Skip to main content
SpringerLink
Log in

Hepatotoxicity after liver irradiation in children and adolescents

Results from the RiSK

Hepatotoxizität nach Leberbestrahlung im Kindes- und Jugendalter

Ergebnisse des RiSK

  • Original Article
  • Published:
Strahlentherapie und Onkologie Aims and scope Submit manuscript

Abstract

Aim

The aim of this study was to evaluate acute and late radiotherapy-associated hepatotoxicity in consideration of dose–volume effects and liver function in childhood and adolescence.

Patients and methods

Since 2001, irradiated children and adolescents in Germany have been prospectively documented in the “Register of Treatment-Associated Late Effects After Radiotherapy of Malignant Diseases in Childhood and Adolescence (RiSK)” using standardized forms. Toxicity was graded according to the Radiation Therapy Oncology Group (RTOG) criteria.

Results

Until April 2012, 1,392 children and adolescents from 62 radiotherapy centers were recruited. In all, 216 patients underwent irradiation of the liver (median age 9 years, range 1–18 years, 70 patients with total-body irradiation, TBI). For 75 % of patients without TBI, information on acute toxicity of the liver was available: 24 patients had acute toxicity of grade 1–4 (grade 1, 2, and 4, in 20, 3, and 1 patient, respectively), including five patients receiving simultaneous hepatotoxic chemotherapy. Information on late toxicity was documented in 465 forms from 216 patients, with a median follow-up of 2 years. A maximum grade of toxicity of ≥ 0 occurred in 18 patients over time (with grade 1, 2, and 3 toxicity occurring in 15, 2, and 1 patient, respectively), including three patients (17 %) with TBI. One of them received simultaneous hepatotoxic chemotherapy. In multivariable analysis, volume–dose correlations showed no statistically noticeable effect on acute or chronic toxicity.

Conclusion

Only low hepatotoxicity developed in children after irradiation of various abdominal and thoracic tumors. Due to the low radiation doses to the liver (median liver dose = 5 Gy) and the low toxicities that were consecutively observed, dose–volume curves for liver toxicity could not be established. These findings reflect the cautious attitude of radiation oncologists in terms of attributable liver doses in the treatment of the investigated tumor entities. It offers the option of increasing these conservative doses if tumor control is necessary.

Zusammenfassung

Zielsetzung

Ziel dieser Auswertung war die Bewertung der akuten und späten bestrahlungsassoziierten Hepatotoxizität im Kindes- und Jugendalter unter Berücksichtigung der Dosis-Volumen-Effekte und der Leberfunktion.

Patienten und Methoden

Seit 2001 werden in Deutschland bestrahlte Kinder und Jugendliche prospektiv im "Register zur Erfassung von Spätfolgen nach Strahlentherapie im Kindes- und Jugendalter (RiSK)" mit Hilfe standardisierter Fragebögen dokumentiert. Die Toxizität wurde nach den Kriterien der Radiation Therapy Oncology Group (RTOG) graduiert.

Ergebnisse

Bis April 2012 wurden 1392 Kinder und Jugendliche aus 62 Strahlentherapiezentren erfasst. Davon wurden 216 Patienten an der Leber bestrahlt (medianes Alter 9 Jahre, Spanne 1–18 Jahre, 70 Ganzkörperbestrahlungen [TBI]). Von 75 % der Patienten ohne TBI lagen uns Angaben zur akuten Toxizität der Leber vor: 24 Patienten mit Grad 1–4 (Grad 1, 2 und 4 traten bei jeweils  20, 3 und1 Patienten auf), darunter 5 Patienten mit simultaner hepatotoxischer Chemotherapie. Eine maximale Spättoxizität ≥ 0 (465 Fragebögen von 216 Patienten, medianes Follow-up 2 Jahre, maximaler Grad der Toxizität im zeitlichen Verlauf) trat bei 18 Patienten auf (15 mit Grad 1, 2 mit Grad 2 und 1 Patient mit Grad 3), darunter waren 3 Patienten (17 %) mit TBI. Eine simultane Chemotherapie erhielten 28 % der Patienten. In der multivariaten Analyse zeigten die Volumen-Dosis-Beziehungen keine statistisch auffälligen Effekte hinsichtlich akuter oder chronischer Toxizität.

Fazit

Nach der Bestrahlung verschiedener abdomineller und thorakaler Tumoren entwickelten Kinder eine nur geringe Lebertoxizität. Aufgrund der niedrigen Strahlendosen an der Leber (mediane Leberdosis :  5 Gy) und der konsekutiv geringen beobachteten Toxizitäten konnten Toxizitätskurven der Dosis-Leber-Volumen nicht etabliert werden. Diese Befunde spiegeln die vorsichtige Einstellung der Strahlentherapeuten hinsichtlich der zu verantwortenden Leberdosen bei der Behandlung der untersuchten Tumorentitäten wieder und eröffnen die Option auf vorsichtige Dosiserhöhungen an der Leber in Fällen, in denen dies aus Gründen der Tumorkontrolle erforderlich ist.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Castellino S, Muir A, Shah A et al (2010) Hepato-biliary late effects in survivors of childhood and adolescent cancer: a report from the Children's Oncology Group. Pediatr Blood Cancer 54:663–669

    PubMed Central  PubMed  Google Scholar 

  2. Mertens AC, Liu Q, Neglia JP et al (2008) Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 100:1368–1379

    Article  PubMed Central  PubMed  Google Scholar 

  3. Mounessi FS, Lehrich P, Haverkamp U et al (2013) Pelvic Ewing sarcomas. Three-dimensional conformal vs. intensity-modulated radiotherapy. Strahlenther Onkol 189:308–314

    Article  CAS  PubMed  Google Scholar 

  4. Andolino DL, Johnson CS, Maluccio M et al (2011) Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 81:e447–453

    Article  PubMed  Google Scholar 

  5. Dorr W, Kallfels S, Herrmann T (2013) Late bone and soft tissue sequelae of childhood radiotherapy. Relevance of treatment age and radiation dose in 146 children treated between 1970 and 1997. Strahlenther Onkol 189:529–534

    Article  CAS  PubMed  Google Scholar 

  6. Bölling T, Schuck A, Rube C et al (2006) Therapy-associated late effects after irradiation of malignant diseases in childhood and adolescence. Feasibility analyses of a prospective multicenter register study. Strahlenther Onkol 182:443–449

    Article  PubMed  Google Scholar 

  7. Bölling T, Schuck A, Pape H et al (2008) Study protocol of the German “Registry for the detection of late sequelae after radiotherapy in childhood and adolescence”; (RiSK). Radiat Oncol 3:10

    Article  PubMed Central  PubMed  Google Scholar 

  8. Bölling T, Ernst I, Pape H et al (2011) Dose-volume analysis of radiation nephropathy in children: preliminary report of the risk consortium. Int J Radiat Oncol Biol Phys 80:840–844

    Article  PubMed  Google Scholar 

  9. Bölling T, Geisenheiser A, Pape H et al (2011) Hypothyroidism after head-and-neck radiotherapy in children and adolescents: preliminary results of the “Registry for the Evaluation of Side Effects After Radiotherapy in Childhood and Adolescence”; (RiSK). Int J Radiat Oncol Biol Phys 81:e787–791

    Article  PubMed  Google Scholar 

  10. Cox JD, Stetz J, Pajak TF (1995) Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31:1341–1346

    Article  CAS  PubMed  Google Scholar 

  11. Schmoll HJ, Höffken K, Possinger K et al (2006) Toxizität antineoplastischer Substanzen. In: Schmoll HJ, Höffken K, Possinger K (eds) Kompendium Internistische Onkologie: Standards in Diagnostik und Therapie. Springer, Berlin, pp 867–896

  12. Cheng JC, Wu JK, Huang CM et al (2002) Radiation-induced liver disease after radiotherapy for hepatocellular carcinoma: clinical manifestation and dosimetric description. Radiother Oncol 63:41–45

    Article  PubMed  Google Scholar 

  13. Guha C, Kavanagh BD (2011) Hepatic radiation toxicity: avoidance and amelioration. Semin Radiat Oncol 21:256–263

    Article  PubMed Central  PubMed  Google Scholar 

  14. Marks LB, Yorke ED, Jackson A et al (2010) Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys 76:10–19

  15. Selo N, Bölling T, Ernst I et al (2010) Acute toxicity profile of radiotherapy in 690 children and adolescents: RiSK data. Radiother Oncol 97:119–126

    Article  PubMed  Google Scholar 

  16. Zabel-du Bois A, Milker-Zabel S, Bruns F et al (2014) Evaluation of time, attendance of medical staff and resources for radiotherapy in pediatric and adolescent patients: the DEGRO-QUIRO trial. Strahlenther Onkol 190:582–590

    Article  PubMed  Google Scholar 

  17. Malik IA, Moriconi F, Sheikh N et al (2010) Single-dose gamma-irradiation induces up-regulation of chemokine gene expression and recruitment of granulocytes into the portal area but not into other regions of rat hepatic tissue. Am J Pathol 176:1801–1815

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Rave-Frank M, Malik IA, Christiansen H et al (2013) Rat model of fractionated (2 Gy/day) 60 Gy irradiation of the liver: long-term effects. Radiat Environ Biophys 52:321–338

    Article  PubMed  Google Scholar 

  19. Bölling T, Willich N, Ernst I (2010) Late effects of abdominal irradiation in children: a review of the literature. Anticancer Res 30:227–231

    PubMed  Google Scholar 

  20. Emami B, Lyman J, Brown A et al (1991) Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21:109–122

    Article  CAS  PubMed  Google Scholar 

  21. Dawson LA, Ten Haken RK (2005) Partial volume tolerance of the liver to radiation. Semin Radiat Oncol 15:279–283

    Article  PubMed  Google Scholar 

  22. Flandin I, Hartmann O, Michon J et al (2006) Impact of TBI on late effects in children treated by megatherapy for Stage IV neuroblastoma. A study of the French Society of Pediatric oncology. Int J Radiat Oncol Biol Phys 64:1424–1431

    Article  PubMed  Google Scholar 

  23. Chou RH, Wong GB, Kramer JH et al (1996) Toxicities of total-body irradiation for pediatric bone marrow transplantation. Int J Radiat Oncol Biol Phys 34:843–851

    Article  CAS  PubMed  Google Scholar 

  24. Kun LE, Camitta BM (1978) Hepatopathy following irradiation and adriamycin. Cancer 42:81–84

    Article  CAS  PubMed  Google Scholar 

  25. Bhanot P, Cushing B, Philippart A et al (1979) Hepatic irradiation and adriamycin cardiotoxicity. J Pediatr 95:561–563

    Article  CAS  PubMed  Google Scholar 

  26. Muller K, Schlamann A, Guckenberger M et al (2014) 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. Strahlenther Onkol 190:377–381

    Article  CAS  PubMed  Google Scholar 

  27. Muller K, Schlamann A, Seidel C et al (2013) Craniospinal irradiation with concurrent temozolomide and nimotuzumab in a child with primary metastatic diffuse intrinsic pontine glioma. A compassionate use treatment. Strahlenther Onkol 189:693–696

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge the financial support of RiSK by the German Children’s Cancer Foundation, Bonn. Research of the last author, DS, was supported by the MHH Equal Opportunities Office, Hannover. Furthermore, we would like to thank everyone involved in the documentation of patients in various clinics, the RiSK office for its support, and Silke and David Mainwaring for proofreading.

Author information

Authors and Affiliations

  1. Department of Radiotherapy and Special Oncology, Medical School Hannover, Hannover, Germany

    Pascal Rösler, Hans Christiansen & Diana Steinmann P.D., M.D., Ph.D.

  2. Department of Radiotherapy, University of Leipzig, Leipzig, Germany

    Rolf-Dieter Kortmann

  3. Department of Radiotherapy, University Hospital of Freiburg, Freiburg im Breisgau, Germany

    Carmen Martini

  4. Department of Radiotherapy, Medical Faculty, Heinrich-Heine University of Düsseldorf, Düsseldorf, Germany

    Christiane Matuschek

  5. Department of Radiotherapy, Hospital Augsburg, Augsburg, Germany

    Frank Meyer

  6. Department of Radiotherapy, University Hospital of Homburg/Saar, Homburg/Saar, Germany

    Christian Rübe

  7. Department of Pediatrics, Pediatric Oncology, University Hospital of Schleswig-Holstein, Campus Lübeck, Germany

    Thorsten Langer

  8. Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany

    Raphael Koch

  9. Department of Radiotherapy, University Hospital of Münster, Münster, Germany

    Hans Theodor Eich, Normann Willich & Diana Steinmann P.D., M.D., Ph.D.

Authors
  1. Pascal Rösler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hans Christiansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rolf-Dieter Kortmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carmen Martini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christiane Matuschek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Frank Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christian Rübe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Thorsten Langer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Raphael Koch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hans Theodor Eich
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Normann Willich
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Diana Steinmann P.D., M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Diana Steinmann P.D., M.D., Ph.D..

Ethics declarations

Conflict of interest

P. Rösler, H. Christiansen, R-D. Kortmann, C. Martini, C. Matuschek, F. Meyer, C. Rübe, T. Langer, R. Koch, H.T. Eich, N. Willich, and D. Steinmann state that there are no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rösler, P., Christiansen, H., Kortmann, RD. et al. Hepatotoxicity after liver irradiation in children and adolescents. Strahlenther Onkol 191, 413–420 (2015). https://doi.org/10.1007/s00066-014-0796-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00066-014-0796-9

Keywords

Schlüsselwörter

Search

Navigation