Temozolomide with irinotecan versus temozolomide, irinotecan plus bevacizumab for recurrent medulloblastoma of childhood: Report of a COG randomized Phase II screening trial

Medulloblastoma patients receive adapted therapies stratified according to their risk-profile. Favourable, standard, and high disease-risk groups are each defined by the status of clinical and pathological risk factors, alongside an evolving repertoire of diagnostic and prognostic biomarkers. Medulloblastoma clinical trials in Europe are coordinated by the International Society for Paediatric Oncology (SIOP-Europe) brain tumour group. Favourable and standard-risk patients are eligible for the SIOP-PNET5-MB clinical trial protocol. In contrast, therapies for high-risk disease worldwide have, to date, encompassed a range of different treatment philosophies, with no clear consensus on approach. Higher radiotherapy doses are typically deployed, delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. However, trials to date in high-risk medulloblastoma have commonly been institutional or national, based on modest cohort sizes, and have not evaluated the relative performance of different strategies in a randomised fashion. We describe the concepts and design of the SIOP-E high-risk medulloblastoma clinical trial (SIOP-HR-MB), the first international biomarker-driven, randomised, clinical trial for high-risk medulloblastoma. SIOP-HR-MB is programmed to recruit >800 patients in 16 countries across Europe; its primary objectives are to assess the relative efficacies of the alternative established regimens. The HR-MB patient population is molecularly and clinically defined, and upfront assessments incorporate a standardised central review of molecular pathology, radiology, and radiotherapy quality assurance. Secondary objectives include the assessment of (i) novel therapies within an upfront ‘window’ and (ii) therapy-associated neuropsychology, toxicity, and late effects, alongside (iii) the collection of materials for comprehensive integrated studies of biological determinants within the SIOP-HR-MB cohort.

Section: Relapse Management and Introduction Of Novel Therapiesmentioning

confidence: 99%

Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial

Bailey

André

Gandola

et al. 2022

“…Approximately one-third of all patients diagnosed with medulloblastoma in childhood and adolescence develop a progression or a relapse during and after first-line treatment [1][2][3]. Primary medulloblastoma is currently treated with maximal safe resection, chemotherapy, and cranio-spinal irradiation (CSI) in patients old enough to tolerate CSI [4,5].…”

Section: Introductionmentioning

confidence: 99%

“…While primary therapy is well established and follows distinct guidelines, therapy at recurrence is not standardized [6]. Current curative strategies for relapse therapy include resection, re-irradiation, conventional and high-dose chemotherapy regimens, and metronomic antiangiogenic multi-agent therapy [3,7,8]. Despite these aggressive treatment approaches, patients with recurrent medulloblastomas have a poor prognosis with long-term overall survival rates less than 10%.…”

Section: Introductionmentioning

confidence: 99%

Local and Systemic Therapy of Recurrent Medulloblastomas in Children and Adolescents: Results of the P-HIT-REZ 2005 Study

Gaab¹,

Adolph²,

Tippelt³

et al. 2022

Recurrent medulloblastomas are associated with survival rates <10%. Adequate multimodal therapy is being discussed as having a major impact on survival. In this study, 93 patients with recurrent medulloblastoma treated in the German P-HIT-REZ 2005 Study were analyzed for survival (PFS, OS) dependent on patient, disease, and treatment characteristics. The median age at the first recurrence was 10.1 years (IQR: 6.9–16.1). Median PFS and OS, at first recurrence, were 7.9 months (CI: 5.7–10.0) and 18.5 months (CI: 13.6–23.5), respectively. Early relapses/progressions (<18 months, n = 30/93) found mainly in molecular subgroup 3 were associated with markedly worse median PFS (HR: 2.34) and OS (HR: 3.26) in regression analyses. A significant survival advantage was found for the use of volume-reducing surgery as well as radiotherapy. Intravenous chemotherapy with carboplatin and etoposide (ivCHT, n = 28/93) showed improved PFS and OS data and the best objective response rate (ORR) was 66.7% compared to oral temozolomide (oCHT, n = 47/93) which was 34.8%. Intraventricular (n = 43) as well as high-dose chemotherapy (n = 17) at first relapse was not related to a significant survival benefit. Although the results are limited due to a non-randomized study design, they may serve as a basis for future treatment decisions in order to improve the patients’ survival.

“…For patients with r/rMB, median EFS and OS were 5 and 11 months, respectively, in the two-drug regimen,; 10 and 19 months, respectively, in the three-drug regimen. Based on the initial study aims, the authors concluded that the three-drug regimen significantly reduced the risk of death in r/rMB (one-sided p = 0.024) and warranted further investigation [ 146 ].…”

Section: Treatment Modalities and Considerationsmentioning

confidence: 99%

“…Of the conventional chemotherapy regimens, temozolomide, TOTEM, TEMRI, and temozolomide/irinotecan and bevacizumab, are the most frequently utilised regimens, typically well tolerated, albeit with an increasing number of potential side-effects, respectively. Phase II trial data are available for all these regimens and report comparable prolongation of survival [ 7 , 146 , 149 , 156 ]. Finally, metronomic therapy, such as MEMMAT and COMBAT regimens, are well tolerated, with early reports of benefit.…”

Section: Treatment Modalities and Considerationsmentioning

confidence: 99%

Relapsed Medulloblastoma in Pre-Irradiated Patients: Current Practice for Diagnostics and Treatment

Hill

Plasschaert

Timmermann

et al. 2021

Relapsed medulloblastoma (rMB) accounts for a considerable, and disproportionate amount of childhood cancer deaths. Recent advances have gone someway to characterising disease biology at relapse including second malignancies that often cannot be distinguished from relapse on imaging alone. Furthermore, there are now multiple international early-phase trials exploring drug–target matches across a range of high-risk/relapsed paediatric tumours. Despite these advances, treatment at relapse in pre-irradiated patients is typically non-curative and focuses on providing life-prolonging and symptom-modifying care that is tailored to the needs and wishes of the individual and their family. Here, we describe the current understanding of prognostic factors at disease relapse such as principal molecular group, adverse molecular biology, and timing of relapse. We provide an overview of the clinical diagnostic process including signs and symptoms, staging investigations, and molecular pathology, followed by a summary of treatment modalities and considerations. Finally, we summarise future directions to progress understanding of treatment resistance and the biological mechanisms underpinning early therapy-refractory and relapsed disease. These initiatives include development of comprehensive and collaborative molecular profiling approaches at relapse, liquid biopsies such as cerebrospinal fluid (CSF) as a biomarker of minimal residual disease (MRD), modelling strategies, and the use of primary tumour material for real-time drug screening approaches.