Cancer Causes & Control

, Volume 20, Issue 6, pp 965–980 | Cite as

Case–control study on the therapy of childhood cancer and the occurrence of second malignant neoplasms in Germany

  • Peter Kaatsch
  • Irene Reinisch
  • Claudia Spix
  • Frank Berthold
  • Gritta Janka-Schaub
  • Andreas Mergenthaler
  • Jörg Michaelis
  • Maria Blettner
Original Paper


We report on a nested case–control study with 328 cases with second malignant neoplasm (SMN) following childhood cancer and 639 matched controls based on the German Childhood Cancer Registry. In the adjusted overall analysis, the odds ratio (OR) for SMN following any radiotherapy or chemotherapy is 2.1 [95% confidence interval (CI): 1.8–3.3] and 1.8 (95% CI: 0.98–3.1), respectively. The strongest effect is seen for alkylating agents (OR=2.0, 95% CI: 1.2–3.3). The risk of SMN after leukemia is pronounced for antimetabolites (OR=17.2, 95% CI: 1.7–177) and asparaginase (OR=4.3, 95% CI: 1.7–11.0). Following solid tumors, the greatest effect is seen for platinum derivatives (OR=4.1, 95% CI: 1.7–10.1). For anthracyclines, a decreased risk is observed (OR=0.3, 95% CI: 0.1–0.6). Secondary solid tumors are mainly associated with radiotherapy (OR=4.5, 95% CI: 2.5–8.0), especially secondary carcinomas. Secondary acute myeloid leukemia and myelodysplastic syndrome are mainly associated with alkylating agents (OR=8.5, 95% CI: 0.97–74.8), asparaginase (OR=6.8, 95% CI: 2.3–20.6), and platinum derivatives (OR=4.5, 95% CI: 1.5–13.6). The observed risks are in many instances lower than the ones published in previous studies relating to earlier treatment eras of the primary diseases. These differences may be attributed to less toxic but still effective treatment regimes but also to differences in the length of follow-up.


Childhood Cancer Epidemiology Population-based Case–control study Chemotherapy Second cancer 



Acute lymphoid leukemia


Acute myeloid leukemia


Confidence interval


Central nervous system


German Childhood Cancer Registry


Gesellschaft für Pädiatrische Onkologie und Hämatologie (Society of Pediatric Oncology and Hematology)


Myelodysplastic syndrome


Odds ratio


Second malignant neoplasm


Therapy optimization study (cooperative clinical trial for optimization of therapy)

Abbreviations for chemotherapeutic agents


Actinomycin D








Bleomycin sulfate







































The authors also gratefully acknowledge the contribution by the German Society for Pediatric Oncology and Hematology (GPOH) and the associated Therapy Optimization Trials who provided data. For qualified discussion, we would like to thank especially the pediatric oncologists Prof. V. Gerein and Prof. B. Kornhuber. The authors also are grateful to the former research associates (MD) of the project (U. Derichs, G. Klein, U. Mendelssohn, B. Schulz, R. Wibbing) as well as to members of our staff (M. Decher-Neff, B. Hillebrecht, I. Kerenyi, M. Lückel) for preparing data and to I. Jung for helping with the analyses.

Financial support

The project was funded by the Federal Ministry for Education and Research in the framework of the Competence Network in Paediatric Oncology and Haematology (Funding No. 01GI0419). For ongoing financial support of the registry’s work, the authors would like to thank the Federal Ministry for Health and Social Security and the 16 ministries of health of the German states, particularly of Rhineland-Palatinate.


  1. 1.
    Magnani C, Pastore G, Coebergh JW, Viscomi S, Spix C, Steliarova-Foucher E (2006) Trends in survival after childhood cancer in Europe, 1978-97: the ACCIS project. Eur J Cancer 42:1981–2005. doi: 10.1016/j.ejca.2006.05.006 PubMedCrossRefGoogle Scholar
  2. 2.
    Neglia JP, Friedman DL, Yasui Y, Mertens AC, Hammond S, Stovall M, Donaldson SS, Meadwos AT, Robison LL (2001) Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst 93:618–629. doi: 10.1093/jnci/93.8.618 PubMedCrossRefGoogle Scholar
  3. 3.
    Jenkinson HC, Hawkins MM, Stiller CA, Winter DL, Marsden HB, Stevens MC (2004) Long-term population-based risks of second malignant neoplasms after childhood cancer in Britain. Br J Cancer 91:1905–1910. doi: 10.1038/sj.bjc.6602226 PubMedCrossRefGoogle Scholar
  4. 4.
    Meadows AT (2001) Second tumours. Eur J Cancer 37:2074–2079. doi: 10.1016/S0959-8049(01)00264-7 PubMedCrossRefGoogle Scholar
  5. 5.
    Garwicz S, Anderson H, Olsen JH, Dollner H, Hertz H, Jonmundsson G, Langmark F, Lanning M, Möller T, Sankila R, Tulinius H (2000) Second malignant neoplasms after cancer in childhood and adolescence: a population-based case control study in the 5 Nordic countries. Int J Cancer 88:672–678. doi: 10.1002/1097-0215(20001115)88:4<672::AID-IJC24>3.0.CO;2-N PubMedCrossRefGoogle Scholar
  6. 6.
    MacArthur AC, Spinelli JJ, Rogers PC, Goddard KJ, Phillips N, McBride ML (2007) Risk of a second malignant neoplasm among 5-year survivors of cancer in childhood and adolescence in British Columbia, Canada. Pediatr Blood Cancer 48:453–459. doi: 10.1002/pbc.20921 PubMedCrossRefGoogle Scholar
  7. 7.
    de Vathaire F, Hawkins M, Campbell S, Oberlin O, Raquin MA, Schlienger JY, Shamsaldin A, Diello F, Boll J, Grimaud E, Hardiman C, Langrange JL (1999) Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment. Br J Cancer 79:1884–1893. doi: 10.1038/sj.bjc.6690300 PubMedCrossRefGoogle Scholar
  8. 8.
    Cardous-Ubbink MC, Heinen RC, Bakker PJ, van den Berg H, Oldenburger F, Caron HN, Voute PA, van Leeuwen FE (2007) Risk of second malignancies in long-term survivors of childhood cancer. Eur J Cancer 43:351–362. doi: 10.1016/j.ejca.2006.10.004 PubMedCrossRefGoogle Scholar
  9. 9.
    Westermeier T, Kaatsch P, Schoetzau A, Michaelis J (1998) Multiple primary neoplasms in childhood: data from the German Children’s Cancer Registry. Eur J Cancer 34:687–693. doi: 10.1016/S0959-8049(97)00326-2 PubMedCrossRefGoogle Scholar
  10. 10.
    Bhatia S, Yasui Y, Robison LL, Birch JM, Bogue MK, Diller L, DeLaat C, Fossati-Bellani F, Morgan E, Oberlin O, Reaman G, Ruymann FB et al (2003) Late Effects Study Group. High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin’s disease: report from the Late Effects Study Group. J Clin Oncol 21:4386–4394. doi: 10.1200/JCO.2003.11.059 PubMedCrossRefGoogle Scholar
  11. 11.
    Schellong G, Riepenhausen M (2004) Late effects after therapy of Hodgkin’s disease: update 2003/04 on overwhelming post-splenectomy infections and second malignancies. Klin Padiatr 216:364–369. doi: 10.1055/s-2004-832340 PubMedCrossRefGoogle Scholar
  12. 12.
    Löning L, Zimmermann M, Reiter A, Kaatsch P, Henze G, Riehm H, Schrappe H (2000) Second neoplasms subsequent to Berlin-Frankfurt-Munster therapy of acute lymphoblastic leukemia in childhood: significantly lower risk without cranial radiotherapy. Blood 95:2770–2775PubMedGoogle Scholar
  13. 13.
    Bhatia S, Sather HN, Pabustan OB, Trigg ME, Gaynon PS, Robison LL (2002) Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983. Blood 99:4257–4264. doi: 10.1182/blood.V99.12.4257 PubMedCrossRefGoogle Scholar
  14. 14.
    Pui CH, Relling MV, Behm FG, Hancock ML, Boyett JM, Raimondi SC, Krance RA, Mahmoud HH, Ribeiro RC, Sandlund JT, Head DR, Evans WE et al (1995) l-Asparaginase may potentiate effect of the epipodophyllotoxins. Leukemia 9:1680–1684PubMedGoogle Scholar
  15. 15.
    Hijiya N, Hudson MM, Lensing S, Zacher M, Onciu M, Behm FG, Razzouk BI, Ribeiro RC, Rubnitz JE, Sandlund JT, Rivera GK, Evans WE et al (2007) Cumulative incidence of second neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA 297:1207–1215. doi: 10.1001/jama.297.11.1207 PubMedCrossRefGoogle Scholar
  16. 16.
    Maule M, Scelo G, Pastore G, Brennan P, Hemminki K, Tracey E, Sankila R, Weiderpass E, Olsen JH, McBride ML, Brewster DH, Pompe-Kirn V et al (2007) Risk of second malignant neoplasms after childhood leukemia and lymphoma: an international study. J Natl Cancer Inst 99:790–800. doi: 10.1093/jnci/djk180 PubMedCrossRefGoogle Scholar
  17. 17.
    Cohen RJ, Curtis RE, Inskip PD, Fraumeni JF Jr (2005) The risk of developing second cancers among survivors of childhood soft tissue sarcoma. Cancer 103:2391–2396. doi: 10.1002/cncr.21040 PubMedCrossRefGoogle Scholar
  18. 18.
    Haddy N, Le Deley MC, Samand A, Diallo I, Guerin S, Guibout C, Oberlin O, Hawkins M, Zucker JM, de Vathaire F (2006) Role of radiotherapy and chemotherapy in the risk of second leukemia after a solid tumour in childhood. Eur J Cancer 42:2757–2764. doi: 10.1016/j.ejca.2006.05.034 PubMedCrossRefGoogle Scholar
  19. 19.
    Guerin S, Hawkins M, Shamsaldin A, Guibout C, Diallo I, Oberlin O, Brugieres L, de Vathaire F (2007) Treatment-adjusted predisposition to second malignant neoplasms after a solid cancer in childhood: a case-control study. J Clin Oncol 25:2833–2839PubMedCrossRefGoogle Scholar
  20. 20.
    Borgmann A, Zinn C, Hartmann R, Herold R, Kaatsch P, Escherich G, Möricke A, Henze G, von Stackelberg A, for the ALL-REZ BFM Study Group (2008) Secondary malignant neoplasms after intensive treatment of relapsed acute lymphoblastic leukaemia in childhood. Eur J Cancer 44:257–268. doi: 10.1016/j.ejca.2007.09.019 PubMedCrossRefGoogle Scholar
  21. 21.
    Le Deley MC, Leblanc T, Shamsaldin A, Raquin MA, Lacour B, Sommelet D, Champret A, Cayuela JM, Bayle C, Bernheim A, de Vathaire F, Vassal G (2003) Risk of second leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Societe Francaise d’Oncologie Pediatrique. J Clin Oncol 21:1074–1081. doi: 10.1200/JCO.2003.04.100 PubMedCrossRefGoogle Scholar
  22. 22.
    Kenney LB, Yasui Y, Inskip PD, Hammond S, Neglia JP, Mertens AC, Meadows AT, Friedman D, Robison LL, Diller L (2004) Breast cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Intern Med 141:590–597PubMedGoogle Scholar
  23. 23.
    Taylor AJ, Winter DL, Stiller CA, Murphy M, Hawkins MM (2007) Risk of breast cancer in female survivors of childhood Hodgkin’s disease in Britain: a population-based study. Int J Cancer 120:384–391. doi: 10.1002/ijc.22261 PubMedCrossRefGoogle Scholar
  24. 24.
    Bassal M, Mertens AC, Taylor L, Neglia JP, Greffe BS, Hammond S, Ronchers CM, Friedman DL, Stovall M, Yasui YY, Robison LL, Meadows AT (2006) Risk of selected subsequent carcinomas in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 24:476–483. doi: 10.1200/JCO.2005.02.7235 PubMedCrossRefGoogle Scholar
  25. 25.
    Neglia JP, Robison LL, Stovall M, Liu Y, Packer RJ, Hammond S, Yasui Y, Kasper CE, Mertens AC, Donaldson SS, Meadows AT, Inskip PD (2006) New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 98:1528–1537PubMedCrossRefGoogle Scholar
  26. 26.
    Henderson TO, Whitton J, Stovall M, Mertens AC, Mitby P, Friedman D, Strong LC, Hammond S, Neglia JP, Meadows AT, Robison L, Diller L (2007) Second sarcomas in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 99:300–308. doi: 10.1093/jnci/djk052 PubMedCrossRefGoogle Scholar
  27. 27.
    Tebbi CK, London WB, Friedman D, Villaluna D, De Alarcon PA, Constine LS, Mendenhall NP, Sposto R, Chauvenet A, Schwartz CL (2007) Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other second malignancies in pediatric Hodgkin’s disease. J Clin Oncol 25:493–500. doi: 10.1200/JCO.2005.02.3879 PubMedCrossRefGoogle Scholar
  28. 28.
    Kaatsch P, Spix J (2008) German Childhood Cancer Registry—annual report 2006/07 (1980-2006). Institute for Medical Biostatistics, Epidemiology and Informatics, University of Mainz, Germany.
  29. 29.
    Klein G, Michaelis J, Spix C, Wibbing R, Eggers G, Ritter J, Kaatsch P (2003) Second malignant neoplasms after treatment of childhood cancer. Eur J Cancer 39:808–817. doi: 10.1016/S0959-8049(02)00875-4 PubMedCrossRefGoogle Scholar
  30. 30.
    Kramarova E, Stiller CA (1996) The International Classification of Childhood Cancer. Int J Cancer 68:759–765. doi: 10.1002/(SICI)1097-0215(19961211)68:6<759::AID-IJC12>3.0.CO;2-W PubMedCrossRefGoogle Scholar
  31. 31.
    Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P (2005) International Classification of Childhood Cancer, third edition. Cancer 103:1457–1467. doi: 10.1002/cncr.20910 PubMedCrossRefGoogle Scholar
  32. 32.
    Tucker MA, Meadows AT, Boice JD Jr, Stovall M, Oberlin O, Stone BJ, Birch J, Voute PA, Hoover RN, Fraumeni JF Jr (1987) Leukemia after therapy with alkylating agents for childhood cancer. J Natl Cancer Inst 78:459–464PubMedGoogle Scholar
  33. 33.
    Pui CH, Ribeiro RC, Hancock ML, Rivera GK, Evans WE, Raimondi SC, Head DR, Behm JG, Mahmoud HH, Sandlund JT, Christ WM (1991) Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med 325:1682–1687PubMedGoogle Scholar
  34. 34.
    Hawkins MM, Kinnier Wilson LM, Stovall MA, Marsden HB, Potok MHN, Kingston JE, Chessells JM (1992) Epipodophyllotoxins, alkylating agents, and radiation and risk of secondary leukaemia after childhood cancer. Br Med J 304:951–958CrossRefGoogle Scholar
  35. 35.
    Le Deley MC, Vassal G, Taibi A, Shamsaldin A, Leblanc T, Hartmann O (2005) High cumulative rate of second leukemia after continuous etoposide treatment for solid tumors in children and young adults. Pediatr Blood Cancer 45:25–31. doi: 10.1002/pbc.20380 PubMedCrossRefGoogle Scholar
  36. 36.
    Hawkins MM, Kinnier Wilson LM, Burton HS, Potok MHN, Winter DL, Marsden HB, Stovall MA (1996) Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst 88:270–278. doi: 10.1093/jnci/88.5.270 PubMedCrossRefGoogle Scholar
  37. 37.
    Jenkinson HC, Winter DL, Marsden HB, Stovall MA, Stevens MCH, Stiller CA, Hawkins MM (2007) A study of soft tissue sarcomas after childhood cancer in Britain. Br J Cancer 97:695–699. doi: 10.1038/sj.bjc.6603908 PubMedCrossRefGoogle Scholar
  38. 38.
    Debling D, Spix C, Blettner M, Michaelis J, Kaatsch P (2008) The cohort of long-term survivors at the German Childhood Cancer Registry. Klin Padiatr 220:371–377. doi: 10.1055/s-0028-1086027 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Peter Kaatsch
    • 1
  • Irene Reinisch
    • 1
  • Claudia Spix
    • 1
  • Frank Berthold
    • 2
  • Gritta Janka-Schaub
    • 3
  • Andreas Mergenthaler
    • 1
  • Jörg Michaelis
    • 4
  • Maria Blettner
    • 4
  1. 1.German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and InformaticsJohannes Gutenberg-University MainzMainzGermany
  2. 2.Paediatric Oncology and HaematologyUniversity Hospital of CologneCologneGermany
  3. 3.Paediatric Haematology and OncologyUniversity Hospital Hamburg-EppendorfHamburgGermany
  4. 4.Institute of Medical Biostatistics, Epidemiology and InformaticsJohannes Gutenberg-University MainzMainzGermany

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