NcXHF

RETHINKING TREATMENT FOR CHONDROSARCOMA: A ROLE FOR IDH INHIBITION?
greatly. A recent retrospective study showed prolonged
overall survival in patients with extraskeletal myxoid
chondrosarcoma despite high rates of local and distant recurrence.
52 Although anthracycline chemotherapy has not
been effective historically, recent reports of clinical responses
from sunitinib are encouraging for patients with
metastatic disease. 53
TREATMENT CONSIDERATIONS
As previously discussed, understanding the histologic subtype
and grade of chondrosarcoma is helpful in predicting
biologic behavior. However, regardless of subtype, surgical
resection remains the cornerstone of therapy with the best
potential for cure of primary chondrosarcoma. 9
Several retrospective studies have shown that wide excision
with negative margins is associated with higher event-free
survival and overall survival rates for patients with large tumors
and pelvic localization, regardless of the histologic
grade. 54,55 A meta-analysis published in 2011 showed that in
select patients with low-grade, nonpelvic chondrosarcomas,
intralesional excision may be used as an alternative to wide
excision without affecting outcomes. 56 In general, the recommended
approach by the National Comprehensive Cancer
Network Guidelines (Bone Sarcoma Version 1.2015) is wide
local excision of the chondrosarcoma for any intermediate or
high-grade histologies, large tumor size, pelvic locations, and
intra-articular or soft-tissue involvement. This should be
performed in a high-volume sarcoma center with experienced
orthopedic oncologists.
Chondrosarcomas are relatively radiotherapy (RT)-resistant.
Currently, there is not enough data to support its routine use
in patients with this disease. However, RT may be considered
if there is incomplete resection, for palliation of symptoms, in
patients with advanced or unresectable tumors, or for mesenchymal
chondrosarcoma. 57 In a large series involving 229
patients with chondrosarcomas of the skull base, the combination
of proton and photon beam RT resulted in a sustained
local control rate in most patients. 58
The role of chemotherapy in the treatment of patients with
chondrosarcoma remains unclear and should be considered on
a case-by-case basis. At our center, we generally reserve chemotherapy
for dedifferentiated and mesenchymal subtypes for patients
with reasonable performance status.
Although the vast majority of patients with recurrent or
metastatic chondrosarcoma do not respond to conventional
sarcoma chemotherapy regimens, there are anecdotal reports
of successful treatment with doxorubicin-based regimens,
single-agent ifosfamide or methotrexate. 36,59-61
The mechanisms contributing to resistant to chemotherapy
that are seen in chondrosarcomas are not fully understood.
It has been suggested that because of avascular matrix
and often a low percentage of dividing cells, these tumors
have a poor response to chemotherapy that targets cycling
cells. 57 In the case of mesenchymal chondrosarcoma, the majority
of the tumor may be composed of well-differentiated
chondrosarcoma cells and cartilaginous matrix. Thus, there
may be little shrinkage even when the chemotherapy was effıcacious
against the small round blue cell component of the
biphenotypic tumor cells. It also has been suggested that the
expression of P-glycoprotein plays a role in resistance to
chemotherapy. P-glycoprotein is encoded by the gene multidrug
resistance-1 (MDR-1) and is expressed by chondrosarcoma
cells. 62 It has been demonstrated that the expression of
MRD-1 in human chondrosarcoma cell lines results in resistance
to doxorubicin in vitro. 63
Targeted Therapy for Chondrosarcoma
Within the last several years, there has been increased interest
in exploring targeted therapies for chondrosarcomas. Our
understanding of pathways implicated in chondrosarcomas
is reviewed by Samuel et al. 64 As outlined in their work, one
can consider the early and late genetic events that lead to the
development of chondrosarcomas to design potential pathways
that may be amenable to inhibition.
The indian hedgehog (IHH)/parathyroid hormone-related
peptide pathway (PTHrP) is critical to chondrocyte maturation
and development, and constitutive IHH signaling has
been demonstrated in chondrosarcomas. Based on upregulation
of intramembrane receptor patched (PTCH) and
downstream transcription factors, including GLi, clinical trials
were conducted with GDC-0449. Unfortunately, medical
progression-free survival was short at 3.5 months and further
enrollment on the study was halted. 65
Another pathway of interest in chondrosarcoma was PI3K/
mTOR, based on observations of increased receptor-type
tyrosine kinase activity, including high levels of phosphorylated
S6 and marked in vitro response to BEZ235, a PI3K/
mTOR inhibitor. 66 In a recent retrospective analysis, 10
patients with unresectable recurrent chondrosarcoma received
the combination of sirolimus/cyclophosphamide. The
chemotherapy was well tolerated and resulted in a disease
control rate of 70% (10% of patients had objective response
and 60% of patients had stable disease for at least 6 months). 67
Based on these fındings, further exploration of mTOR inhibition
is warranted.
Activation and/or overexpression of PDGFR-alpha
(PDGFRA) and PDGFR-beta (PDGFRB) has been described
in conventional chondrosarcomas, but activating mutations
have not been found. 68 Unfortunately, trials have failed to
show signifıcant clinical activity. 69
Finally, another mechanism with interesting preclinical results
in chondrosarcomas focuses on targeting epigenetic
regulatory mechanisms via histone deacetylase inhibitors.
Several studies have revealed the key roles played by acetylation
or deacetylation in specifıc gene expressions of chondrocytes.
70,71 Further research revealed that HDAC inhibitors
cause a variety of phenotypic changes, such as cell cycle arrest,
morphologic reversion of transformed cells, apoptosis,
and differentiation. 72,73 Sakimura et al recently reported the
inhibition of tumor growth and the induction of differentiation
of chondrosarcoma cells using the HDAC inhibitor depsipeptide.
74 Because of the promising results, several HDAC
inhibitors currently are being used in clinical trials.
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