NcXHF

BONE SARCOMAS IN ADULTS
local disease only and can be treated effectively with surgery. GIANT CELL TUMOR OF BONE
Conventional chondrosarcomas are divided into central
chondrosarcomas, which arise from enchondromas, and
peripheral chondrosarcomas, which arise from osteochondromas.
The majority of chondrosarcomas are central
chondrosarcomas. 4 Patients with metastatic disease
usually are treated only on investigational protocols,
which have not yet generated positive data. Preclinical data
implicate the hedgehog pathway in the development and
proliferation of chondrosarcoma cells. 4,5 A clinical trial of the
hedgehog inhibitor GDC-0449 did not meet its objectives,
however. 6 The presence of frequent mutations of IDH1 and
IDH2 in central chondrosarcomas 7 suggests a new target for
therapy. We await clinical data.
We treat dedifferentiated chondrosarcoma, a composite
tumor with a low-grade chondrosarcoma juxtaposed to
a high-grade osteosarcoma or UPS of bone-like osteosarcoma.
Dedifferentiated chondrosarcoma has a dismal
prognosis when treated by surgery alone; all patients experienced
disease relapse within 1 year, and all but one
were dead within 2 years. 8 We noted a 51% relapse-free
survival in a 15-patient series treated as if they had
osteosarcoma (vide infra). 9 We treat mesenchymal chondrosarcoma,
a composite tumor with a low-grade chondrosarcoma
juxtaposed to a malignant small round cell
tumor, like Ewing sarcoma. Although we have not analyzed
our data, obvious responses to therapy have been
noted. In support of our strategy, a recent review by Italiano
et al, 10 which observed 180 patients treated with chemotherapy
in 15 institutions in Europe and the United
States, noted a response rate of 31% for mesenchymal
chondrosarcoma, 20.5% for dedifferentiated chondrosarcoma,
only 11.5% for conventional chondrosarcoma, and
0% for clear cell chondrosarcoma. 10
KEY POINTS
Older patients with osteosarcoma and Ewing sarcoma have
inferior outcomes than pediatric patients.
To treat osteosarcoma, induction chemotherapy with
doxorubicin and cisplatin permits administration of full
doses of both agents.
Unlike some pediatric studies, our data support the
addition of ifosfamide as well as high-dose methotrexate to
poor responders but do not support the routine use of
high-dose methotrexate for all patients.
Our data suggest that vincristine, doxorubicin, and
ifosfamide is a good choice of primary chemotherapy for
Ewing sarcoma.
PET-CT is the best imaging modality to assess response,
especially in osteosarcoma, but MRI is the most sensitive
method to detect subtle metastases in bone or bone
marrow.
Giant cell tumor of bone is a fascinating tumor. Although
histologically benign, approximately 2% of tumors can
metastasize. 11 The metastases also are histologically benign.
Histologic malignant transformation (dedifferentiation)
may occur spontaneously or, more commonly, after
radiation therapy. Although pathologists refer to giant
cell tumor of bone as a benign tumor, we consider it a
low-grade malignancy, analogous to (or worse than) welldifferentiated
liposarcoma or grade 1 chondrosarcoma,
which cannot be distinguished histologically from their
benign counterparts but which do not metastasize without
further malignant change. In the majority of occurrences,
intralesional resection (curettage and instillation of polymethyl
methacrylate) is curative, whereas en bloc resection
is preferred for lesions in expendable bones or those extending
into soft tissue. 12 Until recently, medical oncologists
have rarely been involved in the management of this
tumor, seeing only the occasional patient with metastatic
disease or with a primary tumor in the spine or sacrum,
where resection would cause excessive morbidity. We prefer
to avoid the use of radiation therapy because it has been
associated with secondary malignancy, but we have used it
when there are no reasonable alternatives. This should be
even less necessary in the future.
Giant cell tumors are highly vascular lesions, and we
have treated sacral lesions with arterial embolization since
the 1970s. 13 Therapy is effective in approximately 50%
of the cases, and long-term follow-up times show that
most patients whose tumors respond are essentially
cured. 14 Since 1992, we have treated patients who experience
disease progression after embolization or those who
have metastatic disease with interferon alfa. 15 It was the
only antiangiogenic agent available at the time, 16 and,
like embolization, it is effective in approximately 50% of
the cases and has curative potential. 14 Interestingly, we
have noted delayed responses to therapy after clear progression,
sometimes only after the therapy has been discontinued.
The biology of giant cell tumor of bone is now much
better understood. 17 The tumor cells (or malignant cells)
are stromal cells with an immature osteoblast phenotype.
These cells secrete RANKL (RANK ligand, a member of
the tumor necrosis factor [TNF] family), a key mediator of
osteoclast biology. Under RANKL signaling, the tumor
cells recruit monocyte precursors that are transformed
into osteoclast-like giant cells that represent the bulk of
the actual giant cell tumor. Denosumab, a fully human
monoclonal antibody that selectively binds RANKL, has
been highly effective in the treatment of giant cell tumor of
bone; 86% of patients experienced objective evidence of
response in the initial phase II study 18 and, in the larger
expansion study, 72% of patients responded likewise. 19
Because denosumab does not treat the malignant cell directly,
however, it is unclear whether life-long therapy
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