Clinical research tools in pediatric oncology: challenges and opportunities

  • Teresa de RojasEmail author
  • Anouk Neven
  • Alexander J. Towbin
  • Fernando Carceller
  • Francisco Bautista
  • David Riedl
  • Samantha Sodergren
  • Anne-Sophie Darlington
  • Ana Fernandez-Teijeiro
  • Lucas Moreno


Survival for childhood cancers has improved significantly over the last decades. However, patient outcomes have plateaued over the last decade for difficult-to-treat diseases. With high cure rates, decreasing long-term toxicities and sequelae remains crucial. Since many advances in childhood cancer research come from the adult oncology world, one of the key areas is improving the adaptation of tools that are essential for clinical trial conduct that were developed for adults into pediatrics. These include tools to evaluate toxicity, quality of life, radiological response, statistical methodology, or indicators of cancer care quality. In this review, we present ongoing international efforts to validate and adapt these tools for children and adolescents and discuss remaining challenges. These efforts will hopefully accelerate and improve the quality of pediatric oncology research in the upcoming years.


RECIST CTCAE Quality of life Quality assurance Childhood cancer AYA oncology 



Teresa de Rojas’ work as Fellow at EORTC Headquarters was supported by a grant from EORTC Cancer Research Fund (ECRF) from Belgium. Fernando Carceller is supported by George and the Giant Pledge via the Royal Marsden Cancer Charity.

Compliance with ethical standards

Conflict of interest

Francisco Bautista had a consultant or advisory role for Bayer, Amgen, and EusaPharma, received honoraria for speaking at symposia from Amgen and Jazz Pharmaceuticals and support for attending symposia from Takeda, EusaPharma, Shire, and Jazz Pharmaceuticals. Ana Fernández-Teijeiro has had a consulting or advisory role for Amgen, Novartis, Takeda, SOBI and Bayer. She received honoraria from Takeda and Amgen for educational events and travel expenses from Servier, Shire, and Gilead. Alexander Towbin has received grants from Guerbet and the Cystic Fibrosis Foundation. He receives royalties from Elsevier. He has served as consultant for Applied Radiology, IBM Watson Health Imaging, and KLAS. Lucas Moreno has served in a consulting or advisory role for Novartis, AstraZeneca, Roche Genentech, Bayer, Amgen, and MundiPharma; has received honoraria for educational events from Celgene and Novartis; and has received travel expenses from MundiPharma, Celgene, and Amgen. The rest of the authors declare that they have no conflict of interest.


  1. 1.
    Gatta, G., Botta, L., Rossi, S., Aareleid, T., Bielska-Lasota, M., Clavel, J., et al. (2014). Childhood cancer survival in Europe 1999-2007: Results of EUROCARE-5-a population-based study. The Lancet Oncology, 15(1), 35–47. Scholar
  2. 2.
    Trama, A., Botta, L., Foschi, R., Ferrari, A., Stiller, C., Desandes, E., Maule, M. M., Merletti, F., Gatta, G., & EUROCARE-5 Working Group. (2016). Survival of European adolescents and young adults diagnosed with cancer in 2000-07: Population-based data from EUROCARE-5. The Lancet. Oncology, 17(7), 896–906. Scholar
  3. 3.
    Noone AM, Howlader N, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, C. K. (eds). (2018). SEER Cancer Statistics Review, 1975–2015, National Cancer Institute. Retrieved September 3, 2018, from
  4. 4.
    The European Society for Paediatric Oncology. (2015). The SIOPE Strategic Plan; a European Cancer Plan for Children and Adolescents (1st ed.). SIOPE. Retrieved from
  5. 5.
    Oeffinger, K. C., Mertens, A. C., Sklar, C. A., Kawashima, T., Hudson, M. M., Meadows, A. T., et al. (2006). Chronic health conditions in adult survivors of childhood cancer. The New England Journal of Medicine, 355(15), 1572–1582. Scholar
  6. 6.
    Bhakta, N., Liu, Q., Ness, K. K., Baassiri, M., Eissa, H., Yeo, F., et al. (2017). The cumulative burden of surviving childhood cancer: An initial report from the St Jude Lifetime Cohort Study (SJLIFE). The Lancet, 390(10112), 2569–2582. Scholar
  7. 7.
    Vassal, G., Rousseau, R., Blanc, P., Moreno, L., Bode, G., Schwoch, S., et al. (2015). Creating a unique, multi-stakeholder Paediatric Oncology Platform to improve drug development for children and adolescents with cancer. European journal of cancer (Oxford, England : 1990), 51(2), 218–224. Scholar
  8. 8.
    Vassal, G., Zwaan, C. M., Ashley, D., Le Deley, M. C., Hargrave, D., Blanc, P., & Adamson, P. C. (2013). New drugs for children and adolescents with cancer: The need for novel development pathways. The Lancet Oncology. Scholar
  9. 9.
    Boklan, J. (2006). Little patients, losing patience: Pediatric cancer drug development. Molecular Cancer Therapeutics, 5(8), 1905–1908. Scholar
  10. 10.
    Vassal, G., Fitzgerald, E., Schrappe, M., Arnold, F., Kowalczyk, J., Walker, D., et al. (2014). Challenges for children and adolescents with cancer in Europe: The SIOP-Europe agenda. Pediatric Blood & Cancer. Scholar
  11. 11.
    Vassal, G., Geoerger, B., & Morland, B. (2013). Is the European Pediatric Medicine Regulation working for children and adolescents with cancer? Clinical Cancer Research, 19(6), 1315–1325. Scholar
  12. 12.
    Moreno, L., Pearson, A. D. J., Paoletti, X., Jimenez, I., Geoerger, B., Kearns, P. R., et al. (2017). Early phase clinical trials of anticancer agents in children and adolescents—An ITCC perspective. Nature Reviews. Clinical Oncology, 14(8), 497–507. Scholar
  13. 13.
    Institute, N. C (2010). Common Terminology Criteria for Adverse Events v4.3. NCI, NIH, DHHS. Retrieved from
  14. 14.
    Aaronson, N. K., Ahmedzai, S., Bergman, B., Bullinger, M., Cull, A., Duez, N. J., et al. (1993). The European Organisation for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. Journal of the National Cancer Institute, 85, 365–376. Scholar
  15. 15.
    Therasse, P., Arbuck, S. G., Eisenhauer, E. A., Wanders, J., Kaplan, R. S., Rubinstein, L., et al. (2000). New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. Journal of the National Cancer Institute, 92(3), 205–216 Retrieved from Scholar
  16. 16.
    Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., Rubinstein, L., Shankar, L., Dodd, L., Kaplan, R., Lacombe, D., & Verweij, J. (2009). New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer, 45(2), 228–247. Scholar
  17. 17.
    de Rojas, T., Bautista, F. J., Madero, L., & Moreno, L. (2016). The first step to integrating adapted common terminology criteria for adverse events for children. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 34(18), 2196–2197. Scholar
  18. 18.
    Schmiegelow, K., Attarbaschi, A., Barzilai, S., Escherich, G., Frandsen, T. L., Halsey, C., et al. (2016). Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: A Delphi consensus. The Lancet Oncology. Scholar
  19. 19.
    Sodergren, S. C., Husson, O., Robinson, J., Rohde, G. E., Tomaszewska, I. M., Vivat, B., et al. (2017). Systematic review of the health-related quality of life issues facing adolescents and young adults with cancer. Quality of Life Research, 26, 1659–1672. Scholar
  20. 20.
    Litière, S., Collette, S., De Vries, E. G. E., Seymour, L., & Bogaerts, J. (2017). RECIST-learning from the past to build the future. Nature Reviews. Clinical Oncology, 14, 187–192. Scholar
  21. 21.
    Drilon, A., Laetsch, T. W., Kummar, S., DuBois, S. G., Lassen, U. N., Demetri, G. D., et al. (2018). Efficacy of larotrectinib in TRK fusion–positive cancers in adults and children. New England Journal of Medicine, 378(8), 731–739. Scholar
  22. 22.
    McHugh, K., & Kao, S. (2003). Response evaluation criteria in solid tumours (RECIST): Problems and need for modifications in paediatric oncology? The British Journal of Radiology, 76(907), 433–436. Scholar
  23. 23.
    Moon, L., & McHugh, K. (2005). Advances in paediatric tumour imaging. Archives of Disease in Childhood, 90(6), 608–611. Scholar
  24. 24.
    Barnacle, A. M., & McHugh, K. (2006). Limitations with the Response Evaluation Criteria in Solid Tumors (RECIST) guidance in disseminated pediatric malignancy. Pediatric Blood & Cancer, 46(2), 127–134. Scholar
  25. 25.
    Therasse, P., Eisenhauer, E. A., & Verweij, J. (2006). RECIST revisited: A review of validation studies on tumour assessment. European journal of cancer (Oxford, England : 1990), 42(8), 1031–1039. Scholar
  26. 26.
    Carceller, F., Bautista, F. J., Fowkes, L. A., Marshall, L. V., Sirvent, S. I., Chisholm, J. C., Pearson, A. D., Koh, D. M., & Moreno, L. (2016). Response assessment in paediatric phase I trials according to RECIST guidelines: Survival outcomes, patterns of progression and relevance of changes in tumour measurements. Pediatric Blood & Cancer, 63(8), 1400–1406. Scholar
  27. 27.
    Steliarova-Foucher, E., Colombet, M., Ries, L. A. G., Moreno, F., Dolya, A., Bray, F., et al. (2017). International incidence of childhood cancer, 2001–10: A population-based registry study. The Lancet Oncology, 18(6), 719–731. Scholar
  28. 28.
    Brodeur, G. M., & Bagatell, R. (2014). Mechanisms of neuroblastoma regression. Nature Reviews. Clinical Oncology. Scholar
  29. 29.
    Sturm, D., Bender, S., Jones, D. T. W., Lichter, P., Grill, J., Becher, O., et al. (2014). Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nature Reviews Cancer, 14(2), 92–107. Scholar
  30. 30.
    Weeda, V. B., Aronson, D. C., Verheij, J., & Lamers, W. H. (2019). Is hepatocellular carcinoma the same disease in children and adults? Comparison of histology, molecular background, and treatment in pediatric and adult patients. Pediatric Blood & Cancer, 66(2), e27475. Scholar
  31. 31.
    Ferrari, A., Miceli, R., Meazza, C., Zaffignani, E., Gronchi, A., Piva, L., Collini, P., Podda, M., Massimino, M., Luksch, R., Cefalo, G., Terenziani, M., Spreafico, F., Polastri, D., Fossati-Bellani, F., Casanova, M., & Mariani, L. (2009). Soft tissue sarcomas of childhood and adolescence: The prognostic role of tumor size in relation to patient body size. Journal of Clinical Oncology, 27(3), 371–376. Scholar
  32. 32.
    Nguyen, R., McCarville, M. B., Sykes, A., Mao, S., Wu, J., Langham, M. R., & Furman, W. L. (2018). Rapid decrease of serum alpha-fetoprotein and tumor volume predicts outcome in children with hepatoblastoma treated with neoadjuvant chemotherapy. International Journal of Clinical Oncology, 23, 900–907. Scholar
  33. 33.
    O’Neill, A. F., Towbin, A. J., Krailo, M. D., Xia, C., Gao, Y., McCarville, M. B., et al. (2017). Characterization of pulmonary metastases in children with hepatoblastoma treated on Children’s Oncology Group Protocol AHEP0731 (the treatment of children with all stages of hepatoblastoma): A report from the Children’s Oncology Group. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 35(30), 3465–3473. Scholar
  34. 34.
    Schoot, R. A., McHugh, K., van Rijn, R. R., Kremer, L. C. M., Chisholm, J. C., Caron, H. N., & Merks, J. H. M. (2013). Response assessment in pediatric rhabdomyosarcoma: Can Response Evaluation Criteria in Solid Tumors replace three-dimensional volume assessments? Radiology, 269(3), 870–878. Scholar
  35. 35.
    Bagatell, R., McHugh, K., Naranjo, A., Van Ryn, C., Kirby, C., Brock, P., et al. (2016). Assessment of primary site response in children with high-risk neuroblastoma: An International Multicenter Study. Journal of Clinical Oncology, 34(7), 740–746. Scholar
  36. 36.
    Guenther, L. M., Rowe, R. G., Acharya, P. T., Swenson, D. W., Meyer, S. C., Clinton, C. M., et al. (2017). Response Evaluation Criteria in Solid Tumors (RECIST) following neoadjuvant chemotherapy in osteosarcoma. Pediatric Blood & Cancer, e26896. Scholar
  37. 37.
    Park, J. R., Bagatell, R., Cohn, S. L., Pearson, A. D., Villablanca, J. G., Berthold, F., Burchill, S., Boubaker, A., McHugh, K., Nuchtern, J. G., London, W. B., Seibel, N. L., Lindwasser, O. W., Maris, J. M., Brock, P., Schleiermacher, G., Ladenstein, R., Matthay, K. K., & Valteau-Couanet, D. (2017). Revisions to the international neuroblastoma response criteria: A consensus statement from the National Cancer Institute Clinical Trials Planning Meeting. Journal of Clinical Oncology, 35(22), 2580–2587. Scholar
  38. 38.
    Aghighi, M., Boe, J., Rosenberg, J., Von Eyben, R., Gawande, R. S., Petit, P., et al. (2016). Three-dimensional radiologic assessment of chemotherapy response in Ewing sarcoma can be used to predict clinical outcome. Radiology, 280(3), 905–915. Scholar
  39. 39.
    Trout, A. T., Towbin, A. J., Klingbeil, L., Weiss, B. D., & von Allmen, D. (2017). Single and multidimensional measurements underestimate neuroblastoma response to therapy. Pediatric Blood & Cancer, 64(1), 18–24. Scholar
  40. 40.
    ped-RECIST - RECIST in pediatric trials? (n.d.). Retrieved October 17, 2019, from
  41. 41.
    Common Terminology Criteria for Adverse Events (CTCAE). (n.d.). Retrieved November 8, 2019, from
  42. 42.
    Reeve, B. B., McFatrich, M., Pinheiro, L. C., Weaver, M. S., Sung, L., Withycombe, J. S., Baker, J. N., Mack, J. W., Waldron, M. K., Gibson, D., Tomlinson, D., Freyer, D. R., Mowbray, C., Jacobs, S., Palma, D., Martens, C. E., Gold, S. H., Jackson, K. D., & Hinds, P. S. (2017). Eliciting the child’s voice in adverse event reporting in oncology trials: Cognitive interview findings from the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events initiative. Pediatric Blood & Cancer, 64(3), e26261. Scholar
  43. 43.
    Gipson, D. S., Kirkendall, E. S., Gumbs-Petty, B., Quinn, T., Steen, A., Hicks, A., McMahon, A., Nicholas, S., Zhao-Wong, A., Taylor-Zapata, P., Turner, M., Herreshoff, E., Jones, C., Davis, J. M., Haber, M., & Hirschfeld, S. (2017). Development of a pediatric adverse events terminology. Pediatrics, 139(1). Scholar
  44. 44.
    Ruland, C. M., Hamilton, G. A., & Schjødt-Osmo, B. (2009). The complexity of symptoms and problems experienced in children with cancer: A review of the literature. Journal of Pain and Symptom Management, 37(3), 403–418. Scholar
  45. 45.
    Kestler, S. A., & LoBiondo-Wood, G. (2012). Review of symptom experiences in children and adolescents with cancer. Cancer Nursing, 35(2), E31–E49. Scholar
  46. 46.
    Hudson, M. M., Ness, K. K., Gurney, J. G., Mulrooney, D. A., Chemaitilly, W., Krull, K. R., Green, D. M., Armstrong, G. T., Nottage, K. A., Jones, K. E., Sklar, C. A., Srivastava, D. K., & Robison, L. L. (2013). Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA, 309(22), 2371–2381. Scholar
  47. 47.
    Heath, J. A., Clarke, N. E., Donath, S. M., McCarthy, M., Anderson, V. A., & Wolfe, J. (2010). Symptoms and suffering at the end of life in children with cancer: An Australian perspective. The Medical Journal of Australia, 192(2), 71–75 Retrieved from Scholar
  48. 48.
    U.S. Food and Drug Administration (FDA). (2009). Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Retrieved October 30, 2019, from
  49. 49.
    Matza, L. S., Patrick, D. L., Riley, A. W., Alexander, J. J., Rajmil, L., Pleil, A. M., & Bullinger, M. (2013). Pediatric patient-reported outcome instruments for research to support medical product labeling: Report of the ISPOR PRO good research practices for the assessment of children and adolescents task force. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research, 16(4), 461–479. Scholar
  50. 50.
    Pinheiro, L. C., McFatrich, M., Lucas, N., Walker, J. S., Withycombe, J. S., Hinds, P. S., Sung, L., Tomlinson, D., Freyer, D. R., Mack, J. W., Baker, J. N., & Reeve, B. B. (2018). Child and adolescent self-report symptom measurement in pediatric oncology research: A systematic literature review. Quality of Life Research, 27(2), 291–319. Scholar
  51. 51.
    Anthony, S. J., Selkirk, E., Sung, L., Klaassen, R. J., Dix, D., Scheinemann, K., & Klassen, A. F. (2014). Considering quality of life for children with cancer: A systematic review of patient-reported outcome measures and the development of a conceptual model. Quality of Life Research, 23(3), 771–789. Scholar
  52. 52.
    Varni, J. W., Limbers, C., & Burwinkle, T. M. (2007). Literature review: Health-related quality of life measurement in pediatric oncology: Hearing the voices of the children. Journal of Pediatric Psychology, 32(9), 1151–1163. Scholar
  53. 53.
    Zhukovsky, D. S., Rozmus, C. L., Robert, R. S., Bruera, E., Wells, R. J., Chisholm, G. B., Allo, J. A., & Cohen, M. Z. (2015). Symptom profiles in children with advanced cancer: Patient, family caregiver, and oncologist ratings. Cancer, 121(22), 4080–4087. Scholar
  54. 54.
    Ravens-Sieberer, U., Karow, A., Barthel, D., & Klasen, F. (2014). How to assess quality of life in child and adolescent psychiatry. Dialogues in Clinical Neuroscience, 16(2), 147–158 Retrieved from Scholar
  55. 55.
    Upton, P., Lawford, J., & Eiser, C. (2008). Parent–child agreement across child health-related quality of life instruments: A review of the literature. Quality of Life Research, 17(6), 895–913. Scholar
  56. 56.
    Eiser, C., & Varni, J. W. (2013). Health-related quality of life and symptom reporting: Similarities and differences between children and their parents. European Journal of Pediatrics, 172(10), 1299–1304. Scholar
  57. 57.
    Germain, N., Aballéa, S., & Toumi, M. (2019). Measuring health-related quality of life in young children: How far have we come? Journal of Market Access & Health Policy, 7(1), 1618661. Scholar
  58. 58.
    Grange, A., Bekker, H., Noyes, J., & Langley, P. (2007). Adequacy of health-related quality of life measures in children under 5 years old: Systematic review. Journal of Advanced Nursing, 59(3), 197–220. Scholar
  59. 59.
    Riley, A. W. (2004). Evidence that school-age children can self-report on their health. Ambulatory Pediatrics, 4(4 SUPPL), 371–376. Scholar
  60. 60.
    Varni, J. W., Limbers, C. A., & Burwinkle, T. M. (2007). How young can children reliably and validly self-report their health-related quality of life? An analysis of 8,591 children across age subgroups with the PedsQL™ 4.0 Generic Core Scales. Health and Quality of Life Outcomes, 5.
  61. 61.
    Mokkink, L. B., Terwee, C. B., Knol, D. L., Stratford, P. W., Alonso, J., Patrick, D. L., et al. (2010). The COSMIN checklist for evaluating the methodological quality of studies on measurement properties: A clarification of its content. BMC Medical Research Methodology, 10.
  62. 62.
    Klassen, A. F., Strohm, S. J., Maurice-Stam, H., & Grootenhuis, M. A. (2010). Quality of life questionnaires for children with cancer and childhood cancer survivors: A review of the development of available measures. Supportive Care in Cancer, 18(9), 1207–1217. Scholar
  63. 63.
    Anthony, S. J., Selkirk, E., Sung, L., Klaassen, R. J., Dix, D., & Klassen, A. F. (2017). Quality of life of pediatric oncology patients: Do patient-reported outcome instruments measure what matters to patients? Quality of Life Research, 26(2), 273–281. Scholar
  64. 64.
    Bleyer, A. (2005). The adolescent and young adult gap in cancer care and outcome. Current Problems in Pediatric and Adolescent Health Care, 35(5), 182–217. Scholar
  65. 65.
    Thomas, D. M., Albritton, K. H., & Ferrari, A. (2010). Adolescent and young adult oncology: An emerging field. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 28(32), 4781–4782. Scholar
  66. 66.
    Tricoli, J. V., & Bleyer, A. (2018, November 1). Adolescent and young adult cancer biology. Cancer Journal (United States). Lippincott Williams and Wilkins. Scholar
  67. 67.
    Ramphal, R., Aubin, S., Czaykowski, P., De Pauw, S., Johnson, A., McKillop, S., et al. (2016). Adolescent and young adult cancer: Principles of care. Current oncology (Toronto, Ont.), 23(3), 204–209. Scholar
  68. 68.
    Kim, B., Patterson, P., & White, K. (2018). Developmental considerations of young people with cancer transitioning to adulthood. European Journal of Cancer Care, 27(6), e12836. Scholar
  69. 69.
    Sansom-Daly, U. M., & Wakefield, C. E. (2013). Distress and adjustment among adolescents and young adults with cancer: An empirical and conceptual review. Translational pediatrics, 2(4), 167–197. Scholar
  70. 70.
    Zebrack, B. J. (2011). Psychological, social, and behavioral issues for young adults with cancer. Cancer, 117(SUPPL. 10), 2289–2294. Scholar
  71. 71.
    Adolescent and Young Adult Oncology Group. (2006). Care imperatives for adolescents and young adults with cancer. Report of the adolescent and young adult oncology group. Retrieved November 8, 2019, from
  72. 72.
    Sodergren, S. C., Husson, O., Rohde, G. E., Tomasewska, I. M., Griffiths, H., Pessing, A., Yarom, N., Hooker, L., Din, A., Darlington, A. S., EORTC Quality of Life Group, & EORTC Quality of Life Group. (2018). Does age matter? A comparison of health-related quality of life issues of adolescents and young adults with cancer. European Journal of Cancer Care, 27(6), e12980. Scholar
  73. 73.
    Thompson, K., Palmer, S., & Dyson, G. (2009). Adolescents & young adults: Issues in transition from active therapy into follow-up care. European Journal of Oncology Nursing, 13(3), 207–212. Scholar
  74. 74.
    Sodergren, S. C., Husson, O., Rohde, G. E., Tomasewska, I. M., Vivat, B., Yarom, N., Griffiths, H., & Darlington, A. S. (2018). A life put on pause: An exploration of the health-related quality of life issues relevant to adolescents and young adults with cancer. Journal of Adolescent and Young Adult Oncology, 7(4), 453–464. Scholar
  75. 75.
    Varni, J. W., Burwinkle, T. M., Katz, E. R., Meeske, K., & Dickinson, P. (2002). The PedsQL™ in pediatric cancer. Cancer, 94(7), 2090–2106. Scholar
  76. 76.
    Kendall, J. M. (2003, March). Designing a research project: Randomised controlled trials and their principles. Emergency Medicine Journal. Scholar
  77. 77.
    Bothwell, L. E., Greene, J. A., Podolsky, S. H., Jones, D. S., & Malina, D. (2016). Assessing the gold standard—Lessons from the history of RCTs. New England Journal of Medicine, 374(22), 2175–2181. Scholar
  78. 78.
    Hilgers, R.-D., König, F., Molenberghs, G., & Senn, S. (2016). Design and analysis of clinical trials for small rare disease populations. Dis Res Treat, 1 Retrieved from
  79. 79.
    Joseph, P. D., Craig, J. C., & Caldwell, P. H. Y. (2015). Clinical trials in children. British Journal of Clinical Pharmacology, 79(3), 357–369. Scholar
  80. 80.
    Jones, S. R., Carley, S., & Harrison, M. (2003, September). An introduction to power and sample size estimation. Emergency Medicine Journal. Scholar
  81. 81.
    Casali, P. G., Bruzzi, P., Bogaerts, J., Blay, J.-Y., & Rare Cancers Europe (RCE) Consensus Panel. (2015). Rare Cancers Europe (RCE) methodological recommendations for clinical studies in rare cancers: A European consensus position paper. Annals of oncology : official journal of the European Society for Medical Oncology, 26(2), 300–306. Scholar
  82. 82.
    Biau, D. J., Kernéis, S., & Porcher, R. (2008). Statistics in brief: The importance of sample size in the planning and interpretation of medical research. Clinical Orthopaedics and Related Research. New York: Springer. Scholar
  83. 83.
    Friedman, L. M., Furberg, C. D., & Demets, D. L. (2010). Fundamentals of clinical trials. Fundamentals of Clinical Trials. New York: Springer. Scholar
  84. 84.
    Kairalla, J. A., Coffey, C. S., Thomann, M. A., & Muller, K. E. (2012, August 23). Adaptive trial designs: A review of barriers and opportunities. Trials.
  85. 85.
    Abdel-Rahman, S. M., Reed, M. D., Wells, T. G., & Kearns, G. L. (2007). Considerations in the rational design and conduct of phase I/II pediatric clinical trials: Avoiding the problems and pitfalls. Clinical Pharmacology and Therapeutics, 81(4), 483–494. Scholar
  86. 86.
    Klassen, T. P., Hartling, L., Craig, J. C., & Offringa, M. (2008, August). Children are not just small adults: The urgent need for high-quality trial evidence in children. PLoS Medicine. Scholar
  87. 87.
    Gagne, J. J., Thompson, L., O’Keefe, K., & Kesselheim, A. S. (2014). Innovative research methods for studying treatments for rare diseases: Methodological review. BMJ (Clinical research ed.), 349, g6802. Scholar
  88. 88.
    Pallmann, P., Bedding, A. W., Choodari-Oskooei, B., Dimairo, M., Flight, L., Hampson, L. V., et al. (2018). Adaptive designs in clinical trials: Why use them, and how to run and report them. BMC Medicine, 16(1), 29. Scholar
  89. 89.
    Kelly, L. E., Dyson, M. P., Butcher, N. J., Balshaw, R., London, A. J., Neilson, C. J., Junker, A., Mahmud, S. M., Driedger, S. M., & Wang, X. (2018). Considerations for adaptive design in pediatric clinical trials: Study protocol for a systematic review, mixed-methods study, and integrated knowledge translation plan. Trials, 19(1), 572. Scholar
  90. 90.
    Jack Lee, J., & Chu, C. T. (2012). Bayesian clinical trials in action. Statistics in Medicine, 31(25), 2955–2972. Scholar
  91. 91.
    European Medicines Agency. (2017). ICH E11(R1) guideline on clinical investigation of medicinal products in the pediatric population.Google Scholar
  92. 92.
    European Medicines Agency. (2006). Guideline On Clinical Trials In Small Populations. Retrieved from
  93. 93.
    Driscoll, J. J., & Rixe, O. (2009, September). Overall survival: Still the gold standard: Why overall survival remains the definitive end point in cancer clinical trials. Cancer Journal. Scholar
  94. 94.
    Devidas, M., & Anderson, J. R. (2013). Considerations in the design of clinical trials for pediatric acute lymphoblastic leukemia. Clinical Investigation, 3(9), 849–858. Scholar
  95. 95.
    Fleming, T. R., & Powers, J. H. (2012). Biomarkers and surrogate endpoints in clinical trials. Statistics in Medicine, 31(25), 2973–2984. Scholar
  96. 96.
    Molenberghs, G., & Orman, C. (n.d.). Surrogate endpoints: Application in pediatric clinical trials.Google Scholar
  97. 97.
    Korn, E. L., McShane, L. M., & Freidlin, B. (2013). Statistical challenges in the evaluation of treatments for small patient populations. Science Translational Medicine. Scholar
  98. 98.
    de Rojas, T., Puertas, M., Bautista, F., de Prada, I., López-Pino, M. Á., Rivero, B., Gonzalez-San Segundo, C., Gonzalez-Vicent, M., Lassaletta, A., Madero, L., & Moreno, L. (2019). Improving the quality of care in the molecular era for children and adolescents with medulloblastoma. Clinical & Translational Oncology, 21, 1687–1698. Scholar
  99. 99.
    Kowalczyk J, Samardakiewicz M, Kowalewska-Bajor M, Pomaska EA, Fitzgerald E, Essiaf S. (2011). European Standards of Care for Children with Cancer. Retrieved from
  100. 100.
    From the American Academy of Pediatrics. (2014). Standards for pediatric cancer centers. Section on hematology/oncology. Pediatrics, 134, 410–414 Retrieved from Scholar
  101. 101.
    Knops, R. R. G., Hulscher, M. E. J. L., Hermens, R. P. M. G., Hilbink-Smolders, M., Loeffen, J. L., Kollen, W. J. W., et al. (2012). High-quality care for all children with cancer. Annals of Oncology, 23(7), 1906–1911. Scholar
  102. 102.
    Vlayen, J., Vrijens, F., Devriese, S., Beirens, K., Van Eycken, E., & Stordeur, S. (2012). Quality indicators for testicular cancer: A population-based study. European Journal of Cancer, 48(8), 1133–1140. Scholar
  103. 103.
    Bradley, N. M. E., Robinson, P. D., Greenberg, M. L., Barr, R. D., Klassen, A. F., Chan, Y. L., & Greenberg, C. M. (2013). Measuring the quality of a childhood cancer care delivery system: Quality indicator development. Value in Health, 16(4), 647–654. Scholar
  104. 104.
    de Rojas, T., Clementel, E., Giralt, J., Cruz, O., Boterberg, T., Kortmann, R.-D., et al. (2019). Radiotherapy practice for paediatric brain tumours across Europe and quality assurance initiatives: Current situation, international survey and future perspectives. European Journal of Cancer, 114, 36–46. Scholar
  105. 105.
    van der Graaf, W. T. A., Orbach, D., Judson, I. R., & Ferrari, A. (2017). Soft tissue sarcomas in adolescents and young adults: A comparison with their paediatric and adult counterparts. The Lancet Oncology, 18(3), e166–e175. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  • Teresa de Rojas
    • 1
    Email author
  • Anouk Neven
    • 2
  • Alexander J. Towbin
    • 3
    • 4
  • Fernando Carceller
    • 5
    • 6
  • Francisco Bautista
    • 7
  • David Riedl
    • 8
  • Samantha Sodergren
    • 9
  • Anne-Sophie Darlington
    • 9
  • Ana Fernandez-Teijeiro
    • 10
  • Lucas Moreno
    • 11
  1. 1.Medical DepartmentEORTC HeadquartersBrusselsBelgium
  2. 2.Statistics DepartmentEORTC HeadquartersBrusselsBelgium
  3. 3.Department of RadiologyCincinnati Children’s HospitalCincinnatiUSA
  4. 4.Department of RadiologyUniversity of Cincinnati College of MedicineCincinnatiUSA
  5. 5.Children & Young People’s UnitThe Royal Marsden NHS Foundation TrustLondonUK
  6. 6.Division of Clinical StudiesThe Institute of Cancer ResearchSuttonUK
  7. 7.Pediatric Oncology, Haematology and Stem Cell Transplantation DepartmentHospital Niño JesúsMadridSpain
  8. 8.University Hospital for Medical PsychologyMedical University of InnsbruckInnsbruckAustria
  9. 9.School of Health SciencesUniversity of SouthamptonSouthamptonUK
  10. 10.Pediatric Onco-Hematology UnitHospital Universitario Virgen MacarenaSevillaSpain
  11. 11.Paediatric Oncology & Haematology DepartmentVall d’Hebron University HospitalBarcelonaSpain

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