Dedifferentiated chondrosarcoma

Ifosfamide -based chemotherapy was the only independent prognostic factor for disease-specific
survival based on the multivariate analysis using a Cox regression model (hazard ratio, 0.4; 95%
CI, 0.17–0.92; p = 0.03). We conclude that ifosfamide-based adjuvant chemotherapy combined
with surgical resection provided a survival benefit in the small series of dedifferentiated
chondrosarcoma; however, the prognosis remains generally poor. Whereas the National
Comprehensive Cancer Network guidelines suggest treating dedifferentiated chondrosarcoma in
a fashion similar to the recommended treatment for osteosarcoma, we recommend adding
ifosfamide to the regimen. [1].
One hundred and thirty-one patients (73%) received an anthracycline-containing regimen. Using
RECIST, the objective response rate was significantly different according to histological
subtype, being (...), 20.5% for dedifferentiated chondrosarcoma [2]
We studied protein expression of the estrogen receptor in 35 cartilaginous tumors as well as
mRNA levels for the estrogen receptor and for aromatase. All chondrosarcomas tested showed
mRNA and nuclear protein expression of the estrogen receptor. Also, aromatase mRNA was
detected. The aromatase activity assay showed a functional aromatase enzyme in primary
chondrosarcoma cultures and in a cell line. Growth of chondrosarcoma cell cultures can be
stimulated by adding estrogen or androstenedione, which can be inhibited by exemestane [3].
Recently, we have reported an association between the occurrence of breast cancer and
cartilaginous tumors in the same patient [4]. Breast tumors of patients with a cartilaginous tumor
were significantly more often positive for ERα protein expression [5], thereby providing another
potential link between estrogen signaling and chondrosarcoma.
The presence of ESR1 and aromatase in chondrosarcoma tumors and primary cultures supports a
possible role of estrogen signaling in chondrosarcoma proliferation. However, our in vitro and
pilot in vivo studies have shown no effect of estrogen-signaling inhibition on tumor growth. [6]
Chondrosarcoma displays diverse histopathology and clinical behavior. The clinical management
is exceptionally challenging as they are inherently resistant to conventional chemo and radiation
therapy, therefore new therapeutic approaches are urgently needed [7]
The emerging role of IDH mutations in chondrosarcoma

 Preclinical data indicate antitumor activity of IDH inhibitors in chondrosarcoma cell

lines. Ongoing early phase clinical trials are evaluating the clinical activity of novel IDH
inhibitors in patients with advanced solid tumors, including chondrosarcoma with
an IDH1 and/or IDH2 mutation.

Targeting the hedgehog pathway

 Emerging evidence proposes constitutive Indian Hedgehog signaling to have a key role in
the pathogenesis of chondrosarcomas. However, the clinical data of a Phase II trial of IPI-
 926 (saridegib) in patients with advanced chondrosarcoma have been discouraging,
although preclinical data have demonstrated activity in a wide range of malignancies.

The SRC pathway

 Src has been proposed to play an important role in signal transduction in human sarcomas
and a number of Src inhibitors, including dasatinib (BMS354825) are currently at various
stages in the development process.

 Dasatinib has shown some preclinical activity in chondrosarcomas as a single agent, but
there is, also, evidence to support the use of dasatinib in combination with other
antineoplastic drugs, for example, doxorubicin.

Targeting the PI3K–Akt–mTOR pathway

 Preclinical data indicate that inhibition of the PI3K/Akt/mTOR pathway has suppressant
effect on chondrosarcoma tumor progression.

 Several early phase clinical trials are evaluating the combined mTORC1 and IGF-1R
inhibition in sarcoma patients, with early results indicating that the combination may
have greater clinical efficacy than treatment with each agent alone.

Histone deacetylase inhibitors

 Preclinical data show that histone deacetylase inhibitors induce growth arrest, apoptosis
and differentiation in sarcoma cancer stem cells, as well as in chondrosarcoma cells.
There is an ongoing Phase II clinical trial of the histone deacetylase inhibitors
Romidepsin in metastatic or unresectable soft tissue sarcomas (NCT00112463).

The role of angiogenesis

 Evidence from preclinical data implicates angiogenesis with the pathogenesis of

chondrosarcomas, while angiogenesis inhibitors show tumor growth inhibition in
chondrosarcoma animal models and cell lines.

We have reviewed our experience with this neoplasm in 22 patients, all of whom were treated
using modern oncological principles of planned resection and chemotherapy. (...) Those patients
who received chemotherapy, and in whom wide margins of excision were achieved at operation,
did best. It is essential to have an accurate preoperative diagnosis in order to plan treatment
which may offer a better prospect of cure [8].

Dedifferentiated chondrosarcoma carries a dismal prognosis. Although 30% of patients received

chemotherapy in this study we were not able to prove that it improved survival. Early diagnosis
and complete surgical excision still offer the best prognosis for this condition [9].
1. Kawaguchi S, Sun T, Lin PP, Deavers M, Harun N, Lewis VO. Does ifosfamide therapy
improve survival of patients with dedifferentiated chondrosarcoma?. Clin Orthop Relat Res.
2014;472(3):983–989. doi:10.1007/s11999-013-3360-5
2. Italiano A, Mir O, Cioffi A, et al. Advanced chondrosarcomas: role of chemotherapy and
survival. Ann Oncol. 2013;24(11):2916–2922. doi:10.1093/annonc/mdt374
3. Cleton-Jansen AM, van Beerendonk HM, Baelde HJ, et al. Estrogen signaling is active in
cartilaginous tumors: implications for antiestrogen therapy as treatment option of metastasized or
irresectable chondrosarcoma. Clin Cancer Res. 2005;11:8028–8035. 
4. Odink AE, van Asperen CJ, Vandenbroucke JP, Cleton-Jansen AM, Hogendoorn PC. An
association between cartilaginous tumours and breast cancer in the national pathology
registration in The Netherlands points towards a possible genetic trait. J Pathol 2001;193:190–2.
5. Cleton-Jansen AM, Timmerman MC, Van de Vijver MJ, et al. A distinct phenotype
characterizes tumors from a putative genetic trait involving chondrosarcoma and breast cancer
occurring in the same patient. Lab Invest 2004;84:191–202.
6. Meijer D, Gelderblom H, Karperien M, Cleton-Jansen AM, Hogendoorn PC, Bovee JV.
Expression of aromatase and estrogen receptor alpha in chondrosarcoma, but no beneficial effect
of inhibiting estrogen signaling both in vitro and in vivo. Clin Sarcoma Res. 2011;1(1):5.
doi:10.1186/2045-3329-1-5
7. https://www.futuremedicine.com/doi/full/10.2217/fon-2016-0226
8. Experience in the treatment of dedifferentiated chondrosarcoma A. D. Mitchell, The Bone &
Joint Journal, 2000

9. Dedifferentiated chondrosarcoma: Prognostic factors and outcome from a European group

Grimer, Robert J. et al. European Journal of Cancer, Volume 43, Issue 14, 2060 - 2065