A Holistic Review on the Current and Future Status of Biology-Driven and Broad-Spectrum Therapeutic Options for Medulloblastoma

With a thorough investigation of the etiology of medulloblastomas, a comprehensive review was done to categorize available clinical trials in order to discuss the future potential of breakthroughs in treatment options. The pertinent issues of medulloblastoma therapy with radiation being inapplicable to children under the age of 3, and therapies causing toxicity are detailed and discussed in the context of understanding how the current therapies may address these suboptimal treatment modalities. This study aggregated published studies from the US government clinical trials website and filtered them based on their direct treatment towards medulloblastomas. Thirty-two clinical trials were applicable to be analyzed and the treatment mechanisms were discussed along with the efficacy; molecular groupings of medulloblastomas were also investigated. The investigated therapies tend to target sonic hedgehog (SHH)-subtype medulloblastomas, but there is a necessity for group 3 subtype and group 4 subtype to be targeted as well. Due to the heterogeneous nature of tumor relapse in groups 3 and 4, there are less specified trials towards those molecular groupings, and radiation seems to be the main scope of treatment. Medulloblastomas being primarily a pediatric tumor require treatment options that minimize radiation to increase the quality of living in children and to prevent long-term symptoms of over radiation. Exploring symptomatic treatment with donepezil in children with combination therapies may be a potential route for future trials; immunotherapies seem to hold potential in treating patients reacting adversely to radiation therapy.


Introduction And Background
Medulloblastomas are classified as WHO grade IV malignant tumors occurring primarily in the cerebellum in pediatric patients; they vary in prognosis depending on the subtype of the tumor. Usually occurring in children under 16, a large majority of patients are under 10 [1].
Pediatric populations diagnosed with medulloblastomas comprise 15%-20% of all brain tumors [2]. Unfortunately, the quality of life for many of these children severely deteriorates despite high survival rates with aggressive chemotherapy, radiotherapy, and neurosurgery [3]. Due to the prevalence of medulloblastomas situated in the posterior fossa, they often rapidly metastasize into the cerebrospinal fluid and affect different parts of the brain, aside from the infratentorial region [4]. Surgical intervention can delay the metastasis of medulloblastomas; however, one or more neurological impairments are a common side effect in 25% of the population. Unfortunately, a familiar condition is posterior fossa syndrome which interferes with communicative activities and manifests into ataxia and hypotonia [5]. Thus, it has become imperative to assess combination therapies that may be used alongside traditional treatment protocols to delay treatment in younger children until they are three and thereby reduce neurological impairment.
The current treatment strategy for medulloblastomas, in children under three, consists primarily of surgery and chemotherapy and yields beneficial results in effectively reducing tumors. The best outcome has been observed with wingless (WNT)-activated medulloblastomas in the cohort of children under 16, but that statistic does not apply to children under five. However, for some subtypes of medulloblastoma, there remain high rates of diffuse metastasis [6]. Treatment in these aggressive situations results in a reduction in quality of survival for patients in terms of decreased intelligence quotient, while neuroendocrine side effects (i.e. growth hormone deficiency and hypothyroidism) generate a necessity for chronic symptomatic treatment [7]. Additionally as previously mentioned, ataxia and hypertonia can be side effects that will generate further medical complications requiring physical therapy, reduced muscle function, and difficulty in performing involuntary actions like swallowing. In this review, we initially focus on the subtypes of medulloblastomas and then review current treatment options, including immunotherapy, stem cell therapy, and pharmacological compounds.

Types of medulloblastoma
Medulloblastoma tumors are categorized into four subgroups by the Cancer Genome Atlas (WNT, sonic hedgehog (SHH), group 3, and group 4); in spite of current treatments, 30% of patients have a relapse which portends a poor outcome [8]. Any current treatment regimen is not equally effective against the different subgroups of medulloblastoma, and patients that survive past five years may face a recurrence of the disease [9]. Novel treatments are required for individualized subtypes of medulloblastomas since current protocols generalize patients with a similar treatment plan and leave patients with degenerative conditions as a result of long-term treatment toxicity [10].

Group 4
Group 4 medulloblastomas are the most common type and it is prevalent in males three times more frequently than in females [11]. Group 4, SHH-group, and group 3 tumors tend to originate from the intermediary area under the vermis of the cerebellum. Despite its frequency in patients, it is difficult to treat because the tumor metastasizes prior to diagnosis in 30%-40% of patients, which contributes to a low fiveyear survival rate of 60% [12,13]. Patients with group 3 tumors constitute a high-risk group compared to other sub-types as subtotal resection of the tumor during surgery increases the risk of disease progression, complicating the benefit of gross total or near-total resection [14]. Group 4 tumors have a high rate of recurrence as 30%-40% of patients are at high risk and the five-year survival for children is 60% while for adults there is a high degree of variability with a five-year survival between 45%-75% [15]. The 10-year survival rate is 36% for high-risk group four patients while for low-risk patients it is 72% and this is characterized by their chromosome 11 loss [16].

SHH-Group
SHH group medulloblastomas occur in both infants and adults and are the second most common subgroup. Treatment is a challenge because radiotherapy is highly debilitative in infants under 36 months and adults have a recurrence rate of 50%-60%, regardless of treatment intervention [17,18]. Adults make for difficult patients to treat as their medulloblastoma genomic profiles are very different in adult medulloblastomas and there is a connection between the amplification of CDK6 and rapidly terminal outcomes [19]. Due to the rarity of adult cases, pediatric regimens tend to be used as treatment protocol and prognosis is not ideal. SHH group tumors are conventionally found in the posterior fossa of the brain in the cerebral hemispheres [20]. This is due to SHH signaling being part of the morphogenesis and maintenance of neurons that form both hemispheres of the brain [21]. SHH-group medulloblastomas tend to happen in infants, and the 10year survival rate for infants is 77%, children have around 51% success, while for adults it is 35% [22].

Group 3
Group 3 tumors are the most aggressive and metastatic of the sub-types due to the amplification of the MYC gene, which causes tumorigenesis [23][24][25]. Unfortunately, due to the prognosis of this disease, outside of the conventional treatment of surgery and chemotherapy, there have yet to be targeted treatments developed for group 3 due to the heterogeneity in the nature of tumor recurrence [26]. Current treatments also include craniospinal irradiation for high-risk patients like those with group 3 medulloblastomas, but due to the slowed progression to metastasis, they can be ineffective [27]. 35%-45% of initial group-3 medulloblastoma survivors experience fatal relapse [28]. The 10-year survival rate for this medulloblastoma in infants is 39% and in children, it is 50% [29].

WNT-Group
WNT-activated medulloblastomas have the best prognosis of all the sub-groups; however, they are the least common type of medulloblastoma [30]. WNT signaling, especially when canonical, is associated with many types of cancers [31]. Due to its prevalent nature, the signaling pathway of WNT-activated tumors and metastatic cancers has been thoroughly researched to discover its role in immune evasion. Aberrations in the WNT pathway (i.e., hyperactivation of WNT resulting in medulloblastoma tumors) result in an ideal tumor microenvironment as WNT ligands released by tumor cells bypass the host immune response [32]. Surgery and radiation tend to improve the prognosis for children towards a 10-year survival ≥ 95% when compared to the other subtypes of medulloblastomas [33].

Current therapies available and potential of clinical trials
Standard care of treatment is generally successful to some extent in patients with more common subtypes, and it is primarily a combination of surgery, radiotherapy, and chemotherapy. There are many clinical trials assessing the efficiency of combinations of currently approved treatments, but many patients are more interested in knowing about their clinical trial options, especially at the time of relapse.
For examining the current clinical trials for medulloblastomas, the US government clinical trials website (ClinicalTrials.gov) database was utilized and filtered using the following: medulloblastoma therapies, active, recruiting, enrolling by invitation, and completed studies. The inclusion criteria were comprehensive of both systemic therapies; radiation or surgery-based studies were also considered. Terminated, withdrawn, and unknown status studies were excluded. Of the 82 studies available for medulloblastomas, 32 matched the listed criteria. Treatments with preliminary or interim positive results were grouped based on the type of therapy and mechanisms of action; the preliminary results and the potential of the therapy for medulloblastomas were then summarized and discussed ( Table 1).  Many of the oncolytic virus and vaccine immunotherapies with radiotherapy are still in the trial stage, but it seems that of the three categories, immunotherapies seem to be the future of medulloblastoma treatment [44]. There are many types of viruses that may initiate gliomas, and there is evidence suggesting that measles, myxoma virus, picornavirus, and cytomegalovirus can be involved in the case of medulloblastomas [45][46][47][48].
Natural killer cell therapy represents another type of immunotherapy that has been speculated to hold a strong potential for therapy due to strong in vitro results [49]. But the only trial available identified as NCT02271711 does not demonstrate or notify of any results related to the trial [50]. Another therapy, G207 HSV viral therapy or herpes viral therapy with radiation, identified as NCT02457845, demonstrated an increased count for lymphocytes targeting tumor cells. The therapy alone was not effective for aggressively chronic conditions, but combinations can be explored [51] ( Table 2).  NCT00004078 [72][73] Oxaliplatin and Irinotecan Mechanism: Oxaliplatin is a neurotoxic chemotherapeutic and has been shown to cause a large portion of patients to demonstrate chemotherapy-induced peripheral neuropathy. The drug is very potent and aggressive and there are not much clinical data on its efficiency for reducing CNS tumor cell growth.
NCT00101270 [74] Lenalidomide Pediatric patients with CNS tumors tolerated this drug and short-term toxicity was not seen. However, this compound is effective when increasing the dosage to the maximum of 116 mg/m2/d. In vitro studies have shown that this compound suppresses glioma cell growth and has the potential to be used in brain tumor treatment. Medulloblastoma-specific trials have not been conducted yet.
NCT00100880 [75][76] Valproic Acid In broad CNS condition trials determining toxicity, only partial and minor responses were seen in 2 patients out of 16. NCT00107458 [77] Donepezil With

Previous Radiation Therapy
Donepezil is primarily used to treat symptoms of dementia in patients with Alzheimer's by replenishing neurotransmitters. One Phase III trial results demonstrated positive maintenance of memory, motor speed, and dexterity in patients with CNS tumors. A pilot study assessing the effects on pediatric brain tumors has favorable findings as cognitive functions showed an improvement.
NCT00452868 [78][79] Arsenic Trioxide Arsenic trioxide acts as a radiosensitizer in solid tumors, and this result has been seen with pediatric SHH-subtype cell lines. This treatment holds potential for becoming protocol as it increases the efficiency of conventional therapy for other types of tumors.

NCT00024258 [80]
Busulfan Busulfan is an alkylating agent that attaches to DNA strands of the cancerous cell and prevents further division. There have been positive results in some trials. One of which saw no toxic death but saw hepatic veno-occlusive disease which was manageable.
NCT00006246 [81][82]  Many of the trials solely used one pharmacological compound paired with surgical resection and radiation therapy. The type of radiation therapy available at the location and time of the trials may have affected the results, but rather than that, combination therapies seemed to be ideal for some trials. The mechanism of many of the drugs targets SHH-subtype medulloblastomas and cannot be used in broad-spectrum therapies.
For the increasing quality of life, donepezil seems to be a drug that may be useful for early intervention to delay symptoms in children under the age of five, however, the success of donepezil may be due to the combination with radiation. Donepezil is a cholinesterase inhibitor that increases the concentration of neurotransmitter acetylcholine in the brain, further inducing synaptic plasticity in the brain. Often relapses in WNT-activated medulloblastomas are a result of continuous aggressive treatment regimens which cause an accumulation of cyclophosphamide doses, but this is being improved with a stronger emphasis on abatement of both chemotherapy and radiation [83]. Other pharmacological interventions need to be used on a case-by-case basis to identify suitable or unsuitable combinations (Figure 1).

FIGURE 1: Comprehensive diagram of molecular mechanisms of potential therapies
CMV: cytomegalovirus; CAR T cell therapy: chimeric antigen receptor T cell therapy.
The image was created by the authors.

Discussion
From analyzing the results and current statuses of clinical trials associated with functional medulloblastoma treatment, it is plausible to state that SHH-subtypes are the most targeted; recurrent medulloblastoma patients are also a target. Children under three tend to be neglected for treatment options as combination therapies with radiation provide ideal outcomes. Immunotherapies with combination treatments may be suitable for protocol treatments for patients with specific profiles, and pharmacological compounds or stem cell therapy may be potential treatment avenues with promising results when done with conventional surgical resection and radiation therapy. These treatment options may also allow for children under three to avoid radiation therapy until they are of age.
Many of the treatments and clinical trials aim to target a plethora of CNS tumors rather than specifically targeting medulloblastomas. This may be due to the rarity of the condition or the lack of participation from the small subset of patients in experimental clinical trials, but this reduces the overall specificity of treatment for different types of medulloblastomas. Many completed clinical trials also did not report their study results in the form of a publication or data in the clinicaltrials.gov website which may indicate unfavorable data results.
When comparing the studies, it is essential to realize that combination therapies hold the most promise in these experimental treatment plans. There are some forward therapies which are used in older populations like vismodegib and others which simply target the SHH-group medulloblastomas and that can be seen with CX-4945 and arsenic trioxide in addition to vismodegib for pharmaceutical therapies. Immunotherapy holds promise as there is a genetic component of medulloblastomas; training the innate system to destroy the cancer cells, in addition to surgical resection and adaptive radiotherapy, seems to hold the most potential for widespread intervention protocol development as they attempt to minimize the complications that many pharmaceutical reagents can bring. Donepezil may also be helpful in pediatric patients who require radiation minimization for the quality of future development, but radiotherapy becomes essential with any of the therapy options offered in trials.

Conclusions
It is important to investigate individualized treatment plans in reference to the sub-type of medulloblastoma targeted. Future studies should also be comprehensive of international clinical studies as many data-recording platforms are not translated or exclusively demonstrate national studies. Doing so would allow for more clinical trial options for patients and their families. Children who are medulloblastoma survivors have a severe need for symptomatic treatment to preserve their cognitive and neuroendocrine functions. Since the pertinent issue is increasing length of survival, there should also be trials investigating the quality of survival through methods of combating impaired cognition and reducing radiotherapy. Since medulloblastoma treatment, especially when recurring, is mainly focused on increasing the quality of living while extending life expectancy, there are caveats in available treatments; experimental therapy consent becomes a sensitive issue for families when treating children. Prospective successful treatments may be a combination of chemotherapy, radiation, and immunotherapy post-surgical resection and the combination of chemotherapy and immunotherapy could be a sustained solution for children without radiation. This would allow many medulloblastoma survivors to have a more cognizant and independent experience of living as their developmental functions would not be toxically affected.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.