**16. Newer therapies/future**

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

Medulloblastoma is much less common in adults, accounting for less than 1% - 3% of primary CNS tumors [24, 113, 114]. The annual incidence of medulloblastoma is 1–1.5 cases per million in the general adult population and 80% occur before the end of the fourth decade [24, 113–115]. Treatment protocols are limited for adults and they are treated by heterogeneous ways using various chemo-radiotherapy regimens with surgery with post-operative CSI being the mainstay of treatment [115]. As late relapse is common among adult medulloblastoma patients, long-term follow-up is warranted. Spinal seeding at presentation is a poor prognostic factor for recurrence [114, 115]. Adult medulloblastomas are clinically similar to that in the pediatric population, but lateral location and desmoplastic type is more frequent in adults as opposed to the pediatric age group. Adult medulloblastomas are thus, more amenable to complete resection and better outcome is expected because of their locations and histopathological variants respectively [24, 113–116]. Relapse following complete treatment is relatively late in adults as compared to children and they have a relatively prolonged time from relapse to death [116]. As most treatment recommendations for adults are extrapolated from the experience in pediatric patients, a protocol from the time of diagnosis includes: increasing the intensity to identify metastasis; increasing the radiotherapy dose to the primary site; adding chemotherapy following radiotherapy in medically fit patients; and following-up the patients

Though the outcomes need to be judged cautiously because of the marked heterogeneity between studies, overall outcome of medulloblastoma patients has improved tremendously over the last decades. Still, outcome in a good number of patients with metastatic disease, adverse molecular or cytogenetic features, infants and relapsed or refractory patients remains

Many factors play role in outcome of medulloblastoma patients and outcomes have been variable in different series. The outcome has gradually improved from survival from onset to death of 8–9 months in 1930s to 54% 3-year survival in 1950s, about 75% 5-year survival in 1980s [71]. Till the last decade the five-year EFS and OS has raised to 81 ± 2.1 and 86 ± 9%, respectively [68]. Among the factors that play role in poor outcome, the noteworthy are younger age, larger residual tumor volume after surgery, inadequate dose of radiotherapy, presence of metastatic disease at diagnosis, presence of hydrocephalus, anaplastic or large cell histology, insufficient chemotherapy, MYC amplification or expression, 17p loss or 1q gain, and tumors of

with PET or bone scan every 6 months for at least 3 years [117, 118].

treated with craniospinal irradiation [6].

154 Brain Tumors - An Update

**14. Medulloblastoma in adults**

**15. Outcome**

depressing.

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

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 Irinotecan in a study with short follow-up has shown to have good prospect with a DCR of 73% [89]. Trials with multiagent oral antiangiogenic regimen like Bevacizumab, Cilengitide, Lenalidomide and Thalidomide either in monotherapy or in combination with Vincristine, Irinotecan, Temozolomide or Temsirolimus in patients with medulloblastoma yielded only short-lasting disease stabilizations with a tolerable toxicity profile [132–137].

educational assistance for the children who survive the multi-modality therapy [71]. Optimum therapy has led to long-term survival in patients of medulloblastoma and it is expected to be increased with time with the anticipated need of more intense and dedicated rehabilitation regime for this group of patients. Thus the long-term survivors of medulloblastoma badly require multifaceted medical rehabilitation care involving team of subspecialists including oncologist, neurologist, endocrinologist, psychologist, psychiatrist and physiotherapist to

Medulloblastoma

157

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

Medulloblastomas have been neurosurgeons' nightmare for years. MB, a highly aggressive tumor of the cerebellum, treated with a combination of surgery, craniospinal irradiation and chemotherapy, still remains a challenge. Enriched knowledge of histological and molecular subgroups with their aberrant signaling pathways has provided novel therapeutic targets for MB to regress their growth and has enhanced both the prognostic and therapeutic implications. Efforts to modify and refine the MB treatment strategy are ongoing as toxicity and off-target effects of various newer drugs are yet not under total control. Regardless of marked advancements in overall survival for medulloblastoma patients over the past decades, substantial successes remain to be achieved, especially concerning improvement in survival, mitigating treatment-related morbidities as well as improving quality of life for survivors. These have led to modifications of therapies and research, with the emphasis on novel, less toxic and more targeted agents for the best possible survival with least long-term adverse consequences for a worthwhile post-therapy quality of life. The combination of molecular pharmacology, neurogenetics, cell biology, and biophysics will ultimately drive the utmost hope of a cure for medulloblastoma. With the advancement of modern research, medulloblastoma, once a

overcome the challenges that they have to face in the longer run [8, 64].

dreaded and hopeless entity, is looming to be a potentially curable disease.

I am very grateful to my colleagues Dr. Abu Saleh Mohammad Abu Obaida and Dr. Muhtamim Chowdhury for their critical advices in preparing this chapter. I am immensely indebted to my colleague Dr. Nazmin Ahmed for her beautiful schematic diagrams that have made this

Department of Neurosurgery, Bangabandhu Sheikh Mujib Medical University, Shahbag,

**18. Conclusion**

**Acknowledgements**

chapter colorful.

**Author details**

Asifur Rahman

Dhaka, Bangladesh

Address all correspondence to: bijoun14@yahoo.com

Tyrosine kinase inhibitors (TKIs) like imatinib, sorafenib, lapatinib, nilotinib, dasatinib, ponatinib and bafetinib have shown to block the migration and invasion properties of MB cells which may prove to be effective alternative agents in the treatment of medulloblastomas [128].

In order to reduce treatment related side effects, newer radiotherapy techniques are being evaluated. IMRT and helical tomotherapy have been evaluated, but results were not very pleasing [24].

Immunotherapy is another novel therapeutic approach that is being evaluated for the treatment of medulloblastoma. The target antigens that have been identified are cancer testis antigens (CTAs), MAGE and GAGE proteins. MAGE-4, MAGE-A and GAGE expression have been found in 50, 62 and 84% of medulloblastomas respectively [138, 139]. MAGE antigens, are a promising targets for immunotherapy in patients with medulloblastoma as it has paved the way of immunotherapy already by targeting successfully in some other tumors [140, 141]. Vaccinations against EGFRvIII in combination with GM-CSF, is another potential immunotherapeutic approach, which have already been tested in other brain tumors [142].

In the post-surgery treatment process, delivery of anticancer drugs across the BBB remains a challenge. A number of methods have been tried to facilitate effective drug delivery across the BBB to the brain. Of those, a very promising technique is Nanoparticles (NP) encapsulating magnetic materials such as iron oxide. Upon entering the systemic circulation, through NPs a drug can be directed remotely to the disease site. The addition of receptor-specific ligands to magnetic NPs for active targeting can significantly increase their efficacy [128].
