Prognostic factors of overall survival in children and adolescents enrolled in dose-finding trials in Europe: An Innovative Therapies for Children with Cancer study.
Dose-finding trials are fundamental to develop novel drugs for children and adolescents with advanced cancer. It is crucial to maximise individual benefit, whilst ensuring adequate assessment of key study end-points. We assessed prognostic factors of survival in paediatric phase I trials, including two predictive scores validated in adult oncology: the Royal Marsden Hospital (RMH) and the MD Anderson Cancer Center (MDACC) scores.



Data of patients with solid tumours aged <18 years at enrolment in their first dose-finding trial between 2000 and 2014 at eight centres of the Innovative Therapies for Children with Cancer European consortium were collected. Survival distributions were compared using log-rank test and Cox regression analyses.



Overall, 248 patients were evaluated: median age, 11.2 years (range 1.0-17.9); 46% had central nervous system (CNS) tumours and 54% extra-CNS tumours. Complete responses were observed in 2.1%, partial responses in 7.2% and stable disease in 25.9%. Median overall survival (OS) was 6.3 months (95% confidence interval, 5.2-7.4). Lansky/Karnofsky ≤80%, no school/work attendance, elevated creatinine and RMH score ≥1 correlated with worse OS in the multivariate analysis. The RMH and MDACC scores correlated with OS in adolescents (12-17 years), p = 0.002, but not in children (2-11 years).



Performance status of 90-100% and school/work attendance at enrolment are strong indicators of longer OS in paediatric phase I trials. Adult predictive scores correlate with survival in adolescents. These findings provide a useful orientation about potential prognosis and could lead in the future to more paediatric-adapted eligibility criteria in early-phase trials.
Paediatric and Adolescent Drug Development, Children and Young People's Unit, The Royal Marsden NHS Foundation Trust, London, UK; Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, London, UK. Electronic address: Fernando.Carceller@icr.ac.uk.
Fernando
F
Carceller
Department of Paediatric and Adolescent Oncology, Gustave Roussy, Université Paris-Sud, Villejuif, France. Electronic address: franciscojose.bautista@salud.madrid.org.
Francisco J
FJ
Bautista
Department of Paediatric, Adolescents and Young Adults Oncology, Institut Curie, Paris, France. Electronic address: irene.jimenez@curie.fr.
Irene
I
Jiménez
Department of Paediatric and Adolescent Oncology, Gustave Roussy, Université Paris-Sud, Villejuif, France. Electronic address: rhladun@vhebron.net.
Raquel
R
Hladun-Álvaro
Department of Paediatric Clinical Trials, Institut Hématologique et d'Oncologie Pédiatrique, Lyon, France; Department of Paediatric Neuro-Oncology, Institut Hématologique et d'Oncologie Pédiatrique, Lyon, France. Electronic address: cecile.giraud@lyon.unicancer.fr.
Cécile
C
Giraud
Paediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Luca.Bergamaschi@istitutotumori.mi.it.
Luca
L
Bergamaschi
Department of Paediatric Oncology, Birmingham Children's Hospital, Birmingham, UK. Electronic address: Madhumita.Dandapani@bch.nhs.uk.
Madhumita
M
Dandapani
Department of Paediatric, Adolescents and Young Adults Oncology, Institut Curie, Paris, France. Electronic address: isabelle.aerts@curie.fr.
Isabelle
I
Aerts
Department of Paediatric, Adolescents and Young Adults Oncology, Institut Curie, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France. Electronic address: francois.doz@curie.fr.
François
F
Doz
Department of Paediatric Clinical Trials, Institut Hématologique et d'Oncologie Pédiatrique, Lyon, France; Department of Paediatric Neuro-Oncology, Institut Hématologique et d'Oncologie Pédiatrique, Lyon, France. Electronic address: didier.frappaz@ihope.fr.
Didier
D
Frappaz
Paediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Michela.Casanova@istitutotumori.mi.it.
Michela
M
Casanova
Department of Paediatric Oncology, Birmingham Children's Hospital, Birmingham, UK. Electronic address: BRUCE.MORLAND@bch.nhs.uk.
Bruce
B
Morland
Paediatric Oncology Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. Electronic address: Darren.Hargrave@gosh.nhs.uk.
Darren R
DR
Hargrave
Paediatric and Adolescent Drug Development, Children and Young People's Unit, The Royal Marsden NHS Foundation Trust, London, UK; Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, London, UK. Electronic address: LynleyVanessa.Marshall@icr.ac.uk.
Lynley V
LV
Marshall
Department of Clinical Research, Gustave Roussy, Université Paris-Sud, Villejuif, France. Electronic address: Gilles.Vassal@gustaveroussy.fr.
Gilles
G
Vassal
Paediatric and Adolescent Drug Development, Children and Young People's Unit, The Royal Marsden NHS Foundation Trust, London, UK; Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, London, UK. Electronic address: andy1pearson@btinternet.com.
Andrew D J
AD
Pearson
Department of Paediatric and Adolescent Oncology, Gustave Roussy, Université Paris-Sud, Villejuif, France. Electronic address: Birgit.GEOERGER@gustaveroussy.fr.
Birgit
B
Geoerger
Clinical Trials Unit, Paediatric Oncology Department, Hospital Niño Jesús, Madrid, Spain. Electronic address: lmorenom@ext.cnio.es.
Lucas
L
Moreno
D000293:Adolescent; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D017321:Clinical Trials, Phase I as Topic; D004651:Employment; D004806:Ependymoma / Q000188:drug therapy / Q000401:mortality; D005060:Europe; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000401:mortality; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy / Q000401:mortality; D015999:Multivariate Analysis; D009369:Neoplasms / Q000188:drug therapy / Q000401:mortality*; D009447:Neuroblastoma / Q000188:drug therapy / Q000401:mortality; D018242:Neuroectodermal Tumors, Primitive / Q000188:drug therapy / Q000401:mortality; D012516:Osteosarcoma / Q000188:drug therapy / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000401:mortality; D012509:Sarcoma / Q000188:drug therapy / Q000401:mortality; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000401:mortality; D012574:Schools; D015996:Survival Rate; D035703:Therapies, Investigational
Adolescents; Children; Dose-finding trial; Innovative Therapies for Children with Cancer; Phase I trial; Prognostic factor; Survival