**10. Treatment**

#### **10.1. General**

**Figure 3.** Medulloblastomas in T2-weighted imaging (T2WI), T1-weighted imaging (T1WI), with gadolinium enhancement (CONT), fluid-attenuated inversion recovery (FLAIR) (D) and diffusion-weighted imaging (DWI) in axial planes.

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Treatment strategies for medulloblastomas have advanced slowly over the past 5 decades. Generally based on the histology and clinical factors, especially, disease dissemination at presentation and residual tumor after surgical resection, management of medulloblastoma has evolved to maximal safe surgical resection followed by radiation therapy and adjuvant chemotherapy [20, 22–24, 26, 69].

Adjuvant chemotherapy is recommended for all patients as this improves outcomes significantly. Following surgery, risks of recurrence and of neurocognitive effects of radiation therapy, doses of radiation and the type of chemotherapy protocol vary depending on extent of disease and age of the patient as well as institutional preferences [20, 29].

Though the medulloblastoma subgroups (Wnt, Shh, Groups 3 and 4) have distinct molecular and clinical profile, current adjuvant chemotherapy that are in practice are for the nontargated ones. However, significant improvements, approximately 70% 5-year survival rate with these combined therapies are achieved at the high cost of the quality of life, resulting mostly from the effects of radiotherapy and nonspecific, antimitotic agents on the developing brains of young medulloblastoma patients [27–31]. A general approach carries significant risk of over or under-treatment. [30, 34].

#### **10.2. Surgery and surgical techniques**

In March 1925, Cushing first succeeded in gross total removal of a medulloblastoma [1, 2]. Since then, the first-line treatment for medulloblastoma is surgery with the aim of maximal safe resection, along with treatment of any concomitant hydrocephalus [8]. But Cushing also cautioned that "the temptation will always be present for the surgeon to attempt an enucleation, a conservative attitude in this respect is the course of wisdom" [1, 8].

The basic principles of surgery for medulloblastoma have changed little in the modern era, but technological revolutions in surgical technique and supportive care have made surgery safer. Development of surgical skill and other facilities has dramatically reduced the perioperative mortality from 25.2% during the period of Cushing to less than 1% in expert hands at the present time [70]. With recent technological advancements the goal of surgery is always a complete excision, but practically it can safely be accomplished only in about one fourth of cases [71].

of maximal safe resection, gross total resection can often be accomplished. Superiorly, the tumor is often projected into the aqueduct, filling it and obstructing the CSF pathway. The part projecting into the aqueduct can be meticulously removed with gentle suction, reestablishing the CSF flow (**Figure 5**). The part of the tumor that is attached to the brain stem or peduncles, is carefully removed, keeping a thin mantle leaving behind to ensure not to injure any vital structure. To alleviate the post-operative morbidity or mortality, immediate postoperative care of the patient is of immense importance. This is a factor that can make enormous difference in outcome.

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Whether preoperative shunting should be done to relieve hydrocephalus prior to tumor surgery remains controversial. A ventriculoperitoneal (VP) shunt permanently or an external ventricular drain (EVD) as a temporary measure can be employed to treat hydrocephalus, if present at the time of diagnosis [8, 26, 71]. An EVD can be placed in the operating room, just prior to posterior fossa craniotomy, if the hydrocephalus is not treated preoperatively. About 20% of patients require long-term treatment of hydrocephalus with a VP shunt insertion or an endoscopic third ventriculostomy (ETV), when the hydrocephalus persists even after tumor removal [8, 71]. There is high possibility that a preoperative shunt

**Figure 5.** Schematic diagram of expanded aqueduct after removal of the medulloblastoma extending into the aqueduct.

Most surgeons prefer the prone position than to the sitting position to minimize the risk of air embolism, frontal pneumocephalus, and systemic hypotension. The straight vertical skin incision employed by almost all neurosurgeons today was described first by Naffziger in 1928 [70]. A wide craniectomy or craniotomy extending from the transverse sinuses to the foramen magnum is performed with or without removal of the posterior arch of C1. The dura is usually opened in a Y-shaped manner extending down to the level of C1 when the posterior arch is removed. The tumor may be readily evident as a red, semi circumscribed mass peeping into the vallecula when the tumor is large. The dorsal surface of the tumor is exposed and even though not truly encapsulated, medulloblastomas often have a clear interface between the tumor and surrounding brain where a dissection plane can be created. The tumor is excised in piece meal fashion either through the telovaler approach or by splitting the vermis (**Figure 4**). With the goal

**Figure 4.** Schematic diagram showing the exposure of medulloblastoma after splitting the vermis in the midline.

of maximal safe resection, gross total resection can often be accomplished. Superiorly, the tumor is often projected into the aqueduct, filling it and obstructing the CSF pathway. The part projecting into the aqueduct can be meticulously removed with gentle suction, reestablishing the CSF flow (**Figure 5**). The part of the tumor that is attached to the brain stem or peduncles, is carefully removed, keeping a thin mantle leaving behind to ensure not to injure any vital structure. To alleviate the post-operative morbidity or mortality, immediate postoperative care of the patient is of immense importance. This is a factor that can make enormous difference in outcome.

Whether preoperative shunting should be done to relieve hydrocephalus prior to tumor surgery remains controversial. A ventriculoperitoneal (VP) shunt permanently or an external ventricular drain (EVD) as a temporary measure can be employed to treat hydrocephalus, if present at the time of diagnosis [8, 26, 71]. An EVD can be placed in the operating room, just prior to posterior fossa craniotomy, if the hydrocephalus is not treated preoperatively. About 20% of patients require long-term treatment of hydrocephalus with a VP shunt insertion or an endoscopic third ventriculostomy (ETV), when the hydrocephalus persists even after tumor removal [8, 71]. There is high possibility that a preoperative shunt

**Figure 5.** Schematic diagram of expanded aqueduct after removal of the medulloblastoma extending into the aqueduct.

**Figure 4.** Schematic diagram showing the exposure of medulloblastoma after splitting the vermis in the midline.

mortality from 25.2% during the period of Cushing to less than 1% in expert hands at the present time [70]. With recent technological advancements the goal of surgery is always a complete excision, but practically it can safely be accomplished only in about one fourth of cases [71].

148 Brain Tumors - An Update

Most surgeons prefer the prone position than to the sitting position to minimize the risk of air embolism, frontal pneumocephalus, and systemic hypotension. The straight vertical skin incision employed by almost all neurosurgeons today was described first by Naffziger in 1928 [70]. A wide craniectomy or craniotomy extending from the transverse sinuses to the foramen magnum is performed with or without removal of the posterior arch of C1. The dura is usually opened in a Y-shaped manner extending down to the level of C1 when the posterior arch is removed. The tumor may be readily evident as a red, semi circumscribed mass peeping into the vallecula when the tumor is large. The dorsal surface of the tumor is exposed and even though not truly encapsulated, medulloblastomas often have a clear interface between the tumor and surrounding brain where a dissection plane can be created. The tumor is excised in piece meal fashion either through the telovaler approach or by splitting the vermis (**Figure 4**). With the goal may serve as a pathway of dissemination of the medulloblastoma, which has a tendency to spread by the CSF pathways. The use of millipore filters has been described to prevent dissemination [26, 70].

*10.3.3. Treatment of infants and children <3 years of age*

after surgery [84].

*10.3.4. Radiation hazards*

tolerance and efficacy.

As patients younger than 3 years are in risk of poor outcome of neurocognitive function following CSI, delay or omission of radiotherapy is recommended for this group of patients. M0 patients following gross total resection have commendable outcome with only chemotherapy

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The long-term sequelae of radiation therapy are well described, among which the most common ones are endocrinopathies, neurocognitive and neurosensory impairment following craniospinal irradiation depending on age of patient and radiation dose [85, 86]. Cancer survivors with a history of cranial irradiation have more tendency to have cerebrovascular disease and an increased risk of second malignancies in the radiation field [6]. Skin reactions, hair loss, growth problems, nausea and vomiting, chronic otitis media and/or otitis externa,

As medulloblastoma is a highly radiosensitive tumor, chemotherapy for this formidable tumor has been an adjunct in the treatment strategy for years. Various combinations of chemotherapeutic agents are used in conjunction with radiotherapy. The toxic effect of different chemotherapeutic agents have forced their use to be restricted in different circumstances. Now a days, the newer drugs are more soothing to the patients with better acceptability,

Penetrability of the blood-brain barrier of a drug is the most important feature for a chemotherapeutic agent to be a worthy regimen for brain tumors. Vincristine, Cisplatin, Cyclophosphamide, Lomustine, Etoposide, Methotrexate, Temozolomide, and Carboplatin are the commonly used effective chemotherapeutic agents for medulloblastomas [8, 87].

For average-risk medulloblastoma patients two common chemotherapy regimens are practiced. One is with a combination of Cisplatin, Lomustine, and Vincristine, while the second one comprises of a combination of Cisplatin, Cyclophosphamide, and Vincristine. These two regimens do not have significant difference in outcome regarding event-free survival (EFS) and overall survival (OS) [68]. Among conventional chemotherapeutics, Temozolomidecontaining regimens have shown most promising activity. Two studies, one in monotherapy [88] and another in combination with Irinotecan [89], have shown the best results in a relatively large population, although follow up for disease-free survival is short. Its tolerable toxicity profile and synergies with other chemotherapeutics and targeted agents make it an

As children under the age of 3 years has worse long term cognitive effects, they are not commonly treated with the radiotherapy. To compensate this more intense chemotherapy is initiated instead [87]. In the last few decades, with the intension to avoid radiation and to have an equally better outcome in younger patients, protocols have been developed consisting of

myelosuppression are other commonly encountered side effects [71].

attractive compound to serve as backbone for new strategies [20].

**10.4. Chemotherapy and combined radio-chemo therapy**

#### *10.2.1. Complications of surgery*

Clinical or subclinical venous air embolism, which is more common in sitting position, can happen in the prone position as well. With the goal of complete resection, major complications during tumor removal are usually caused by damage to the brain stem and injury to the lower cranial nerves. Aspiration pneumonia and respiratory failure often follows if the post-operative lower cranial nerve injuries are not handled meticulously. Though described frequently, cerebellar mutism, a commonly described complication of posterior fossa surgery, is less likely to occur now a days with microsurgical techniques. Meningitis, pseudomeningocele, postoperative tumor bed hematoma, epidural hematoma, subdural hematoma are among the other less often encountered complications.

#### **10.3. Radiotherapy**

Radiotherapy has been an adjunct of the treatment modality for medulloblastomas since the early twentieth century as these tumors are very responsive to radiotherapy. The survival rate has improved dramatically after the introduction of radiotherapy. Post-operative craniospinal irradiation (CSI) with or without boost to the posterior fossa are the customary protocol, as chosen by different centers [8, 72].

#### *10.3.1. Treatment for average-risk patients ≥3 years of age*

Post-operative radiotherapy dose for average risk medulloblastoma patients aged ≥3 years initially was set as 36 Gy CSI and 54 Gy boost for the posterior fossa (PF) because of high risk of local recurrence. Dose adjustment to 23.4–24 Gy CSI with the addition of adjuvant chemotherapy has been made with successful result [66, 73, 74]. Reduction in the posterior fossa radiation volume, in the form of 3-Dimensional conformal radiotherapy (3D CRT) has enabled to restrict the boost volume to the tumor bed plus a margin without compromising local control that minimizes morbidity associated with full PF irradiation by shielding normal vital structures [74–76]. Intensity-modulated radiotherapy (IMRT) or proton beam therapy similarly can reduce exposure to the heart and liver during CSI [72, 77–79].

#### *10.3.2. Treatment for high-risk patients ≥3 years of age*

The usual radiotherapy schedule for high-risk medulloblastoma patients of 3 years or more consists of standard dose regimen of 36 Gy CSI with a boost to both the posterior fossa and focal sites of metastasis of 55.8 Gy. Adjuvant chemotherapy, consisting of concurrent vincristine followed by maintenance chemotherapy with Lomustine, Vincristine, and Cisplatin has shown progression-free survival of 67% in M1, M2 and M3 stage [66, 80]. Outcomes for highrisk patients are equally poor even with inclusion of some neoadjuvant agents in addition to conventional chemotherapeutic agents [81–83].

#### *10.3.3. Treatment of infants and children <3 years of age*

As patients younger than 3 years are in risk of poor outcome of neurocognitive function following CSI, delay or omission of radiotherapy is recommended for this group of patients. M0 patients following gross total resection have commendable outcome with only chemotherapy after surgery [84].

#### *10.3.4. Radiation hazards*

may serve as a pathway of dissemination of the medulloblastoma, which has a tendency to spread by the CSF pathways. The use of millipore filters has been described to prevent

Clinical or subclinical venous air embolism, which is more common in sitting position, can happen in the prone position as well. With the goal of complete resection, major complications during tumor removal are usually caused by damage to the brain stem and injury to the lower cranial nerves. Aspiration pneumonia and respiratory failure often follows if the post-operative lower cranial nerve injuries are not handled meticulously. Though described frequently, cerebellar mutism, a commonly described complication of posterior fossa surgery, is less likely to occur now a days with microsurgical techniques. Meningitis, pseudomeningocele, postoperative tumor bed hematoma, epidural hematoma, subdural hematoma are

Radiotherapy has been an adjunct of the treatment modality for medulloblastomas since the early twentieth century as these tumors are very responsive to radiotherapy. The survival rate has improved dramatically after the introduction of radiotherapy. Post-operative craniospinal irradiation (CSI) with or without boost to the posterior fossa are the customary protocol,

Post-operative radiotherapy dose for average risk medulloblastoma patients aged ≥3 years initially was set as 36 Gy CSI and 54 Gy boost for the posterior fossa (PF) because of high risk of local recurrence. Dose adjustment to 23.4–24 Gy CSI with the addition of adjuvant chemotherapy has been made with successful result [66, 73, 74]. Reduction in the posterior fossa radiation volume, in the form of 3-Dimensional conformal radiotherapy (3D CRT) has enabled to restrict the boost volume to the tumor bed plus a margin without compromising local control that minimizes morbidity associated with full PF irradiation by shielding normal vital structures [74–76]. Intensity-modulated radiotherapy (IMRT) or proton beam therapy

The usual radiotherapy schedule for high-risk medulloblastoma patients of 3 years or more consists of standard dose regimen of 36 Gy CSI with a boost to both the posterior fossa and focal sites of metastasis of 55.8 Gy. Adjuvant chemotherapy, consisting of concurrent vincristine followed by maintenance chemotherapy with Lomustine, Vincristine, and Cisplatin has shown progression-free survival of 67% in M1, M2 and M3 stage [66, 80]. Outcomes for highrisk patients are equally poor even with inclusion of some neoadjuvant agents in addition to

similarly can reduce exposure to the heart and liver during CSI [72, 77–79].

dissemination [26, 70].

150 Brain Tumors - An Update

**10.3. Radiotherapy**

as chosen by different centers [8, 72].

*10.2.1. Complications of surgery*

among the other less often encountered complications.

*10.3.1. Treatment for average-risk patients ≥3 years of age*

*10.3.2. Treatment for high-risk patients ≥3 years of age*

conventional chemotherapeutic agents [81–83].

The long-term sequelae of radiation therapy are well described, among which the most common ones are endocrinopathies, neurocognitive and neurosensory impairment following craniospinal irradiation depending on age of patient and radiation dose [85, 86]. Cancer survivors with a history of cranial irradiation have more tendency to have cerebrovascular disease and an increased risk of second malignancies in the radiation field [6]. Skin reactions, hair loss, growth problems, nausea and vomiting, chronic otitis media and/or otitis externa, myelosuppression are other commonly encountered side effects [71].

#### **10.4. Chemotherapy and combined radio-chemo therapy**

As medulloblastoma is a highly radiosensitive tumor, chemotherapy for this formidable tumor has been an adjunct in the treatment strategy for years. Various combinations of chemotherapeutic agents are used in conjunction with radiotherapy. The toxic effect of different chemotherapeutic agents have forced their use to be restricted in different circumstances. Now a days, the newer drugs are more soothing to the patients with better acceptability, tolerance and efficacy.

Penetrability of the blood-brain barrier of a drug is the most important feature for a chemotherapeutic agent to be a worthy regimen for brain tumors. Vincristine, Cisplatin, Cyclophosphamide, Lomustine, Etoposide, Methotrexate, Temozolomide, and Carboplatin are the commonly used effective chemotherapeutic agents for medulloblastomas [8, 87].

For average-risk medulloblastoma patients two common chemotherapy regimens are practiced. One is with a combination of Cisplatin, Lomustine, and Vincristine, while the second one comprises of a combination of Cisplatin, Cyclophosphamide, and Vincristine. These two regimens do not have significant difference in outcome regarding event-free survival (EFS) and overall survival (OS) [68]. Among conventional chemotherapeutics, Temozolomidecontaining regimens have shown most promising activity. Two studies, one in monotherapy [88] and another in combination with Irinotecan [89], have shown the best results in a relatively large population, although follow up for disease-free survival is short. Its tolerable toxicity profile and synergies with other chemotherapeutics and targeted agents make it an attractive compound to serve as backbone for new strategies [20].

As children under the age of 3 years has worse long term cognitive effects, they are not commonly treated with the radiotherapy. To compensate this more intense chemotherapy is initiated instead [87]. In the last few decades, with the intension to avoid radiation and to have an equally better outcome in younger patients, protocols have been developed consisting of intense systemic chemotherapy, followed by a consolidation cycle with myeloablative chemotherapy along with autologous stem cell rescue (AuHCR) as an alternative management in these patients under the age of 3 years [90]. The 5 year EFS and OS varies between patients with localized disease, and patients with disseminated disease as well as between patients with desmoplastic, classical and anaplastic MB [91].

bone marrow, lymph nodes, and viscera. Though very rare, metastasis to skin, liver, lung,

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Surveillance is important as relapses encountered on surveillance imaging can be better dealt with and show improved survival as paralleled to those identified by reemergence of the clinical symptoms [108]. Though consensus about the schedule is debated, generally clinical and radiographic follow-up is recommended at three-month intervals during the first year after completion of scheduled therapy, at three to four-month intervals in the second year, every 6 months during the third year, and annually thereafter [109–112] (**Figure 6**). It is generally

**Figure 6.** Preoperative contrast enhanced MRI in sagittal (A), axial (C) and coronal (E) planes and 1 year post-operative contrast enhanced MRI following radiotherapy in sagittal (B), axial (D) and coronal (F) planes of a 9 years old boy.

mediastinum and retroperitoneal structures has also been reported [8, 9].

**13. Surveillance**

#### *10.4.1. Side effects of chemotherapy*

Adverse effects of adjuvant chemotherapy have been significant and needs to be modified in a good number of patients because of adverse reactions [92, 93]. The commonnest side effect of chemotherapy is hematologic toxicity in the form of leukothrombocytopenia. Other common adverse effects being anemia, somnolence, peripheral neuropathy, headaches, constipation, paresthesias, mucositis, nausea and vomiting, immune compromise and bone marrow suppression, renal toxicities with electrolyte abnormalities, hepatotoxicity, infertility [8, 71]. Some drugs carry the risk of development of treatment-related cancers which is 4.2% at 10 years [94]. Vincristine and cisplatin is known to cause various types of neurotoxicity particularly peripheral neuropathy and ototoxicity [95].

#### **11. Recurrence**

The majority of treatment failures develop within the first 2–3 years, and then the failure rate tends to decrease. Tumor recurrence occurs most frequently in the posterior fossa and that may or may not be associated with subarachnoid dissemination in the craniospinal axis [8, 9]. Inadequate post-operative dose of the radiotherapy and large volume of residual tumor are the major causes of recurrence. Commonly the outcomes in patients with relapsed disease are grave, with fiveyear survival rate of only about 25% and which has not improved much, even with development in treatment strategies [96–98]. Repeat surgical resection, re-irradiation, stereotactic radiosurgery, high-dose chemotherapy with AuHCR, low-dose oral Etoposide, the use of biologically targeted agents, singly or in combination, have been tried and success in control was more for localized recurrence than for disseminated recurrence [97–107]. At recurrence medulloblastomas often change towards a more anaplastic pathological variant. Interestingly Shh tumors tend to recur locally while Groups 3 and 4 recur almost entirely with metastases [10, 20, 44].

#### **12. Metastasis**

Medulloblastomas exhibit a strong propensity to metastasize through CSF pathways and tend to form tumors of variable size along ventricular surfaces, in subarachnoid space, or along nerve roots or may grow en plaque on surface of brain or spinal cord or may deposit in the ventricles [25]. Dissemination through the CSF route may be augmented by ventricular or spinal punctures or by manipulations of the lesion during operation. VP shunting has frequently been reported to cause extraneural metastases to the peritonium. Invasion of the meninges is not very uncommon [2, 9]. Extra CNS metastases have been reported to be in the bone marrow, lymph nodes, and viscera. Though very rare, metastasis to skin, liver, lung, mediastinum and retroperitoneal structures has also been reported [8, 9].
