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How ten-years of reirradiation for paediatric high-grade glioma may shed light on first line treatment

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Abstract

Purpose

Recurrence incidence for paediatric/adolescent high-grade glioma (HGG) exceeds 80%. Reirradiation (reRT) palliates symptoms and delays further progression. Strategies for reRT are scarce: we retrospectively analysed our series to develop rational future approaches.

Methods

We re-evaluated MRI + RT plans of 21 relapsed HGG-patients, accrued 2010–2021, aged under 18 years. All underwent surgery and RT + chemotherapy at diagnosis. Pathologic/molecular re-evaluation allowed classification based on WHO 2021 criteria in 20/21 patients. Survival analyses and association with clinical parameters were performed.

Results

Relapse after 1st RT was local in 12 (7 marginal), 4 disseminated, 5 local + disseminated. Re-RT obtained 8 SD, 1 PR, 1PsPD, 1 mixed response, 10 PD; neurological signs/symptoms improved in 8. Local reRT was given to 12, followed again by 6 local (2 marginal) and 4 local + disseminated second relapses in 10/12 re-evaluated. The 4 with dissemination had 1 whole brain, 2 craniospinal irradiation (CSI), 1 spine reRT and further relapsed with dissemination and local + dissemination in 3/four assessed. Five local + disseminated tumours had 3 CSI, 1 spine reRT, further progressing locally (2), disseminated (1), n.a. (1). Three had a third RT; three were alive at 19.4, 29, 50.3 months after diagnosis. Median times to progression/survival after re-RT were 3.7 months (0.6–16.2 months)/6.9 months (0.6–17.9 months), improved for longer interval between 1st RT and re-RT (P = 0.017) and for non-PD after reRT (P < 0.001). First marginal relapse showed potential association with dissemination after re-RT (P = 0.081).

Conclusions

This is the biggest series of re-RT in paediatric HGG. Considering the dissemination observed at relapse, our results could prompt the investigation of different first RT fields in a randomized trial.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Fangusaro J (2012) Pediatric high grade glioma: a review and update on tumor clinical characteristics and biology. Front Oncol 2:1–10. https://doi.org/10.3389/fonc.2012.00105

    Article  Google Scholar 

  2. MacDonald TJ, Aguilera D, Kramm CM (2011) Treatment of high-grade glioma in children and adolescents. Neuro Oncol 13:1049–1058. https://doi.org/10.1093/neuonc/nor092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kline C, Felton E, Allen IE, Tahir P, Mueller S (2018) Survival outcomes in pediatric recurrent high-grade glioma: results of a 20-year systematic review and meta-analysis. J Neurooncol 137:103–110. https://doi.org/10.1007/s11060-017-2701-8

    Article  PubMed  Google Scholar 

  4. Sturm D, Pfister SM, Jones DTW (2017) Pediatric gliomas: current concepts on diagnosis, biology, and clinical management. J Clin Oncol 35:2370–2377. https://doi.org/10.1200/JCO.2017.73.0242

    Article  PubMed  Google Scholar 

  5. Cohen AR (2022) Brain tumors in children. N Engl J Med 386:1922–1931. https://doi.org/10.1056/NEJMra2116344

    Article  CAS  PubMed  Google Scholar 

  6. Hauser P (2021) Classification and treatment of pediatric gliomas in the molecular era. Children 8:739. https://doi.org/10.3390/children8090739

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lucas JT Jr, Cooper DA, Hwang S, Tinkle C, Li X, Li Y, Orr B, Merchant TE, Broniscer A (2017) Prognostic relevance of treatment failure patterns in pediatric high-grade glioma: is there a role for a revised failure classification system? Int J Radiat Oncol Biol Phys 99:450–458. https://doi.org/10.1016/j.ijrobp.2017.04.039

    Article  PubMed  PubMed Central  Google Scholar 

  8. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW (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 

  9. Grill J, Massimino M, Bouffet E, Azizi AA, McCowage G, Cañete A, Saran F, Le Deley MC, Varlet P, Morgan PS, Jaspan T, Jones C, Giangaspero F, Smith H, Garcia J, Elze MC, Rousseau RF, Abrey L, Hargrave D, Vassal G (2018) Phase II, open-label, randomized, multicenter trial (HERBY) of bevacizumab in pediatric patients with newly diagnosed high-grade glioma. J Clin Oncol 36:951–995. https://doi.org/10.1200/jco.2017.76.0611

    Article  CAS  PubMed  Google Scholar 

  10. Massimino M, Biassoni V, Miceli R, Schiavello E, Warmuth-Metz M, Modena P, Casanova M, Pecori E, Giangaspero F, Antonelli M, Buttarelli FR, Potepan P, Pollo B, Nunziata R, Spreafico F, Podda M, Anichini A, Clerici CA, Sardi I, De Cecco L, Bode U, Bach F, Gandola L (2014) Results of nimotuzumab and vinorelbine, radiation and re-irradiation for diffuse pontine glioma in childhood. J Neurooncol 118:305–312. https://doi.org/10.1007/s11060-014-1428-z

    Article  CAS  PubMed  Google Scholar 

  11. Massimino M, Gandola L, Luksch R, Spreafico F, Riva D, Solero C, Giangaspero F, Locatelli F, Podda M, Bozzi F, Pignoli E, Collini P, Cefalo G, Zecca M, Casanova M, Ferrari A, Terenziani M, Meazza C, Polastri D, Scaramuzza D, Ravagnani D, Fossati-Bellani F (2005) Sequential chemotherapy, high-dose thiotepa, circulating progenitor cell rescue, and radiotherapy for childhood high-grade glioma. Neuro Oncol 7:41–48. https://doi.org/10.1215/S1152851704000304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jones C, Karajannis MA, Jones DTW, Kieran MW, Monje M, Baker SJ, Becher OJ, Cho YJ, Gupta N, Hawkins C, Hargrave D, Haas-Kogan DA, Jabado N, Li XN, Mueller S, Nicolaides T, Packer RJ, Persson AI, Phillips JJ, Simonds EF, Stafford JM, Tang Y, Pfister SM, Weiss WA (2017) Pediatric high-grade glioma: biologically and clinically in need of new thinking. Neuro Oncol 19:153–161. https://doi.org/10.1093/neuonc/now101

    Article  CAS  PubMed  Google Scholar 

  13. Roux A, Pallud J, Saffroy R, Edjlali-Goujon M, Debily MA, Boddaert N, Sanson M, Puget S, Knafo S, Adam C, Faillot T, Cazals-Hatem D, Mandonnet E, Polivka M, Dorfmüller G, Dauta A, Desplanques M, Gareton A, Pages M, Tauziede-Espariat A, Grill J, Bourdeaut F, Doz F, Dhermain F, Mokhtari K, Chretien F, Figarella-Branger D, Varlet P (2020) High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts. Neuro Oncol 22:1190–1202. https://doi.org/10.1093/neuonc/noaa024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820. https://doi.org/10.1007/s00401-016-1545-1

    Article  PubMed  Google Scholar 

  15. Krauze AV, Peters C, Cheng J, Ning H, Mackey M, Rowe L, Cooley-Zgela T, Smart DD, Camphausen K (2017) Re-irradiation for recurrent glioma- the NCI experience in tumor control, OAR toxicity and proposal of a novel prognostic scoring system. Radiat Oncol 12:191. https://doi.org/10.1186/s13014-017-0930-9

    Article  PubMed  PubMed Central  Google Scholar 

  16. Navarria P, Minniti G, Clerici E, Tomatis S, Pinzi V, Ciammella P, Galaverni M, Amelio D, Scartoni D, Scoccianti S, Krengli M, Masini L, Draghini L, Maranzano E, Borzillo V, Muto P, Ferrarese F, Fariselli L, Livi L, Pasqualetti F, Fiorentino A, Alongi F, BuglionediMonale M, Magrini S, Scorsetti M (2019) Re-irradiation for recurrent glioma: outcome evaluation, toxicity and prognostic factors assessment. A multicenter study of the Radiation Oncology Italian Association (AIRO). J Neurooncol 142:59–67. https://doi.org/10.1007/s11060-018-03059-x

    Article  CAS  PubMed  Google Scholar 

  17. García-Cabezas S, Rivin Del Campo E, Solivera-Vela J, Palacios-Eito A (2021) Re-irradiation for high-grade gliomas: has anything changed? World J Clin Oncol 12:767–786. https://doi.org/10.5306/wjco.v12.i9.767

    Article  PubMed  PubMed Central  Google Scholar 

  18. Komori T (2021) The 2021 WHO classification of tumors, 5th edition, central nervous system tumors: the 10 basic principles. Brain Tumor Pathol. https://doi.org/10.1007/s10014-022-00428-3

    Article  PubMed  Google Scholar 

  19. Müller K, Scheithauer H, Pietschmann S, Hoffmann M, Rössler J, Graf N, Baumert BG, Christiansen H, Kortmann RD, Kramm CM, von Bueren AO (2014) Reirradiation as part of a salvage treatment approach for progressive non-pontine pediatric high-grade gliomas: preliminary experiences from the German HIT-HGG study group. Radiat Oncol 9:177. https://doi.org/10.1186/1748-717X-9-177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tsang DS, Oliveira C, Bouffet E, Hawkins C, Ramaswamy V, Yee R, Tabori U, Bartels U, Huang A, Millar BA, Crooks B, Bowes L, Zelcer S, Laperriere N (2019) Repeat irradiation for children with supratentorial high‐grade glioma. Pediatr Blood Cancer 66:e27881. https://doi.org/10.1002/pbc.27881

    Article  CAS  PubMed  Google Scholar 

  21. Rodriguez D, Calmon R, Aliaga ES, Warren D, Warmuth-Metz M, Jones C, Mackay A, Varlet P, Le Deley MC, Hargrave D, Cañete A, Massimino M, Azizi AA, Saran F, Zahlmann G, Garcia J, Vassal G, Grill J, Peet A, Dineen RA, Morgan PS, Jaspan T (2022) MRI and molecular characterization of pediatric high-grade midline thalamic gliomas: the HERBY phase II trial. Radiology 12:211464. https://doi.org/10.1148/radiol.211464

    Article  Google Scholar 

  22. Wagner S, Benesch M, Berthold F, Gnekow AK, Rutkowski S, Sträter R, Warmuth-Metz M, Kortmann RD, Pietsch T, Wolff JE (2006) Secondary dissemination in children with high-grade malignant gliomas and diffuse intrinsic pontine gliomas. Br J Cancer 95:991–997. https://doi.org/10.1038/sj.bjc.6603402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. O’Leary B, Mandeville HC, Fersht N, Solda F, Mycroft J, Zacharoulis S, Vaidya S, Saran F (2016) Craniospinal irradiation with concomitant and adjuvant temozolomide—a feasibility assessment of toxicity in patients with glioblastoma with a PNET component. J Neurooncol 127:295–302. https://doi.org/10.1007/s11060-015-2033-5

    Article  CAS  PubMed  Google Scholar 

  24. Kocakavuk E, Anderson KJ, Varn FS, Johnson KC, Amin SB, Sulman EP, Lolkema MP, Barthel FP, Verhaak RGW (2021) Radiotherapy is associated with a deletion signature that contributes to poor outcomes in patients with cancer. Nat Genet 53:1088–1096. https://doi.org/10.1038/s41588-021-00874-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Janssens GO, Gandola L, Bolle S, Mandeville H, Ramos-Albiac M, van Beek K, Benghiat H, Hoeben B, Morales La Madrid A, Kortmann RD, Hargrave D, Menten J, Pecori E, Biassoni V, von Bueren AO, van Vuurden DG, Massimino M, Sturm D, Peters M, Kramm CM (2017) Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: a matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group. Eur J Cancer 73:38–47. https://doi.org/10.1016/j.ejca.2016.12.007

    Article  PubMed  Google Scholar 

  26. Cacciotti C, Liu KX, Haas-Kogan DA, Warren KE (2020) Reirradiation practices for children with diffuse intrinsic pontine glioma. Neurooncol Pract 8:68–74. https://doi.org/10.1093/nop/npaa063

    Article  PubMed  PubMed Central  Google Scholar 

  27. Lassaletta A, Strother D, Laperriere N, Hukin J, Vanan MI, Goddard K, Lafay-Cousin L, Johnston DL, Zelcer S, Zapotocky M, Rajagopal R, Ramaswamy V, Hawkins C, Tabori U, Huang A, Bartels U, Bouffet E (2018) Reirradiation in patients with diffuse intrinsic pontine gliomas: the Canadian experience. Pediatr Blood Cancer 65:e26988. https://doi.org/10.1002/pbc.26988

    Article  PubMed  Google Scholar 

  28. Le Tourneau C, Delord JP, Kotecki N, Borcoman E, Gomez-Roca C, Hescot S, Jungels C, Vincent-Salomon A, Cockenpot V, Eberst L, Molé A, Jdey W, Bono F, Trochon-Joseph V, Toussaint H, Zandanel C, Adamiec O, de Beaumont O, Cassier PA (2020) A Phase 1 dose-escalation study to evaluate safety, pharmacokinetics and pharmacodynamics of AsiDNA, a first-in-class DNA repair inhibitor, administered intravenously in patients with advanced solid tumours. Br J Cancer 123:1481–1489. https://doi.org/10.1038/s41416-020-01028-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Associazione Bianca Garavaglia Onlus, Busto Arsizio (VA), AIRC (Associazione Italiana per la Ricerca sul Cancro), LILT (Lega Italiana per la Lotta contro i Tumori, Milano-Monza-Brianza), Ignarro, Rigato, Ragni families. All families and patients that trusted us during all treatments.

Funding

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Author notes

  1. Maura Massimino and Sabina Vennarini equally contributed to this paper.

Authors and Affiliations

  1. Pediatrics (MM, LB, VB, ES, CAC), Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy

    Maura Massimino, Elisabetta Schiavello, Luna Boschetti, Marta Podda, Nadia Puma, Giovanna Gattuso, Giovanna Sironi, Elena Barzanò, Olga Nigro, Luca Bergamaschi, Stefano Chiaravalli, Roberto Luksch, Cristina Meazza, Filippo Spreafico, Monica Terenziani, Michela Casanova, Andrea Ferrari, Carlo Alfredo Clerici & Veronica Biassoni

  2. Pediatric Radiotherapy (SV, FC, EP, OA), Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy

    Sabina Vennarini, Emilia Pecori & Ombretta Alessandro

  3. Medical Statistics, Biometry and Bioinformatics (FB), Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy

    Francesco Barretta

  4. Milan, Italy

    Francesca Colombo

  5. Radiological, Oncological and Anatomo-Pathological Sciences (MA), Department of La Sapienza University, Rome, Italy

    Manila Antonelli

  6. Neuropathology (BP) Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

    Bianca Pollo

  7. Medical Physics (EP), Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy

    Emanuele Pignoli

  8. Pain Therapy and Rehabilitation Units (MC), Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy

    Marco Chisari & Chiara Pellegrini

  9. Laboratory of Genetics (PM), S. Anna General Hospital, Como, Italy

    Piergiorgio Modena

  10. Hemato-Oncology Department La Statale University, Milan, Italy

    Carlo Alfredo Clerici

Authors
  1. Maura Massimino
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  2. Sabina Vennarini
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  3. Francesco Barretta
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  4. Francesca Colombo
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  5. Manila Antonelli
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  9. Ombretta Alessandro
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  10. Elisabetta Schiavello
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  11. Luna Boschetti
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  16. Elena Barzanò
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  17. Olga Nigro
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  18. Luca Bergamaschi
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  19. Stefano Chiaravalli
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  28. Carlo Alfredo Clerici
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  29. Piergiorgio Modena
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  30. Veronica Biassoni
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Contributions

Experimental design (MM, SB, FB, PM, MA, BP, VB), implementation of the design (all authors), analysis and interpretation of the data (MM, SB, FB, FC, EP, PM, MA, BP, VB). All authors have been involved in the writing of the manuscript and have read and approved the final version.

Corresponding author

Correspondence to Maura Massimino.

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This observation protocol was approved by the Institutional Ethical Board as 77/22.

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Written informed consent was obtained from the parents of alive patients.

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Massimino, M., Vennarini, S., Barretta, F. et al. How ten-years of reirradiation for paediatric high-grade glioma may shed light on first line treatment. J Neurooncol 159, 437–445 (2022). https://doi.org/10.1007/s11060-022-04079-4

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