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Concurrent radiotherapy with temozolomide vs. concurrent radiotherapy with a cisplatinum-based polychemotherapy regimen

Acute toxicity in pediatric high-grade glioma patients

Konkomitante Radiochemotherapie mit Temozolomid vs. konkomitante Cisplatin-basierte Radiochemotherapie

Akuttoxizität bei Kindern mit hochmalignen Gliomen

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Abstract

Purpose

As the efficacy of all pediatric high-grade glioma (HGG) treatments is similar and still disappointing, it is essential to also investigate the toxicity of available treatments.

Methods

Prospectively recorded hematologic and nonhematologic toxicities of children treated with radiochemotherapy in the HIT GBM-C/D and HIT-HGG-2007 trials were compared. Children aged 3–18 years with histologically proven HGG (WHO grade III and IV tumors) or unequivocal radiologic diagnosis of diffuse intrinsic pontine glioma (DIPG) were included in these trials. The HIT-HGG-2007 protocol comprised concomitant radiochemotherapy with temozolomide, while cisplatinum/etoposide (PE) and PE plus ifosfamide (PEI) in combination with weekly vincristine injections were applied during radiochemotherapy in the HIT GBM-C/D protocol.

Results

Regular blood counts and information about cellular nadirs were available from 304 patients (leukocytes) and 306 patients (thrombocytes), respectively. Grade 3–4 leukopenia was much more frequent in the HIT GBM-C/D cohort (n = 88, 52%) vs. HIT-HGG-2007 (n = 13, 10%; P <0.001). Grade 3–4 thrombopenia was also more likely in the HIT GBM-C/D cohort (n = 21, 12% vs. n = 3,2%; P <0.001). Grade 3–4 leukopenia appeared more often in children aged 3–7 years (n = 38/85, 45%) than in children aged 8–12 years (n = 39/120, 33%) and 13–18 years (24/100, 24%; P =0.034). In addition, sickness was more frequent in the HIT GBM-C/D cohort (grade 1–2: 44%, grade 3–4: 6% vs. grade 1–2: 28%, grade 3–4: 1%; P <0.001).

Conclusion

Radiochemotherapy involving cisplatinum-based polychemotherapy is more toxic than radiotherapy in combination with temozolomide. Without evidence of differences in therapeutic efficacy, the treatment with lower toxicity, i. e., radiotherapy with temozolomide should be used.

Zusammenfassung

Zielsetzung

Die Wirksamkeit verschiedener Protokolle zur Radiochemotherapie bei Kindern mit hochmalignen Gliomen („high-grade glioma“, HGG) ist ähnlich und leider noch enttäuschend. Es erscheint vordringlich, auch die Toxizität verschiedener Therapieprotokolle zu untersuchen.

Methoden

Es wurden prospektiv erhobene hämatologische und nichthämatologische Toxizitäten von Kindern verglichen, die in der HIT-GBM-C/D- bzw. HIT-HGG-2007-Studie mit einer Radiochemotherapie behandelt wurden. In diesen Studien wurden Kinder im Alter von 3–18 Jahren mit histologisch gesichertem HGG (WHO-Grad-III-und -Grad-IV-Tumore) oder eindeutiger radiologischer Diagnose eines diffusen intrinsischen Ponsglioms (DIPG) eingeschlossen. Das HIT-HGG-2007-Protokoll umfasste eine konkomitante Radiochemotherapie mit Temozolomid; das HIT-GBM-C/D-Protokoll bestand aus Cisplatin/Etoposid (PE) und PE plus Ifosfamid (PEI) in Kombination mit wöchentlichen Vincristin-Injektionen während der Radiochemotherapie.

Ergebnisse

Regelmäßige Blutbilder waren von je 304 (Leukozyten) und 306 Patienten (Thrombozyten) verfügbar. Eine Grad-3/4-Leukopenie trat deutlich häufiger in der HIT-GBM-C/D- (n = 88, 52 %) als in der HIT-HGG-2007-Kohorte (n = 13, 10 %; P <0,001) auf. Ebenso war eine Grad-3/4-Thrombopenie in der HIT-GBM-C/D-Kohorte deutlich wahrscheinlicher (n = 21, 12 % vs. n = 3, 2 %; P <0,001). Eine Grad-3/4-Leukopenie trat bei Kindern zwischen 3–7 Jahren (38/85, 45 %) häufiger auf als bei Kindern zwischen 8–12 (39/120, 33 %) bzw. 13–18 Jahren (24/100, 24 %; P =0,034). Auch nichthämatologische Toxizität, z. B. Übelkeit, war in der HIT-GBM-C/D-Kohorte häufiger (Grad 1–2: 44 %, Grad 3–4: 6 % vs. Grad 1–2: 28 %, Grad 3–4: 1 %; P <0,001).

Schlussfolgerung

Eine Cisplatin-basierte Polychemotherapie ist toxischer als die Radiochemotherapie mit Temozolomid. Bei fehlender Evidenz für therapeutische Überlegenheit sollte die Behandlung mit geringerer Toxizität, d. h. Radiochemotherapie mit Temozolomid, verwendet werden.

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Authors and Affiliations

  1. Department of Radiotherapy and Radiation Oncology, University of Leipzig Medical Center, Stephanstraße 9a, 04103, Leipzig, Germany

    Clemens Seidel & Rolf‑D. Kortmann

  2. Division of Pediatric Hematology and Oncology, University Medical Center Goettingen, Goettingen, Germany

    André O. von Bueren, Sabrina Bojko, Marion Hoffmann & Christof M. Kramm

  3. Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Hospital of Geneva, Geneva, Switzerland

    André O. von Bueren

  4. Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland

    André O. von Bueren

  5. Department of Neuropathology, Brain Tumor Reference Center of the DGNN, University of Bonn Medical Center, Bonn, Germany

    Torsten Pietsch & Gerrit H. Gielen

  6. Department of Neuroradiology, University Hospital Wuerzburg, 97080, Wuerzburg, Germany

    Monika Warmuth-Metz & Brigitte Bison

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  1. Clemens Seidel
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Correspondence to Clemens Seidel.

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Conflict of interest

C. M. Kramm reports grants from Deutsche Kinderkrebsstiftung, Bonn, Germany, during the conduct of the study; grants from Merck, KGaA Darmstadt, Germany, outside the submitted work. B. Bison reports personal fees and nonfinancial support from Deutsche Kinderkrebsstiftung, during the conduct of the study; personal fees and nonfinancial support from Deutsche Kinderkrebsstiftung, outside the submitted work. C. Seidel, A.O. von Bueren, S. Bojko, M. Hoffmann, T. Pietsch, G.H. Gielen, M. Warmuth-Metz and R.‑D. Kortmann declare that they have no competing interests.

Additional information

Clemens Seidel and André O. von Bueren contributed equally to the manuscript.

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Seidel, C., von Bueren, A.O., Bojko, S. et al. Concurrent radiotherapy with temozolomide vs. concurrent radiotherapy with a cisplatinum-based polychemotherapy regimen. Strahlenther Onkol 194, 215–224 (2018). https://doi.org/10.1007/s00066-017-1218-6

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