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Craniospinal irradiation with concurrent temozolomide for primary metastatic pediatric high-grade or diffuse intrinsic pontine gliomas

A first report from the GPOH-HIT-HGG Study Group

Kraniospinale Bestrahlung mit simultanem Temozolomid bei primär metastasierten hochgradigen Gliomen oder diffus intrinsischen Ponsgliomen des Kindesalters

Erste Erfahrungen der GPOH-HIT-HGG-Studiengruppe

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Abstract

Background

High-grade (HGG) and diffuse intrinsic pontine gliomas (DIPG) with primary metastatic spread are extremely rare and have a dismal prognosis. Analogous to simultaneous radiochemotherapy in non-metastatic HGG and DIPG, concurrent craniospinal irradiation (CSI) and metronomic temozolomide (metroTMZ) may represent a reasonable therapeutic approach. However, the antitumor efficacy and toxicity of this treatment still have to be investigated.

Patients and methods

Between March 2007 and December 2012, six children with primary metastatic HGG (n = 4) or DIPG (n = 2) received CSI and concurrent metroTMZ based on individual treatment recommendations and, in some cases, within the HIT-HGG 2007 multicenter trial. Outcome and treatment-related toxicities were evaluated.

Results

All patients received irradiation to the entire craniospinal axis (35.2 Gy, n = 5; 36 Gy, n = 1:) and 5 received a local boost to macroscopic tumor deposits. Simultaneously, metroTMZ (75 mg/m2/day, n = 5; 60 mg/m2/day, n = 1) was administered. Additionally, 1 patient received nimotuzumab once per week. Within a median follow-up of 10.0 months (range 6.5–18.7 months), all patients experienced disease progression and 5 patients died. Median progression-free survival was 4.0 ± 0.8 months (range 2.4–10.7 months) and median overall survival was 7.6 ± 3.5 months (range 4.0–17.6 months). Acute myelosuppression most severely limited application of this aggressive treatment strategy. Severe hematotoxicities (≥ grade 3) occurred in all patients and metroTMZ had to be interrupted or discontinued in 4 out of 6 cases.

Conclusion

Concurrent CSI and metroTMZ might represent a feasible treatment approach for primary metastatic HGG and DIPG. On the basis of our experience, severe but manageable acute hematotoxicity has to be expected. An international effort is warranted to reassess the efficacy and toxicity of this approach within a prospective study.

Zusammenfassung

Hintergrund

Primär metastasierte hochgradige Gliome (HGG) und diffus intrinsische Ponsgliome (DIPG) sind sehr selten und mit einer infausten Prognose verbunden. Als aggressiven Behandlungsansatz kann man durchaus eine Bestrahlung der gesamten kraniospinalen Achse in Kombination mit einer simultanen metronomischen Temozolomidchemotherapie in Erwägung ziehen. Allerdings ist noch wenig über die antitumorale Wirksamkeit und Toxizität dieses Vorgehens bekannt.

Patienten und Methodik

Von März 2007 bis Dezember 2012 erhielten 6 Kindern mit primär metastasierten HGG (n = 4) oder DIPG (n = 2) im Rahmen einer individuellen Therapieempfehlung, z. T. im Rahmen der multizentrischen Therapieoptimierungsstudie HIT-HGG 2007, eine Bestrahlung der kraniospinalen Achse mit einer simultanen Temozolomid-Chemotherapie.

Ergebnisse

Alle Patienten erhielten eine Bestrahlung der gesamten kraniospinalen Achse (5-mal 35,2 Gy, 1-mal 36 Gy), fünf von ihnen zusätzlich eine lokale Dosisaufsättigung der makroskopisch sichtbaren Tumormanifestationen. Simultan zur Bestrahlung erfolgte eine metronomische Chemotherapie mit Temozolomid (5-mal 75 mg/m2/Tag, 1-mal 60 mg/m2/Tag). Ein Patient bekam zusätzlich einmal wöchentlich Nimotuzumab. Während einer medianen Nachbeobachtungszeit von 10 Monaten (Spanne 6,5–18,7 Monate) schritt die Erkrankung bei allen Kindern fort, fünf von ihnen starben. Das mediane progressionsfreie Überleben betrug 4,0 ± 0,8 Monate (Spanne 2,4–10,7 Monate), das mediane Gesamtüberleben 7,6 ± 3,5 Monate (Spanne 4,0–17,6 Monate). Die Durchführbarkeit des agressiven Behandlungskonzepts wurde durch eine ausgeprägte akute Knochenmarkssuppression eingeschränkt. Höhergradige Hämatotoxizitäten (≥ Grad 3, CTCAE v3.0) traten bei allen Patienten auf. Dementsprechend musste die simultane Behandlung mit Temozolomid bei 4 von 6 Patienten zeitweilig aus- oder ganz abgesetzt werden.

Schlussfolgerung

Die Kombination einer kraniospinalen Bestrahlung mit einer simultanen Temozolomidchemotherapie kann als Behandlungsoption für primär metastasierte HGG und DIPG erwogen werden. Eine ausgeprägte aber beherrschbare Myelosuppression ist allerdings zu erwarten. Der vorgeschlagene Behandlungsansatz sollte bezüglich antitumoraler Wirksamkeit und Toxizität auf internationaler Ebene prospektiv untersucht werden.

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Authors’ contributions

KM was responsible for the collection of data and together with AOvB for writing the manuscript. DK, HC and DV were responsible for treatment of the patients and control of the treatment documentation and follow-up data. AOvB, CS, MWM, CMK and RDK critically evaluated and approved the manuscript. CMK, RDK, AOvB and KM were responsible for the analysis and interpretation of this study. All authors read and approved the final manuscript.

Compliance with ethical guidelines

Conflict of interest. K. Müller, A. Schlamann, M. Guckenberger, M. Warmuth-Metz, A. Glück, S. Pietschmann, A. Wawer, R-D. Kortmann, C. Kramm and A. O. von Bueren state that there are no conflicts of interest.

All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.

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Authors and Affiliations

  1. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, Göttingen, Germany

    C. Kramm & A.O. von Bueren

  2. Department of Radiation Oncology, University Medical Center Leipzig, Stephan-Str. 9a, 04103, Leipzig, Germany

    K. Müller, A. Schlamann, S. Pietschmann & R.-D. Kortmann

  3. Department of Radiation Oncology, University Medical Center Würzburg, Würzburg, Germany

    M. Guckenberger

  4. Department of Neuroradiology, University Medical Center Würzburg, Würzburg, Germany

    M. Warmuth-Metz

  5. Clinic for Radiation Oncology Schwabing, München, Germany

    A. Glück

  6. Department of Pediatric Hematology and Oncology, University Medical Center München Schwabing, München, Germany

    A. Wawer

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  1. K. Müller
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  2. A. Schlamann
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  3. M. Guckenberger
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  5. A. Glück
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  7. A. Wawer
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  8. R.-D. Kortmann
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  9. C. Kramm
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  10. A.O. von Bueren
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Corresponding author

Correspondence to K. Müller.

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Müller, K., Schlamann, A., Guckenberger, M. et al. Craniospinal irradiation with concurrent temozolomide for primary metastatic pediatric high-grade or diffuse intrinsic pontine gliomas. Strahlenther Onkol 190, 377–381 (2014). https://doi.org/10.1007/s00066-013-0513-0

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