Medulloblastoma in children and adolescents: a systematic review of contemporary phase I and II clinical trials and biology update

Abstract

Survival rates for patients with medulloblastoma have improved in the last decades but for those who relapse outcome is dismal and new approaches are needed. Emerging drugs have been tested in the last two decades within the context of phase I/II trials. In parallel, advances in genetic profiling have permitted to identify key molecular alterations for which new strategies are being developed. We performed a systematic review focused on the design and outcome of early‐phase trials evaluating new agents in patients with relapsed medulloblastoma. PubMed, clinicaltrials.gov, and references from selected studies were screened to identify phase I/II studies with reported results between 2000 and 2015 including patients with medulloblastoma aged <18 years. A total of 718 studies were reviewed and 78 satisfied eligibility criteria. Of those, 69% were phase I; 31% phase II. Half evaluated conventional chemotherapeutics and 35% targeted agents. Overall, 662 patients with medulloblastoma/primitive neuroectodermal tumors were included. The study designs and the response assessments were heterogeneous, limiting the comparisons among trials and the correct identification of active drugs. Median (range) objective response rate (ORR) for patients with medulloblastoma in phase I/II studies was 0% (0–100) and 6.5% (0–50), respectively. Temozolomide containing regimens had a median ORR of 16.5% (0–100). Smoothened inhibitors trials had a median ORR of 8% (3–8). Novel drugs have shown limited activity against relapsed medulloblastoma. Temozolomide might serve as backbone for new combinations. Novel and more homogenous trial designs might facilitate the development of new drugs.

Phase II study of temozolomide and topotecan (TOTEM) in children with relapsed or refractory extracranial and central nervous system tumors including medulloblastoma with post hoc Bayesian analysis: A European ITCC study

“…Overall, temozolomide continues to be used in medulloblastoma treatment protocols as reviewed by Bautista et al and demonstrated by trials with various temozolomide combinations in salvage protocols and the addition of the agent in front‐line regimens (NCT00936156). The temozolomide‐topotecan combination results in similar activity to other combinations in children with heavily pretreated medulloblastoma with a favorable toxicity profile and will therefore likely be utilized further in front‐line or other salvage therapies.…”

Mixed signals from the cell's antennae: primary cilia in cancer

“…Looking at the extensive list of studies linking PC, Hh signaling, and tumorigenesis, it is not surprising that this pathway became an interesting cancer drug target. Smo inhibitors are FDA‐approved for treatment of advanced BCC and tested in clinical trials in medulloblastoma patients . The success of those therapeutics was, however, limited due to the development of drug resistance.…”

Salvage therapy for progressive, treatment-refractory or recurrent pediatric medulloblastoma: a systematic review protocol

“…Reviewers will develop a comprehensive data extraction form on Microsoft Excel, as guided by Covidence's piloting forms, and data collection forms for RCTs by Cochrane Training, in addition to several peer-reviewed systematic reviews and protocols [36][37][38][39][40][41]. An initial calibration test will be conducted (AAA, SKS) on a set of 5 randomly selected articles and 5 randomly selected clinical trials to ensure high inter-rater agreement; the latter will compare manual and automatic data extraction methods (using Extracting Accurate efficacy and safety information from ClinicalTrials.gov, EXACT) [42].…”