**13. Surveillance**

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

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 particu-

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].

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

with desmoplastic, classical and anaplastic MB [91].

larly peripheral neuropathy and ototoxicity [95].

*10.4.1. Side effects of chemotherapy*

152 Brain Tumors - An Update

**11. Recurrence**

**12. Metastasis**

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.

agreed that surveillance imaging of the brain should be complemented with full spinal MRI as it often might prove to be crucial and beneficial for the patient [110]. It is also recommended that, endocrine screening and neuropsychological testing be performed in those who were treated with craniospinal irradiation [6].

Group 3 or Shh subgroup with TP53 mutations. On the contrary, patients having monosomy 6, mutation of CTNNB1, and trkC expression demonstrate a favorable outcome [6, 9, 33, 41, 49, 59]. Generally, OS for children with medulloblastoma are reported as 50–60%, whereas for

Medulloblastoma

155

http://dx.doi.org/10.5772/intechopen.76783

The future of medulloblastoma treatment lies on the basis of its genetic coding and molecular subgroupings. A few drugs have been tested preliminarily and that made the researchers as well as the patients optimistic. Endeavor is going on to determine whether the intensity of treatment can be reduced safely, keeping the optimum efficacy, to mitigate the treatmentrelated long term developmental and cognitive morbidity without affecting survival rates, thus improving the quality of life for medulloblastoma survivors [6, 10]. The molecular biology of the subgroups have emerged to be the key elements of success in future and, with the early success and the potential utility of molecular biomarkers in prognostication and prediction, researchers are in search of more personalized and tailored therapies for the patients [8, 42, 49].

Of the different pathways of tumor origin and progression, the sonic hedgehog (Shh) pathway is a front-runner in research in this perspective. Smoothened (SMO), is an intriguing protein in developmental processes involving the hedgehog signaling pathway [120]. Assuming the role of SMO in the Shh pathway in tumorogenesis, molecules that target SMO are under intensive research and preliminary success have been achieved in some clinical trials [42, 121]. Of these, smoothened inhibitor Vismodegib showed promising result in studies with varying outcomes, having both short-term and long-lasting response, especially in standard-risk Shh medulloblastoma patients [122–125]. Trial with another SMO inhibitor Sonidegib, in cases of patients with relapsed disease also reveals promise for future [123]. Blocking GLI1 with Arsenic trioxide [126], combining SMO inhibitors with PI3K inhibitors [124], or inhibition of PIN1 by either Juglone or the flavonoids Epigallocatechin gallate and Quercetin [127], have attained certain levels of success as these aberrations are frequently encountered in this subset of patients [20]. Quercetin has been found to be a probable worthy radio-sensitizer [127]. Saridegib and Erismodegib are other potent SMO inhibitors under trial that seem to have

For Non-WNT/Non-SHH medulloblastomas comprising molecular subgroups 3 and 4, Gemcitabine, a nucleoside analog, and Pemetrexed, a folate antimetabolite are currently being investigated in combination to evaluate their role in prognosis [20, 49]. Combination of these two drugs have been found to be active, particularly against Group 3 medulloblastomas [129]. These were tried separately previously in medulloblastoma patients but only combination of Gemcitabine with Oxaliplatin was found to have promising results with a disease control rate (DCR) of 50% [130]. On the other hand, the combination of Vorinostat and Retinoic acid was found to have a 5-month disease stabilization in patients with Group 4 medulloblastomas [131].

Temozolomide-containing regimens are well tolerable and have good antitumor activity against relapsed/refractory medulloblastomas [20]. Evaluation of temozolomide and

potential in regression of tumor and inhibition of tumor progression [128].

average-risk and high-risk patients OS is 70–80 and 30–40% respectively [8, 119].

**16. Newer therapies/future**
