2.2 | Outcome and variables
The primary outcome was event-free survival (EFS), defined as the time
between primary diagnosis and the occurrence of a first event
(progression, relapse, subsequent malignant neoplasm [SMN], or
death) or the end of follow-up (December 31, 2018). Most events were
captured through chart abstraction. To avoid missing events that
occurred at centers different from the primary treatment center,
validated health administrative data-based algorithms using billings for
chemotherapy, radiation, or palliative care with service dates after the
end of the initial therapy were utilized.24
The main exposure variable was a 3-level categorical variable combining
age and LOC. Pediatric LOC included patients aged 15 to 17.9
years old who were treated at a pediatric center. Adult ≥18 LOCcomprised 18 to 21 years old patients who were treated at an adult
center. Patients in pediatric age group (<18 years) who were
treated at an adult facility or diagnosed at a pediatric center but
treated at an adult center, were categorized as adult<18
LOC . A patient’s main treating institution was categorized based on
delivery of the majority of chemotherapy and/or radiotherapy during
first three months after diagnosis. Patients who received upfront
chemotherapy at a pediatric center and radiation at an adult center,
were considered as pediatric-center patients.
Demographic and patient-related variables included sex and socioeconomic
variables (neighborhood median income quintile, rurality, immigrant
status). Neighborhood median income quintile was determined utilizing
the Canadian census and respective postal code at the date closest to
the date of cancer diagnosis. Patients were classified as having urban
or rural residence according to their residential postal code at
diagnosis and the Rurality Index for Ontario
(RIO)-2004.25 The immigration status of each patient
was determined by utilizing the Citizenship and Immigration Canada (CIC)
database and recorded as a binary (yes/no) variable. The main
disease-level variables were histology (OGS or EWS),
DIL, metastatic status at
diagnosis (localized versus metastatic), and site of the primary tumor
(limb versus axial).
To calculate DIL, all healthcare claims and visit records in the year
preceding cancer diagnosis were organized as discrete episodes and each
episode was assigned a single ICD code representing the main purpose
(symptom or diagnosis) of that episode. Two pediatric oncologists
(PN and SG ) defined the diagnostic codes that were
consistent with an underlying OGS
or EWS diagnosis, based on their clinical expertise. The DIL for each
patient was calculated as the time interval between the date of the
first relevant physician encounter with a definite OGS- or EWS-related
symptom and the date of cancer diagnosis. To evaluate the association
between DIL and survival, categorical variables with two levels
according to the calculated median DIL (i.e., short delay ≤
median and prolonged delay > median) were created
separately for OGS and EWS.
Treatment variables other than LOC included clinical trial enrollment
(enrolled vs non-enrolled), time from diagnosis to local therapy, and
chemotherapy cumulative doses (mg/m2). Time to local
therapy was defined as the time from the date of diagnosis to the date
of first definitive local treatment (surgery and/or radiation) and was
categorized as early (≤ 3 months) versus late (>3 months).
The cumulative doses of chemotherapeutic agents were identified and
recorded. The Cyclophosphamide Equivalent Dose (CED) was calculated for
alkylating agents, using the following equation:26