4 DISCUSSION
The prognostic nature of histological tumor necrosis in post-neoadjuvant
chemotherapy surgical specimens in osteosarcoma has been emphasized by
studies across different co-operative groups, where majority have
dichotomized response based on an arbitrary 90% TN cut-off.3,6,8,13 Though good responders with ≥90%TN had
better disease-free survival compared to poor responders, neither
increasing the proportion of good responders nor intensifying treatment
of poor responders has translated into better
survival.3,10,14,15 This questions the predictive
nature of this arbitrary cut-off for survival in management of
osteosarcoma. Studies have also considered alternative cut-offs of 70%,
50% tumor necrosis as surrogate measures of
outcome.11,12 The above studies question the value of
this 90% arbitrary cut-off for TN on a MAP-based chemotherapy backbone.
In this context, our study analyzed the prognostic significance of
various already established TN cut-offs of 100% and 90% on a non-MAP
based indigenous chemotherapy protocol. The relative distribution of the
patients among the various cohorts with respect to above cut-offs of TN
were similar to published data from western world, though the proportion
of larger primary tumors (≥8cm) were higher in our study cohort (60% vs
45-49%), albeit difference in the definition of tumor size across the
published studies (>150ml or >one-third of the
involved bone or ≥8cm).8,16,11 In addition, data on
70% or alternative cut-offs which was shown to be prognostic in a very
small cohort study is not available in these large
cohorts.11
The prognostic significance for EFS persisted across all three cut-offs
for whole and localized cohorts, with a gradual decline in EFS with
decreasing necrosis. This is akin to some of the larger
studies,2,3 though 90% cut-off failed to show
prognostic value in some other studies.11,17 There was
no differential impact on EFS of 100% and 90-99% TN in the above same
studies.11,17 Moreover, all these MAP-chemotherapy
based studies included patients above 15years as well (mostly patients
<40years of age) and non-MAP St Jude study included only
localized osteosarcoma.2 In our study, for the
metastatic cohort though, 70% TN was prognostic for EFS with a HR of
3.41, and both 100% and 90% did not impact EFS. Overall Survival was
affected only by 90% TN, in the whole and localized cohorts and none
affected OS in metastatic cohort. This underlines the controversial role
of tumor necrosis or histological response as a surrogate measure of
outcome in the current defined status. Since our study found 70% TN to
be prognostic for EFS across all groups, we decided to explore the
optimum cut-off value of TN using ROC for these cohorts. A TN cut-off of
85.5% with an AUC of 69% and 70% respectively for whole and localized
cohorts impacted EFS and in the metastatic cohort similar values were
84.5% TN at an AUC of 67%. This suggests the possibility of
investigating better cut-offs of TN for predictive or prognostic value
rather than using an arbitrary cut-off with no clinical meaning. This
has better utility in the context of a non-MAP chemotherapy backbone to
explore the survival incremental value with the addition of HD-MTX in an
adjuvant setting for thus defined poor responders. Also, thus defined TN
cut-off could help in triaging patients who are to be offered further
treatment in the metastatic setting in resource constrained settings,
where extremely poor prognosis is seen for poor responders.
The type of relapses seen in the cohort are similar to what is reported
in western literature,18 mainly metastatic to lungs
with no significant differences in the pattern of relapse based on tumor
necrosis across the various subsets. This is in accord with what is
already known in MAP-based chemotherapy studies.18 The
study also looked at various clinical and laboratory parameters which
predicted good and poor responders at various cut-offs of TN. Though a
previous reported study has shown no predictive value for tumor necrosis
amongst the various parameters,11 our study showed
amputation across all cut-offs and male gender at a cut-off of 90% to
predict poor necrosis, probably driven by bad biology.
This study has its own limitations in that it is a retrospective
analysis with a relatively shorter follow-up and smaller sample size,
especially in the setting of metastatic disease. Despite its
shortcomings, this cohort represents a single center experience of a
large group of a rare disease treated on a uniform non-MAP chemotherapy
protocol. The availability of tumor necrosis data recorded as an
absolute value permits for analysis at various cut-offs of TN compared
to studies which has dichotomized the patients into good and poor
responders based on a single cut-off of TN.
This analysis provides a basis to explore different cut-off levels for
TN especially in LMICs with higher tumor burden and possible different
biology for prognostic as well as predictive value in larger
multicentric studies. Exploring alternative cut-offs with predictive or
prognostic value would also help in tailored risk stratification of
treatment approaches based on newer drugs or biologic agents in future
studies.