METHODS
We analyzed all the patients included on June 11, 2019, in the L.E.A
program (clinicaltrials.gov identifier: NCT 01756599). This is a
national cohort initiated in 2003 to assess the long-term health of
patients who were treated in childhood or adolescence for AL, from 1980.
The precise functioning of the cohort has already been defined
previously 18. Briefly participants are summoned to a
follow-up clinic at predefined dates, starting one year after SCT or
after completion of chemotherapy. These visits continue every two years
until the age of 20 and at least 10 years of complete remission (CR),
and every four years thereafter. Late effects were detected by
physicians through regular visits to reference centers, comprising a
medical examination and adequate additional tests. Thus, fourteen late
effects were prospectively assessed in the entire cohort in which ON was
diagnosed.
All patients (or their parents) provided written informed consent. This
study was approved by the Sud Méditerranée V ethics committee (opinion
n° 2012-A00984-39), in compliance with the General Data Protection
Regulation.
We divided our study in two parts. The first study was conducted on all
patients with a symptomatic ON identified in the L.E.A. program, to
identify the risk factors for the occurrence of this complication, as
well as those for having multifocal involvement at diagnosis, and to
evaluate the impact of this side effect on long term QoL
The second one focused on radiological assessment for patients who met
the following criteria: presence of symptomatic ON with a MRI performed
at diagnosis and available for centralized double blinded review at time
of the study by 2 experienced pediatric radiologists. The proofreading
was performed independently by these radiologists.
The positive diagnosis of ON was retained in the presence of a
serpiginous borderline in T1 hypointense delimiting the necrosis area,
joining the subchondral bone lamina for epiphyseal damage.19 The parameters concerning the location and
extension of the necrosis were collected in order to classify each
location of symptomatic ON according to a grade of severity in
accordance with Niinimäki’s classification 16 (see
Appendix 1) : site of necrosis (epiphysis, metaphysis or diaphysis),
bearing character of the joint, affected articular or epiphyseal
surface, presence of joint deformation. Were also listed parameters
which are known to potentially modify the prognosis 20: presence of bone edema associated with the periphery of the necrosis
area, presence of intra-articular effusion, other ON locations or
distant bone marrow edema in the field of exploration, growth cartilages
fusion and signal in T1 of the necrosis range (variable depending on the
course, initially fatty then progressing to fibrosis).
In the event of disagreement on the severity grade, a joint review was
carried out and a consensus was reached. Radiological severity was
defined by the presence of V grade, i.e., joint deformity. In the event
of multifocal involvement, we have chosen to consider the most severe
impairment.
Quality of life of children and adolescents was assessed using the
parents’ version of the Vécu et Santé Perçue de l’Adolescent et l’enfant
(VSP-Ap) which is completed by the parents of the children and
adolescents 21–23 . The questionnaire is comprised of
nine dimensions and a summary score. All scores range between 0 and 100,
with higher scores indicating a better Health Related Quality of Life
(HRQoL). Reference values are available for the general French
population > 7 years of age for sex- and age-matched
comparison purposes 22,24. Adult patients were asked
to complete SF-36 questionnaires which consists of 36 items. Results are
divided into eight sub scales and two calculated composite scores
(physical and mental composite score). The reliability of this scale
both in survivors of childhood cancers and in its French version has
already been validated 25
Statistical
methods
The data collected is presented in the form of counts and percentages
for the qualitative variables and in the form of means and standard
deviations for the quantitative variables. The normality of the
distribution of quantitative variables was verified. Chi-square tests or
Fisher’s exact tests made it possible to compare the qualitative
variables according to the different groups of interest. For the
quantitative variables, these comparisons were made by Student’s tests.
Logistic regressions were carried out, making it possible to model: the
risk factors for the onset of ON, multifocal and severe involvement.
First univariate analyzes were performed. Variables whose p-value was
less than 0.05 in the univariate analysis were retained for the
multivariate analysis; a descending step-by-step selection was then
carried out. Only the significant variables below the significance level
(p-value < 0.05) were maintained in the final multivariate
model. All analyses were carried out with a significance level of 0.05.
Analyses were performed using IBM SPSS Statistics Version 20 software.
HRQoL scores of our patients were compared with the French reference
scores for age and sex using paired Student’s t-tests. The calculation
of inter-observer reproducibility was determined by kappa statistics
between raters, and the results was interpreted according to guidelines
adapted from Landis and Koch. 26