Discussion
Osteosarcoma remains one of the most challenging pediatric cancers to
treat. Despite therapy advancements in the 1970s to 1980s, survival
rates have plateaued over the past four decades with a 5-year overall
survival rates remaining around 63%.9,10 Advancements
continue to prove challenging, in part due to the rarity of the disease
and very complicated biology. Tumor necrosis has long been known to be a
strong prognostic factor, but its utility in informing changes in
adjuvant regimens remains elusive. A large, international randomized
controlled trial, EURAMOS-1, was conducted to investigate whether
intensified MAP plus ifosfamide and etoposide (MAPIE) therapy in
patients with poor response (tumor necrosis less than 90%) would result
in improved outcome. They also investigated whether maintenance therapy
with pegylated interferon alfa-2b in patients with good histologic
response (tumor necrosis greater than or equal to 90%) was superior to
MAP alone. These studies failed to demonstrate improvement in long-term
outcomes when stratifying treatments based on histologic
response.12,13The results from our study revealed that minor aberrations from the SOC
schedule did not correlate with lower tumor necrosis. This is consistent
with the hypothesis that tumor necrosis is likely a biologic marker of a
specific tumor’s sensitivity to chemotherapy and is thus not improved
with small alterations of the existing neoadjuvant regimen. It should be
noted, however, that in our patient population, all timing aberrations
were relatively minor, with the longest neoadjuvant chemotherapy to
surgery interval being 33 days. It is reasonable to hypothesize that
longer delays could result in tumor regrowth, and thus a lower
percentage of tumor necrosis.
This study did, however, demonstrate that delays in LC may confer worse
outcome, as defined by 5-year EFS. Additionally, longer neoadjuvant
chemotherapy to surgery intervals in general correlate with increased
risk of having an event in patients with localized disease at the time
of diagnosis after adjusting for relevant potential confounders. This is
clinically intuitive, as patients with metastatic disease or very large
primary tumors at the time of diagnosis face poor outcomes regardless of
treatment. Though it is unclear if there is an optimal interval length
between neoadjuvant treatment and surgery, this study suggests that
attempts to reduce delays to surgery may improve outcomes in children
and young adults with osteosarcoma. This requires early surgical
planning, close communication with surgeons regarding treatment delays,
and ample coordination with outside institutions when medical and
surgical management is occurring at different locations.
Notably, a recent study conducted at King Hussein Cancer Center in
Jordan examining patients under the age of 18 with non-metastatic
osteosarcoma demonstrated that a time from diagnosis to LC greater than
or equal to 18 weeks was associated with worse event free survival and
overall survival.20 This is consistent with our
findings that treatment delay generally is associated with worse
outcomes. It is important to note that intervals from diagnosis to LC
greater than 18 weeks are uncommon in our clinical setting. Only one
patient had a time from the initiation of chemotherapy to LC interval
greater than 18 weeks. While this does not include time from diagnosis
to initiation of chemotherapy, delays prior to chemotherapy initiation
are exceedingly uncommon. This study adds context that more minor
delays, particularly after completion of neoadjuvant chemotherapy, also
may confer worse outcomes.
There are limitations to our retrospective study. It does not allow us
to fully control covariate differences between the exposure and control
groups, introducing a greater degree of potential confounders than a
randomized clinical control study. This study can only suggest
correlation, and the possibility of an unmeasured confounder, such as
socioeconomic barriers contributing to treatment delays and contributing
to worse outcomes, cannot be excluded. There are limitations to
assessing current patient status based on accessibility of information.
Attempts to mitigate this included obtaining follow up information from
outside institutions, as is standard practice, when possible and
censoring all follow up information at 5-years. Since OS is such a
highly aggressive cancer, most patients who will relapse do so in the
first five years following completion of chemotherapy. Notably some
patients (2019-2022) do not yet have five years of follow up information
and this is a limitation of this study. Additionally, though tumor
necrosis is a universally established measurement for osteosarcoma,
there may be a certain degree of variability in the exact measurements
between pathologists. Another limitation of this study is the fairly
small sample size; results such as the correlation between interval
length and tumor necrosis were not statistically significant but may
require more data to yield sufficient precision before meaningful
correlations can be ruled out. However, this is a substantial sample
size for a rare disease like OS. Relatedly, interval length was treated
as a linear effect in all models due to limited modeling degrees of
freedom but may have a non-linear effect on EFS. Finally, it is
important to note that we are reducing highly individualized
chemotherapy and disease courses into measurable data. Many factors
affect a patient’s therapeutic course. While the neoadjuvant regimen
largely remains unchanged, toxicities in the adjuvant setting may lead
to non-optimal regimens, altering outcomes but not being captured in the
data.
In conclusion, our study demonstrates that delays in local control are
not strongly associated with lower tumor necrosis. However, surgical
delays from completion of induction chemotherapy correlate to worse
outcome in localized disease. Therefore, minimizing the delay from the
completion of neoadjuvant chemotherapy to LC should continue to be
weighed against the potential risks of infection and wound healing
complications associated with decreasing this interval.