4 | DISCUSSION
In this retrospective population-based cohort study of AYA with OGS or
EWS, we found that despite significant differences in clinical and
treatment exposures between patients treated at pediatric versus adult
centers (Table 1 ), the location of treatment did not impact
survival for either disease.
Previous studies have shown that AYA with ALL or Hodgkin lymphoma have
superior survival when treated at pediatric
centers.7,10 This has been attributed to disparities
in treatment regimens and chemotherapy dose intensity, clinical trial
enrollment, and treatment team experience11,12,14However, there are few studies that have compared the impact of clinical
and treatment differences between pediatric and adult centers on the
outcomes in AYA with bone tumors.12,13,16
Howell et al. investigated the impact of LOC on survival outcomes in a
retrospective study of 1,751 cancer patients (including 76 patients with
OGS or EWS) aged 0 to 19 years, treated at one of five US pediatric
cancer centers (Children’s Oncology Group [COG] members) or in a
non-COG (“adult”) institution.13 Only 36% of
patients, aged 15 to 19 years were treated at a COG (pediatric)
institution. In AYA patients with “pediatric type” cancers (i.e.,
cancers that are more common in pediatric age groups: OGS, EWS, Hodgkin
lymphoma, ALL, neuroblastoma, rhabdomyosarcoma), those treated at
pediatric centers had superior survival outcomes than those who received
care at non-pediatric institutions. However, these differences were not
statistically significant, possibly due to the small number of the
patients.13 In a subsequent report, Bleyer et al.
re-analyzed the same data to assess the likelihood of treatment of the
type of cancer (“pediatric vs adult-type”) by oncologists with
pediatric versus adult cancer experience.12 The
results revealed that AYA with “pediatric-type” cancers had better
survival at COG (pediatric) centers and those with adult-type tumors
(e.g. non-Hodgkin lymphoma) showed a better survival at non-COG (adult)
institutions.12 The authors concluded that the AYA
patients with pediatric types of cancer (including OGS and EWS) fare
better if their care is delivered by pediatric
oncologists.12
In an institution-based retrospective study of 53 patients (29 pediatric
and 24 adult) with localized EWS, Gupta et al. studied survival outcomes
among those treated at an adult or a pediatric tertiary cancer care
center in Ontario between 1990 and 2005.16 The median
age for the pediatric and adult patients was 13.4 years (range,
0.29-16.2 years) and 26.1 years (range, 16.7-66.5 years), respectively.
The total cumulative doses of ifosfamide and cyclophosphamide were lower
(p<0.0001) and the time-to-local therapy was longer (7.4
months vs 3.7 months; p= 0.0003) in the adult center compared to the
pediatric center. The 3-year EFS rates in pediatric and adult patients
were 70% and 43% (p=0.1) and the 3-year OS rates were 81% and 59%
(p=0.02), respectively. The
authors concluded that the inferior survival outcome of EWS patients
treated at an adult center may be related to lower cumulative doses of
alkylating agents and a delay in local therapy in adult-center
patients.16 In our localized EWS cohort, none of LOC,
primary cancer site or time to local therapy was associated with
survival.
In our study, the reason for superior EFS in patients with metastatic
disease who received higher cumulative doses of methotrexate,
doxorubicin, and cisplatin in OGS or cisplatin in EWS is unclear. One
possibility is that the higher dose of chemotherapy effectively impacts
the survival of patients with metastasis. The second, more likely
possibility is that patients with more aggressive disease may have
received lower doses of chemotherapeutic agents with a goal of
controlling symptoms and avoiding toxicities, or that more aggressive
tumors progressed leading to discontinuation of primary therapy, thus
confounding the relationship between chemotherapy dose and survival.
Unfortunately, the relevant data needed to classify metastatic patients
according to their disease severity and aggressiveness were not
available to test this hypothesis. The prognostic impact of cumulative
doses of chemotherapeutic agents are not separately described in
papers that have investigated OGS and EWS prognostic factors. In some
studies, the response to neoadjuvant chemotherapy, measured by necrosis
extent in surgical specimens, has been considered as a prognostic
factor.27,28,29 We did not have access to pathology
data from excised tumors, so could not evaluate this relationship.
Some studies have shown superior outcomes for patients who treated at
pediatric centers with high rate of participation in clinical
trials.30-33 But some authors argue that patients
enrolled in clinical trials might not represent the general population
and thus the results might be biased.11 In our study,
about half of pediatric-center patients with OGS and EWS and only a few
adult-center patients were enrolled in clinical trials. Neither EFS nor
OS rates significantly differed in patients who were enrolled versus
those who were not enrolled in clinical trials.
In our study and several other reports19-21, there was
no association between DIL and survival in either OGS or EWS. Goedhart
et al. reported that prolonged DIL does not necessarily result in
inferior survival in OGS and EWS and concluded that the impact of tumor
location and its resectability on survival is more than the effect of
delay in diagnosis.20
The strength of this study, as one of the few studies in literature that
compares outcomes of AYA OGS and EWS in pediatric versus adult centers,
was the use of health administrative data along with population-based
databases. This combination of datasets provided us with an opportunity
to capture the relevant health data of the entire provincial population
and to assess a wide range of demographic, disease- and
treatment-related variables and their impact on outcome as well as with
access to possible interactions with the health care system. Using this
type of data, improved the generalizability of the results and ensured
that our findings were not susceptible to recall bias and poor
documentation seen in studies based on chart abstraction or
questionnaires.
One of the issues in evaluating the prognostic effect of age in OGS,
EWS, and other cancers is disparities in age ranges and in definitions
of pediatric, adolescent and young adult age groups in various studies.
The limited age range of AYA (15 to 21 years) in our study reduced its
sample size and hence its power and generalizability and made it
difficult to compare our results with those of other studies that
included a wider age ranges of AYA patients. Another limitation was
missing data in some recognized prognostic factors such as tumor size,
response to neoadjuvant chemotherapy (tumor necrosis) and surgical
margin status; so that we had to exclude these variables from the study.
In conclusion, survival outcomes in AYA with OGS and EWS in our study
did not differ by LOC. This stands in contrast to AYA cancers such as
ALL and Hodgkin lymphoma, where studies have shown superior survival
associated with treatment at pediatric centers. In this study, even
though AYA with bone tumors treated at pediatric centers received higher
cumulative doses of chemotherapy than in adult centers, the differences
did not impact outcomes. Lack of outcome differences by LOC in our study
might be explained by the similarities of treatment team expertise and
therapeutic regimens for bone tumors and also biologic characteristics
of the patients (given the narrow AYA age range) between pediatric and
adult cancer centers. Furthermore, although data was not collected, all
bone tumors in Ontario are operated on by specialized orthopedic
oncologists; the quality of surgical resection is known to be an
important prognostic factor in those with localized bone
tumors.34,35
Future studies can work on extending the AYA age range to above 21 years
by either chart abstraction or linkage to other administrative databases
in order to provide a larger sample size and to address the
uncertainties about the prognostic impact of LOC, age, cumulative doses
of chemotherapeutic agents, and other covariates.
ABBREVIATIONS : AYA, adolescents and young adults; CI,
confidence interval; CIC, the Citizenship and Immigration Canada
database; COG, Children’s Oncology Group; Cox PH survival analysis, Cox
proportional hazard survival analysis; EFS, event-free survival; EWS,
Ewing sarcoma; HR, hazard ratio; ICES, Institute for Clinical Evaluative
Sciences; IMPACT, the Initiative to Maximize Progress in Adolescent and
Young Adult Cancer Therapy; IQR, interquartile range; OCR, Ontario
Cancer Registry; OGS, osteogenic sarcoma; POGONIS, Pediatric Oncology
Group of Ontario Networked Information System; SCC, specialized cancer
center; SMN; subsequent malignant neoplasm