combined with recording the change in viewing angle, permits one to estimate the depth or "Z-dimension" of the target lesion [97]. Long used to aid in the biopsy of breast lesions [98], CT-guided stereotactic biopsies have been used for the diagnosis of brain lesions since the nineteen seventies [99;100], but not with brainstem lesions until more recently. Just this year, Cage et al. reported on their results specifically biopsying diffuse brainstem tumours; they also extensively reviewed the literature [81]. In their own series, nine children with pontine lesions were biopsied, with successful tissue collection achieved in all cases. Among these lesions, four were found to be low-grade (grade I or II) astrocytomas, and five high-grade (grade III or IV) gliomas, demonstrating heterogeneity even among diffuse pontine lesions. Moreover, only one patient experienced any post-operative complication – transient seizures and hydrocephalus. In their review of the literature, the same authors identified twenty case series besides their own, ranging in size from a single paediatric patient [101] to 52 children [102]. In this latter series, among 52 paediatric brainstem biopsies, only five patients experienced any post-operative morbidity, in four instances transient; and there were no deaths. Biopsy was felt to alter management in 18% of the cases. In another one of the larger series, Kondziolka and Lunsford reported on their use of CT-guided stereotactic biopsies in 40 consecutive patients seen over a 13-year interval [103]. Of this number, 20 patients had midbrain lesions (n=20), 18 pontine lesions, and two medullary lesions. Midline lesions were approached via a coronal, trans-thalamic trajectory; lateral brain stem lesions usually were approached via a trans-cerebellar route. A histologic diagnosis was achieved in 38 patients (95%), and no post-biopsy haemorrhages were noted on CT performed immediately after the procedure. Only one patient (2.5%) experienced a complication, which was transient diplopia. Altogether across the twenty-one papers Cage et al. reviewed, there were 294 documented brainstem biopsies in paediatric patients, among whom there were 16 cases of an intra-operative complication (5.4%); 42 cases of increased post-operative morbidity (14.3%) that was transient in the vast majority of cases; 29 inconclusive biopsies (9.9%); and two procedure-related deaths (0.7%) [102]. The authors concluded that brainstem biopsies are safer than widely perceived and that, when used judiciously, might be both safe and of advantage in terms of determining treatment. Stereotactic biopsies have been demonstrated to be superior

46 Tumors of the Central Nervous System – Primary and Secondary

to MRI alone in accurately diagnosing brainstem lesions [104].

Many have argued against biopsying diffuse intrinsic brainstem lesions, since they cannot be surgically removed or even de-bulked without causing unacceptable neurological deficits because of their location and infiltrating nature, and given the lack of enduring response that the vast majority of patients demonstrate to traditional chemotherapy and radiation. But this pessimistic outlook may be changing, given emerging knowledge about potential therapeutic

**3.2. Enhanced non-operative management**

Until the last couple of years, the biology of diffuse intrinsic brainstem tumours was entirely unknown. However, tissue analysis has now identified a number of identifiable genetic and molecular alterations — like amplification of receptor tyrosine kinases and cell-cycle regula‐ tory genes, and alterations in membrane proteins and the Hedgehog (Hh) signaling pathway [79;105-109] — that could serve as therapeutic targets. Much of this research is being aided by the development of human glioma cell lines that can be studied in the lab [110]. One particular membrane protein that has garnered considerable recent interest is B7-H3 (also called CD276), a type I trans-membrane glycoprotein that is part of the B7-CD28 family [111]. This glycopro‐ tein is known to interact with host defenses in certain cancers, being recognized by the monoclonal antibody 8H9 [112] that binds to a vast array of different tumours. Among primary brain tumors, for example, it bound to 15 of 17 glioblastomas, three of four mixed gliomas, and six of eight astrocytomas, among others; however, it did not bind to normal neurons or glial cells [113]. Moreover, extremely favourable results were observed in a study in which 21 children with recurrent stage IV neuroblastoma — like gliomas, a neuroectodermal tumor were administered compartmental intra-thecal antibody-based radio-immunotherapy [114]. The therapy consisted of 131I-monoclonal antibodies targeting B7-H3. Among the 21 children treated, 17 (81%) remained alive between seven and 74 months later (median 33 months), significantly longer than the expected, post-disease-recurrence median survival of six months. For all these reasons, the potential is there for B7-H3 to be a future therapeutic target for diffuse intrinsic brainstem gliomas. Considerable interest also has focussed on the epidermal growth factor receptor (EGFR), which has been the target of several chemotherapeutic drugs currently undergoing early phase trials, like gefitinib and erlotinib [115-117]. Another drug currently undergoing early phase testing is vandetanib, a tyrosine kinase inhibitor of both the EGFR and vascular endothelial growth factor receptor (VEGFR) [118]. To date, one-year survival rates have ranged from 38 to 56% [115-118], not significantly better than the median survival of 9 to 12 months reported elsewhere [79].

Promising results were observed when data were combined across four phase II trials [119] in which 18 mostly paediatric (age range 2 – 42 years, median=10) patients with brainstem gliomas were treated with anti-neoplaston A10 (A10I) and AS2-1 injections over a median of five months [120]. Fourteen of the 18 patients had diffuse intrinsic tumors; four were glioblas‐ tomas and 14 anaplastic gliomas. Prior to treatment, twelve patients had suffered a relapse and six had never received either radiation or chemotherapy. Contrary to the expected 2-year survival rate of roughly 10%, 39% remained alive at two years, and 22% at five years, including one patient with an anaplastic astrocytoma who remained alive for 17 years and another with a glioblastoma for more than five years. The only adverse event was a single case of reversible anaemia.

Another potential boon to the treatment of all CNS malignancies may be the development of nanotherapeutic approaches, which include an entire new generation of novel targeteddelivery devices — 'smart' nanoparticles — that facilitate the transfer of a variety of therapies, from drugs to thermotherapy, across the blood-brain barrier [121], a barrier that has tradi‐ tionally hampered the delivery of most anti-neoplastic drugs. Stem cells that are themselves drawn to tumour cells are another potential vehicle that is being explored for the treatment of high-grade gliomas [122;123] and may have applications in the treatment of inoperable brainstem gliomas. Some investigators are also examining the potential to test the effectiveness of anti-neoplastic drugs *ex vivo* prior to patient administration via the use of *in vitro* assays [124]. In this way, drug regimens might be more appropriately taylorized to each patient, and *in vivo* drug effectiveness more accurately predicted prior to initiating therapy, thereby minimizing unnecessary toxicity and enhancing the likelihood of initial treatment response.

There also has been a clear swing in the route selected for brainstem biopsy access, at least in studies involving paediatric patients. For example, over the decade of the nineteen nineties, 82% of reported brainstem biopsies were accessed via a trans-frontal route, versus just 18% trans-cerebellar. Since the year 2000, however, these percentages have completely reversed, with 82% of reported biopsies trans-cerebellar and 18% trans-frontal. In the five studies published since 2006 in which paediatric patients were identified among those biopsied [81;126-129], every one of the ninety biopsies were performed through the cerebellum. Across these ninety biopsies, 77 of them in children, there was one intra-operative complication (1.1%), nine post-operative complications (10%), two inconclusive biopsies (2.2%) and no deaths. The reason(s) for this shift in surgical approach is not entirely clear. In 2012, Dellaretti et al. published the results of their study comparing the two approaches over twenty-three years of practice (1984-2007), and no significant differences were noted [130]; however, whether any children were included within the sample of 142 patients is not stated in the manuscript. Moreover, there was a clear preference for trans-frontal biopsies, which were performed in 123 of the patients versus just 19 via the cerebellum, and no explanation for this preference

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49

Cage et al. described their trans-cerebellar surgical approach in nine children with diffuse intrinsic brainstem tumours as follows [81]: "Preoperatively, patients all completed an MRI with and without gadolinium intravenous contrast of the brain according to Brainlab (Brainlab AG, Germany) protocols to allow for intraoperative neuronavigation. Patients were positioned either supine (n=3) or in the lateral decubitus position (n=6) opposite the side of their lesion with neck flexion in the same direction. The head was then fixed using both a horseshoe headholding device and further immobilized with Mayfield pin fixation. For all stereotactic procedures, the Brainlab neuronavigation system was used to plan the trajectory from the skull to target locations in the brainstem. The biopsy entry point was transcerebellar, either right (n=4) or left (n=5) for all patients. A side-cutting biopsy needle was then passed along the trajectory path. Between one and four samples were obtained from within the lesion.... Target selection was designed to minimize the trajectory through the brainstem. If there was an obvious area of enhancement suggesting a pathologically-aggressive area of the tumour, then this was chosen as the biopsy target. Otherwise, the target was usually just deep to the cerebellar peduncle. Care was taken to avoid the lateral edge of the fourth ventricle and the

Otherwise, surgeons continue to operate successfully on patients with focal, exophytic and cystic brainstem tumours, with survival and quality of life enhanced even by subtotal resec‐ tions, as well as by cyst drainage procedures and the insertion of shunts when necessary [61]. But here too, stereotactic biopsies play a significant role, as some apparent tumours are found to be focal areas of inflammation, infectious lesions, vascular anomalies, or some other pathology necessitating different treatment [29;131]. As such, neurosurgeons now appear to have a role to play in all paediatric patients with brainstem tumours, a far cry from forty years

was offered.

ventral corticospinal tracts." [81]

ago, when they seemed to have no role at all.

Finally, as mentioned earlier, advanced imaging techniques are now allowing for enhanced prospective monitoring of treatment response and the earlier detection of disease recurrence and progression [87;88]. Another previously-unexplored means by which to accomplish such monitoring might be via the analysis of various bodily fluids — like blood, urine and cere‐ brospinal fluid (CSF) — to identify and estimate levels of various CNS tumour markers, similar to how prostate-specific antigen (PSA) is being used to detect and monitor prostate cancer. For example, Saratsis et al. recently performed protein profiling by mass spectrometry of 76 specimens — including CSF, serum, urine, and normal and tumor brainstem tissue [125] from 10 patients with diffuse intrinsic brainstem gliomas and four healthy controls. CSF proteomic analysis revealed selective up-regulation of both cyclophillin A (CypA) and dimethylarginase 1 (DDAH1) in patients relative to controls. Protein expression was validated further via Western blot analysis and immunohistochemical assays. Immunohistochemical staining exhibited selective up-regulation of secreted but not cytosolic CypA and DDAH1 in patients. The authors proposed that the detection of secreted CypA and DDAH1 in serum and urine could have clinical applications in the monitoring of treatment response and disease recurrence in patients with brainstem gliomas [125].

As such, although the prognosis for patients with inoperable brainstem gliomas remains bleak for the time being, beliefs regarding the potential for enhanced survival certainly are changing with the emergence of targeted therapies, better delivery systems, and enhanced imaging and other techniques to monitor disease regression and progression. But what will the neurosur‐ geon's role be in all this?

#### **3.3. Emerging role of the neurosurgeon in the management of diffuse brainstem tumours**

Nothing has changed in terms of neurosurgeons' reluctance to operate on diffuse intrinsic brainstem gliomas; nor does it seem likely to anytime soon, given the known aggressiveness of the vast majority of these tumours, their high degree of infiltration that would preclude anything more than partial resection, and the extreme risks of such surgery, given the anatomical compactness of vital structures and neural pathways. Consequently, the main change in current surgical practices relates to the stereotactic biopsy of these lesions, a practice that this year was formally recommended in a published, multi-disciplinary consensus statement concerning surgical approaches to low-and high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood [82].

There also has been a clear swing in the route selected for brainstem biopsy access, at least in studies involving paediatric patients. For example, over the decade of the nineteen nineties, 82% of reported brainstem biopsies were accessed via a trans-frontal route, versus just 18% trans-cerebellar. Since the year 2000, however, these percentages have completely reversed, with 82% of reported biopsies trans-cerebellar and 18% trans-frontal. In the five studies published since 2006 in which paediatric patients were identified among those biopsied [81;126-129], every one of the ninety biopsies were performed through the cerebellum. Across these ninety biopsies, 77 of them in children, there was one intra-operative complication (1.1%), nine post-operative complications (10%), two inconclusive biopsies (2.2%) and no deaths. The reason(s) for this shift in surgical approach is not entirely clear. In 2012, Dellaretti et al. published the results of their study comparing the two approaches over twenty-three years of practice (1984-2007), and no significant differences were noted [130]; however, whether any children were included within the sample of 142 patients is not stated in the manuscript. Moreover, there was a clear preference for trans-frontal biopsies, which were performed in 123 of the patients versus just 19 via the cerebellum, and no explanation for this preference was offered.

delivery devices — 'smart' nanoparticles — that facilitate the transfer of a variety of therapies, from drugs to thermotherapy, across the blood-brain barrier [121], a barrier that has tradi‐ tionally hampered the delivery of most anti-neoplastic drugs. Stem cells that are themselves drawn to tumour cells are another potential vehicle that is being explored for the treatment of high-grade gliomas [122;123] and may have applications in the treatment of inoperable brainstem gliomas. Some investigators are also examining the potential to test the effectiveness of anti-neoplastic drugs *ex vivo* prior to patient administration via the use of *in vitro* assays [124]. In this way, drug regimens might be more appropriately taylorized to each patient, and *in vivo* drug effectiveness more accurately predicted prior to initiating therapy, thereby minimizing unnecessary toxicity and enhancing the likelihood of initial treatment response.

Finally, as mentioned earlier, advanced imaging techniques are now allowing for enhanced prospective monitoring of treatment response and the earlier detection of disease recurrence and progression [87;88]. Another previously-unexplored means by which to accomplish such monitoring might be via the analysis of various bodily fluids — like blood, urine and cere‐ brospinal fluid (CSF) — to identify and estimate levels of various CNS tumour markers, similar to how prostate-specific antigen (PSA) is being used to detect and monitor prostate cancer. For example, Saratsis et al. recently performed protein profiling by mass spectrometry of 76 specimens — including CSF, serum, urine, and normal and tumor brainstem tissue [125] from 10 patients with diffuse intrinsic brainstem gliomas and four healthy controls. CSF proteomic analysis revealed selective up-regulation of both cyclophillin A (CypA) and dimethylarginase 1 (DDAH1) in patients relative to controls. Protein expression was validated further via Western blot analysis and immunohistochemical assays. Immunohistochemical staining exhibited selective up-regulation of secreted but not cytosolic CypA and DDAH1 in patients. The authors proposed that the detection of secreted CypA and DDAH1 in serum and urine could have clinical applications in the monitoring of treatment response and disease

As such, although the prognosis for patients with inoperable brainstem gliomas remains bleak for the time being, beliefs regarding the potential for enhanced survival certainly are changing with the emergence of targeted therapies, better delivery systems, and enhanced imaging and other techniques to monitor disease regression and progression. But what will the neurosur‐

**3.3. Emerging role of the neurosurgeon in the management of diffuse brainstem tumours**

Nothing has changed in terms of neurosurgeons' reluctance to operate on diffuse intrinsic brainstem gliomas; nor does it seem likely to anytime soon, given the known aggressiveness of the vast majority of these tumours, their high degree of infiltration that would preclude anything more than partial resection, and the extreme risks of such surgery, given the anatomical compactness of vital structures and neural pathways. Consequently, the main change in current surgical practices relates to the stereotactic biopsy of these lesions, a practice that this year was formally recommended in a published, multi-disciplinary consensus statement concerning surgical approaches to low-and high-grade astrocytomas and diffuse

recurrence in patients with brainstem gliomas [125].

48 Tumors of the Central Nervous System – Primary and Secondary

intrinsic pontine gliomas in childhood [82].

geon's role be in all this?

Cage et al. described their trans-cerebellar surgical approach in nine children with diffuse intrinsic brainstem tumours as follows [81]: "Preoperatively, patients all completed an MRI with and without gadolinium intravenous contrast of the brain according to Brainlab (Brainlab AG, Germany) protocols to allow for intraoperative neuronavigation. Patients were positioned either supine (n=3) or in the lateral decubitus position (n=6) opposite the side of their lesion with neck flexion in the same direction. The head was then fixed using both a horseshoe headholding device and further immobilized with Mayfield pin fixation. For all stereotactic procedures, the Brainlab neuronavigation system was used to plan the trajectory from the skull to target locations in the brainstem. The biopsy entry point was transcerebellar, either right (n=4) or left (n=5) for all patients. A side-cutting biopsy needle was then passed along the trajectory path. Between one and four samples were obtained from within the lesion.... Target selection was designed to minimize the trajectory through the brainstem. If there was an obvious area of enhancement suggesting a pathologically-aggressive area of the tumour, then this was chosen as the biopsy target. Otherwise, the target was usually just deep to the cerebellar peduncle. Care was taken to avoid the lateral edge of the fourth ventricle and the ventral corticospinal tracts." [81]

Otherwise, surgeons continue to operate successfully on patients with focal, exophytic and cystic brainstem tumours, with survival and quality of life enhanced even by subtotal resec‐ tions, as well as by cyst drainage procedures and the insertion of shunts when necessary [61]. But here too, stereotactic biopsies play a significant role, as some apparent tumours are found to be focal areas of inflammation, infectious lesions, vascular anomalies, or some other pathology necessitating different treatment [29;131]. As such, neurosurgeons now appear to have a role to play in all paediatric patients with brainstem tumours, a far cry from forty years ago, when they seemed to have no role at all.

## **4. Conclusions**

Over the past forty years, much has changed in the way in which brainstem tumours are treated in children. Though these lesions continue to be the most common cause of CNS cancer-related death in the paediatric population, the discovery of a brainstem tumour is no longer a death sentence. Formerly thought to be pathologically homogeneous and/or of no pathological interest since they were not surgically accessible, paediatric brainstem tumours are now understood to be highly heterogeneous; and knowing the pathology is now considered critical to management decisions. For the minority of children who have focal, exophytic or cystic lesions, long-term survival is now the rule, with 5-and 10-year survival rates often 90% or higher. For those children in the future who will develop diffuse brainstem lesions, mostly high-grade gliomas, emerging therapies are now providing multiple reasons to hope. Besides providing competent, compassionate care to each child and their families, what is critical, from the current neurosurgeon's standpoint, is to assist in the collection of tissue, either by biopsy while a child is alive, or at autopsy via respectful conversations with parents and other caregivers, so that future targeted therapies can be developed, tested and ultimately approved for widespread use.

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