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

Gaab, Christine; Adolph, Jonas E; Tippelt, Stephan; Mikasch, Ruth; Obrecht, Denise; Mynarek, Martin; Rutkowski, Stefan; Pfister, Stefan M.; Milde, Till; Witt, Olaf; Bison, Brigitte; Warmuth‐Metz, Monika; Kortmann, Rolf‐Dieter; Dietzsch, Stefan; Pietsch, Torsten; Timmermann, Beate; Sträter, Ronald; Bode, Udo; Faldum, Andreas; Kwiecien, Robert; Fleischhack, Gudrun

doi:10.3390/cancers14030471

Cited by 13 publications

(26 citation statements)

References 39 publications

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“…All but 2 patients in our study had disease recurrence at distant central nervous system sites with or without disease in the original tumor bed, a pattern that is consistent with previous observations . Prior studies have shown that surgery in isolated medulloblastoma relapses was associated with improved survival, albeit with limited long-term success in patients who had previously received irradiation . To avoid denying patients with complete resection access to the study, MEMMAT allowed patients with recurrent medulloblastoma to undergo resection before enrollment, and maintaining NED after a gross total resection was considered a benefit of the treatment combination.…”

Section: Discussionsupporting

confidence: 87%

Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen

Peyrl,

Chocholous,

Sabel

et al. 2023

JAMA Oncol

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ImportanceMedulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen.ObjectiveTo evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]).Design, Setting, and ParticipantsThis phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021.InterventionsTreatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine.Main Outcomes and MeasuresThe primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety.ResultsOf the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia.Conclusions and RelevanceThis feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation.Trial RegistrationClinicalTrials.gov Identifier: NCT01356290

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Section: Discussionsupporting

confidence: 87%

Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen

Peyrl,

Chocholous,

Sabel

et al. 2023

JAMA Oncol

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“…As also observed by Bakst and Gaab in their publications and now also con rmed in multivariable analyses, surgery, whenever possible, also plays a role at relapse and should be performed [11,29]. The presence of symptoms at relapse correlated with a worse prognosis and therefore, implicitly, with a lower e cacy of re-RT, as observed by the Toronto group [13].…”

Section: Discussionsupporting

confidence: 51%

“…The use of reirradiation (re-RT) was mostly a palliative treatment until a few years ago. It has been implemented only in more recent times, due to the potential toxicity after rst line craniospinal irradiation (CSI) and doubtful e cacy especially after higher CSI doses and in the case of disseminated relapse [11][12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Optimizing reirradiation for relapsed medulloblastoma: identifying the ideal patient and tumor profiles

et al. 2023

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Background. First-line therapies for medulloblastoma(MBL) are obtaining higher survival-rates while decreasing late-effects, but treatment at relapse is not standardized. We report the experience with MBL re-irradiation(re-RT), its timing and outcome in different clinical settings and tumor groups.Methods. Patient's staging/treatment at diagnosis, histotypes/molecular subgroups, relapse site/s, re-treatments outcome are reported.Results. Patients were 25, median age 11.4 years, 8 had metastases, three LCA histotype. According to 2016-2021 WHOclassi cation, 14 had SHH subgroup tumors(6 TP53 mutated,1 + MYC and 1 + NMYC ampli cation), 11 non-WNT/non-SHH (2 with MYC/MYCN ampli cation).Thirteen had received HART-CSI, 11 standard-CSI, one HFRT; all post-radiation chemotherapy(CT), 16 also pre-RT. Median time to relapse (local-LR in 9, distant-DR in 14, LR+DR in two) was 26 months. Fourteen patients were re-operated, in 5 excising single DR-sites, thereafter 3 received CT, two after re-RT; out of 11 not reoperated patients, 4 had re-RT as rst treatment and 7 after CT. Re-RT was administered at median 32 months after rst RT: focally in 20 cases, CSI in 5, never resulting in radionecrosis. Median post-relapse-PFS/after re-RT were 16.7/8.2 months, while overall survival-OS were 35.1/23.9 months, respectively. Metastatic status both at diagnosis/relapse negatively affected outcome and re-surgery was prognostically favorable.MYC,MYCN,P53 status and molecular subgroups, RT extension/fractionation, gender and age were not statistically prognostic; in the multivariable model, OSs were positively in uenced by longer intervals before re-RT, re-surgery and not-SHH subgroups (P=0.019 from recurrence and 0.004 from second RT).Conclusions. Re-surgery+reRT can prolong survival; a substantial fraction of patients with worse outcome belongs to SHHsubgroup. HighlightsMedulloblastoma relapse occurs in 30% of patients and no standard therapeutic strategy exists. Surgical treatment of relapse may improve prognosis.Reirradiation can prolong survival but eld extension, doses and fractionation have not yet been determined.Relapsing patients with SHH subgroup medulloblastoma have a worse prognosis and may be preferentially treated with hypofractionated schedules.

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“…As a result, this approach has become a standard of care that is still used in some institutions. However, the role of high-dose chemotherapy in this setting has been eventually questioned by cooperative groups or in institutional reviews [77][78][79][80]. The recent evidence that medulloblastoma subgrouping influences survival both at the time of diagnosis and after recurrence suggests that most long-term survivors of early reports on high-dose chemotherapy were probably group 4 patients [81].…”

Section: Chemotherapy As a Salvage Treatmentmentioning

confidence: 99%

Evolution of Systemic Therapy in Medulloblastoma Including Irradiation-Sparing Approaches

Mushtaq,

Ul Ain,

Hamid

et al. 2023

Diagnostics

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The management of medulloblastoma in children has dramatically changed over the past four decades, with the development of chemotherapy protocols aiming at improving survival and reducing long-term toxicities of high-dose craniospinal radiotherapy. While the staging and treatment of medulloblastoma were until recently based on the modified Chang’s system, recent advances in the molecular biology of medulloblastoma have revolutionized approaches in the management of this increasingly complex disease. The evolution of systemic therapies is described in this review.

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

Cited by 13 publications

References 39 publications

Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen

Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen

Optimizing reirradiation for relapsed medulloblastoma: identifying the ideal patient and tumor profiles

Evolution of Systemic Therapy in Medulloblastoma Including Irradiation-Sparing Approaches

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