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

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Abstract

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 here 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

25 patients were included, with a median age of 11.4 years; 8 had metastases. According to 2016–2021 WHO-classification, 14 had SHH subgroup tumors(six TP53 mutated,one + MYC,one + NMYC amplification), 11 non-WNT/non-SHH (two with MYC/MYCN amplification).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 nine, distant-DR in 14, LR + DR in two) was 26 months. Fourteen patients were re-operated, in five cases excising single DR-sites, thereafter three received CT, two after re-RT; out of 11 patients not re-operated, four had re-RT as first treatment and seven after CT. Re-RT was administered at median 32 months after first RT: focally in 20 cases, craniospinal-CSI in five. Median post-relapse-PFS/after re-RT was 16.7/8.2 months, while overall survival-OS was 35.1/23.9 months, respectively. Metastatic status both at diagnosis/relapse negatively affected outcome and re-surgery was prognostically favorable. PD after re-RT was however significantly more frequent in SHH (with a suggestive association with TP53 mutation, p = 0.050). We did not observe any influence of biological subgroups on PFS from recurrence while SHH showed apparently worse OS compared to non-WNT/non-SHH group.

Conclusions

Re-surgery + reRT can prolong survival; a substantial fraction of patients with worse outcome belongs to the SHH-subgroup.

Highlights

Medulloblastoma relapse occurs in 30% of patients and no standard therapeutic strategy exists. Surgical treatment of relapse may improve prognosis.

Reirradiation can prolong survival, however field 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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Data Availability

Data are available upon request sent to the first author.

References

  1. Gajjar A, Chintagumpala M, Ashley D et al (2006) Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol 7:813–820 https://doi.org/10.1016/S1470-2045(06)70867-1

    Article  PubMed  Google Scholar 

  2. Massimino M, Biassoni V, Gandola L et al (2016) Childhood medulloblastoma. Crit Rev Oncol Hematol 105:35–51. https://doi.org/10.1016/j.critrevonc.2016.05.012

    Article  PubMed  Google Scholar 

  3. Dufour C, Foulon S, Geoffray A et al (2021) Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase II trial PNET HR + 5. Neuro Oncol 23:1163–1172. https://doi.org/10.1093/neuonc/noaa301

    Article  CAS  PubMed  Google Scholar 

  4. Gandola L, Massimino M, Cefalo G et al (2009) Hyperfractionated accelerated radiotherapy in the Milan strategy for metastatic medulloblastoma. J Clin Oncol 27:566–571. https://doi.org/10.1200/JCO.2008.18.4176

    Article  CAS  PubMed  Google Scholar 

  5. Massimino M, Gandola L, Spreafico et al (2009) No salvage using high-dose chemotherapy plus/minus reirradiation for relapsing previously irradiated medulloblastoma. Int J Radiat Oncol Biol Phys 73:1358–1363. https://doi.org/10.1016/j.ijrobp.2008.06.1930

    Article  CAS  PubMed  Google Scholar 

  6. Sabel M, Fleischhack G, Tippelt S, SIOP-E Brain Tumour Group et al (2016) Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study. J Neurooncol 129:515–524. https://doi.org/10.1007/s11060-016-2202-1

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kieran MW, Chisholm J, Casanova M et al (2017) Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma. Neuro Oncol 19:1542–1552. https://doi.org/10.1093/neuonc/nox109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Slavc I, Mayr L, Stepien N, Gojo J et al (2022) Improved long-term survival of patients with recurrent Medulloblastoma treated with a “MEMMAT-like. Metronomic Antiangiogenic Approach Cancers (Basel) 14:5128. https://doi.org/10.3390/cancers14205128

    Article  CAS  PubMed  Google Scholar 

  9. Donovan LK, Delaidelli A, Joseph SK et al (2020) Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma. Nat Med 26:720–731. https://doi.org/10.1038/s41591-020-0827-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Winnicki C, Leblond P, Bourdeaut F, Pagnier A et al (2023 Feb) Retrospective National “Real Life” experience of the SFCE with the metronomic MEMMAT and MEMMAT-like protocol. J Clin Med 10(4):1415. https://doi.org/10.3390/jcm12041415

  11. Hill RM, Plasschaert SLA, Timmermann B et al (2021) Relapsed Medulloblastoma in Pre-Irradiated Patients: current practice for Diagnostics and Treatment. Cancers (Basel) 14:126. https://doi.org/10.3390/cancers14010126

    Article  CAS  PubMed  Google Scholar 

  12. Gaab C, Adolph JE, Tippelt S, Mikasch R et al (2022) Local and systemic therapy of recurrent Medulloblastomas in Children and Adolescents: results of the P-HIT-REZ 2005 study. Cancers (Basel). 14:471. https://doi.org/10.3390/cancers14030471

  13. Baroni LV, Freytes C, Fernández Ponce N et al (2021) Craniospinal irradiation as part of re-irradiation for children with recurrent medulloblastoma. J Neurooncol 155:53–61

    Article  PubMed  Google Scholar 

  14. Tsang DS, Sarhan N, Ramaswamy V et al (2019) Re-irradiation for children with recurrent medulloblastoma in Toronto, Canada: a 20-year experience. J Neurooncol 145:107–114. https://doi.org/10.1007/s11060-019-03272-2

    Article  CAS  PubMed  Google Scholar 

  15. Gupta T, Maitre M, Sastri GJ et al (2019) Outcomes of salvage re-irradiation in recurrent medulloblastoma correlate with age at initial diagnosis, primary risk-stratification, and molecular subgrou**. J Neurooncol 144:283–291. https://doi.org/10.1007/s11060-019-03225-9

    Article  CAS  PubMed  Google Scholar 

  16. Rao AD, Rashid AS, Chen Q et al (2017) Reirradiation for Recurrent Pediatric Central Nervous System Malignancies: a multi-institutional review. Int J Radiat Oncol Biol Phys 99:634–641. https://doi.org/10.1016/j.ijrobp.2017.07.026

    Article  PubMed  Google Scholar 

  17. Wetmore C, Herington D, Lin T, Onar-Thomas A, Gajjar A, Merchant TE (2014) Reirradiation of recurrent medulloblastoma: does clinical benefit outweigh risk for toxicity? Cancer 120:3731–3737. https://doi.org/10.1002/cncr.28907

    Article  PubMed  Google Scholar 

  18. Louis DN, Perry A, Wesseling P, Brat DJ et al (2021) The 2021 WHO classification of tumors of the Central Nervous System: a summary. Neuro Oncol 23:1231–1251. https://doi.org/10.1093/neuonc/noab106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lannering B, Rutkowski S, Doz F et al (2012) Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: results from the randomized multicenter HIT-SIOP PNET 4 trial. J Clin Oncol 30:3187–3193. https://doi.org/10.1200/JCO.2011.39.8719

    Article  PubMed  Google Scholar 

  20. Rutkowski S, von Hoff K, Emser A et al (2010) Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol 28:4961–4968. https://doi.org/10.1200/JCO.2010.30.2299

    Article  PubMed  Google Scholar 

  21. Ellison DW, Dalton J, Kocak M et al (2011) Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 121:381–396. https://doi.org/10.1007/s00401-011-0800-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Aldosari N, Bigner SH, Burger PC et al (2002) MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children’s Oncology Group. Arch Pathol Lab Med 126:540–544. https://doi.org/10.5858/2002-126-0540-MAMOAI

    Article  PubMed  Google Scholar 

  23. Schwalbe EC, Williamson D, Lindsey JC et al (2013) DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. Acta Neuropathol 125:359–371. https://doi.org/10.1007/s00401-012-1077-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Avula S, Peet A, Morana G, Morgan P, Warmuth-Metz M, Jaspan T (2021) European Society for Paediatric Oncology (SIOPE)-Brain Tumour Imaging Group. European Society for Paediatric Oncology (SIOPE) MRI guidelines for imaging patients with central nervous system tumours. Childs Nerv Syst 37:2497–2508. https://doi.org/10.1007/s00381-021-05199-4

    Article  PubMed  Google Scholar 

  25. Warren KE, Vezina G, Poussaint TY et al (2018) Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatric Neuro-Oncology committee. Neuro Oncol 20:13–23. https://doi.org/10.1093/neuonc/nox087

    Article  CAS  PubMed  Google Scholar 

  26. Durrleman S, Simon R (1989) Flexible regression models with cubic splines. Stat Med 8:551–561

    Article  CAS  PubMed  Google Scholar 

  27. Massimino M, Cefalo G, Riva D et al (2012) Long-term results of combined preradiation chemotherapy and age-tailored radiotherapy doses for childhood medulloblastoma. J Neurooncol 108:163–171. https://doi.org/10.1007/s11060-012-0822-7

    Article  CAS  PubMed  Google Scholar 

  28. Mayer R, Sminia P (2008) Reirradiation tolerance of the human brain. Int J Radiat Oncol Biol Phys 70:1350–1360. https://doi.org/10.1016/j.ijrobp.2007.08.015

    Article  CAS  PubMed  Google Scholar 

  29. Tsang DS, Laperriere NJ (2019) Re-irradiation for paediatric tumours. Clin Oncol (R Coll Radiol). 31:191–198. https://doi.org/10.1016/j.clon.2018.10.003

  30. Bakst RL, Dunkel IJ, Gilheeney S et al (2011) Reirradiation for recurrent medulloblastoma. Cancer 117:4977–4982. https://doi.org/10.1002/cncr.26148

    Article  PubMed  Google Scholar 

  31. Massimino M, Casanova M, Polastri D, Biassoni V, Modena P, Pecori E, Schiavello E, De Pava MV, Indini A, Rampini P, Bauer D, Catania S, Podda M, Gandola L (2013 Jul) Relapse in medulloblastoma: what can be done after abandoning high-dose chemotherapy? A mono-institutional experience. Childs Nerv Syst 29(7):1107–1112. https://doi.org/10.1007/s00381-013-2104-x

  32. Torres CF, Rebsamen S, Silber JH et al (1994) Surveillance scanning of children with medulloblastoma. N Engl J Med 330:892–895. https://doi.org/10.1056/NEJM199403313301303

    Article  CAS  PubMed  Google Scholar 

  33. Yalçin B, Büyükpamukçu M, Akalan N, Cila A, Kutluk MT, Akyüz C (2002) Value of surveillance imaging in the management of medulloblastoma. Med Pediatr Oncol 38:91–97. https://doi.org/10.1002/mpo.1278

    Article  PubMed  Google Scholar 

  34. Saunders DE, Hayward RD, Phipps KP, Chong WK, Wade AM (2003) Surveillance neuroimaging of intracranial medulloblastoma in children: how effective, how often, and for how long? J Neurosurg 99:280–286. https://doi.org/10.3171/jns.2003.99.2.0280

    Article  PubMed  Google Scholar 

  35. Minn AY, Pollock BH, Garzarella L et al (2001) Surveillance neuroimaging to detect relapse in childhood brain tumors: a Pediatric Oncology Group study. J Clin Oncol 19:4135–4140. https://doi.org/10.1200/JCO.2001.19.21.4135

    Article  CAS  PubMed  Google Scholar 

  36. Kumar R, Smith KS, Deng M et al (2021) Clinical outcomes and patient-matched molecular composition of relapsed Medulloblastoma. J Clin Oncol 39:807–821. https://doi.org/10.1200/JCO.20.01359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Garcia-Lopez J, Kumar R, Smith KS, Northcott PA (2021) Deconstructing Sonic hedgehog medulloblastoma: Molecular Subtypes, Drivers, and Beyond. Trends Genet 37:235–250. https://doi.org/10.1016/j.tig.2020.11.001

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by spontaneous donations from many Charities (Associazione Bianca Garavaglia ODV, Busto Arsizio; Con Lorenzo per Mano, Como; Bimbo tu, Bologna, Associazione Italiana per la Lotta al Neuroblastoma, Genova).

Author information

Authors and Affiliations

  1. Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, 20133, Italy

    Maura Massimino, Elisabetta Schiavello, Veronica Biassoni, Olga Nigro & Luna Boschetti

  2. Pediatric Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Sabina Vennarini, Francesca Colombo & Emilia Pecori

  3. Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University, Rome, Italy

    Francesca Romana Buttarelli, Manila Antonelli, Simone Minasi & Francesca Gianno

  4. Neurosurgery Department, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

    Paolo Ferroli & Marco Schiariti

  5. Neurosurgery, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy

    Carlo Giussani

  6. School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy

    Carlo Giussani

  7. Neuroradiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

    Alessandra Erbetta

  8. Neuroradiology Unit, IRCCS Policlinico S. Matteo, Pavia, Italy

    Luisa Chiapparini

  9. Department of Pediatric Onco-Hematology and Transfusion Medicine (EM), Ospedale Pediatrico Bambino Gesù, Roma, Italy

    Evelina Miele

  10. Laboratory of Genetics, S. Anna General Hospital, Como, Italy

    Piergiorgio Modena

  11. Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Loris De Cecco

  12. Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

    Bianca Pollo

  13. Department of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Francesco Barretta

Authors
  1. Maura Massimino
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  2. Sabina Vennarini
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  4. Manila Antonelli
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Contributions

Conceptualization: MM, SV, FB, FRB; Methodology: FB, MM, SV; Formal analysis: MM, SB, FB, FRB, MA, FC, SM, EP, ES, VB, ON, LB, FG, EM, PM, LDC, BP; Investigation: MM, SV, FB, FRB, LB, MA, SM; Resources: MM, SV, FB, FRB, LB, MA, SM; Data curation: MM, SV, FB, FRB, FC; Writing manuscript: All authors; Supervision: MM, SB, FB; Project administration: MM, SB, FB, FRB, LB; Funding acquisition: MM.

Corresponding author

Correspondence to Maura Massimino.

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The authors declare no competing interests.

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Maura Massimino and Sabina Vennarini equally contributed to this paper and are co-first authors.

Electronic supplementary material

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11060_2023_4361_MOESM1_ESM.png

Supplementary Material 1: Supplementary Fig. 1. Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) from first relapse and from the beginning of the radiotherapy at first relapse.

11060_2023_4361_MOESM2_ESM.png

Supplementary Material 2: Supplementary Fig. 2. Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) from first relapse and from the beginning of the radiotherapy at first relapse according to disease localization at primary diagnosis.

11060_2023_4361_MOESM3_ESM.png

Supplementary Material 3: Supplementary Fig. 3. Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) from first relapse and from the beginning of the radiotherapy at first relapse according to the presence of symptoms at first relapse.

11060_2023_4361_MOESM4_ESM.png

Supplementary Material 4: Supplementary Fig. 4. Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) from first relapse and from the beginning of radiotherapy at first relapse according to disease localization at first relapse.

11060_2023_4361_MOESM5_ESM.png

Supplementary Material 5: Supplementary Fig. 5. Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) from first relapse and from the beginning of the radiotherapy at first relapse according to patients’ MBL 2016–2021 WHO-classification.

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Massimino, M., Vennarini, S., Buttarelli, F.R. et al. Optimizing reirradiation for relapsed medulloblastoma: identifying the ideal patient and tumor profiles. J Neurooncol 163, 577–586 (2023). https://doi.org/10.1007/s11060-023-04361-z

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