NcXHF

SYSTEMIC THERAPY FOR OSTEOSARCOMA AND EWING SARCOMA
TABLE 1. Single-Agent Chemotherapy Activity in
Osteosarcoma
Drug
Objective Response Rate
Doxorubicin 43%
Ifosfamide 33%
Methotrexate 32%
Cisplatin 26%
ability of EFS for patients with higher necrosis. 5 The addition
of high-dose ifosfamide and etoposide to MAP did not improve
the probability of EFS for patients with less necrosis. 6
The results of EURAMOS-1 suggest that MAP chemotherapy
can be considered a standard approach to the treatment
of osteosarcoma.
Substantial preclinical evidence suggests that bisphosphonates
might be active against osteosarcoma, and a small pilot
study explored the use of pamidronate in combination with
MAP chemotherapy for the treatment of osteosarcoma. 7 This
was a pilot trial. A larger prospective randomized trial carried
out in France determined that the addition of zoledronate to
chemotherapy did not improve outcome. 8 There does not appear
to be a rationale for pursuing bisphosphonates as part of
osteosarecoma thearpy.
Liposomal muramyl tripeptide (MTP) is a derivative of the
Bacillus Calmette-Guérin cell wall, which stimulates macrophages
to become tumoricidal. Clinical trials of MTP in osteosarcoma
have decreased the probability of subsequent
metastasis for patients with a fırst metastatic recurrence of
osteosarcoma. 9 A prospective randomized trial of the addition
of MTP to chemotherapy for the treatment of osteosarcoma
demonstrated a trend toward improved EFS and a
statistically signifıcant improvement in overall survival (p
0.03). 10 MTP is approved for use in combination with chemotherapy
in the treatment of localized osteosarcoma for
patients age 2 to 30 in the Europe, Mexico, Brazil, Israel, and
Turkey. MTP is not approved for use in the United States.
Strategies under clinical investigation in osteosarcoma
include the use of denosumab, monoclonal antibody therapy
directed against the GD2 antigen, and investigational
chemotherapy.
KEY POINTS
The primary bone sarcomas of young patients require
systemic therapy for cure.
Systemic therapy for osteosarcoma can cure approximately
70% of patients who present with localized disease.
Cure rates for osteosarcoma have not changed for over 20
years.
Systemic therapy for Ewing sarcoma can cure approximately
70% of patients who present with localized disease.
Increased dose intensity of therapy improves the outcome
of treatment for Ewing sarcoma.
EWING SARCOMA
Before the introduction of systemic chemotherapy, Ewing
sarcoma had a cure rate of less than 10%, even among patients
who presented with localized disease. 11 The introduction
of systemic chemotherapy improved the outcome for
Ewing sarcoma. Treatment with multiagent chemotherapy
will achieve long-term EFS for roughly 70% of patients
who present without clinically detectable metastatic
disease. 12-14 When patients present with lung metastasis,
long-term EFS rates are 30% to 50%; when patients present
with metastasis to distant bones or bone marrow, EFS is
less than 20%. 12
An intergroup study conducted by the Pediatric Oncology
Group and the Children’s Cancer Group demonstrated that
the addition of ifosfamide and etoposide to cyclophosphamide,
doxorubicin, and vincristine signifıcantly improved
outcomes for patients with localized Ewing sarcoma. 12 Following
this study, the fıve-drug combination became the preferred
background for treatment and for clinical trials in
North America. In these trials, chemotherapy was administered
as cycles of cyclophosphamide, doxorubicin, and vincristine
and cycles of ifosfamide and etoposide. A singleinstitution
study from the Memorial Sloan Kettering Cancer
Center (MSKCC) reported a high rate of EFS with the use of
very high-dose alkylating agent therapy given over a shorter
duration (21 weeks). 15 The Children’s Oncology Group
(COG) performed a trial in which patients treated with the
fıve-drug combination were randomly selected to receive
conventional doses or higher doses of cyclophosphamide. 13
They reported no improvement in outcome with higher-dose
cyclophosphamide, but the regimen called for higher doses of
cyclophosphamide in only early cycles and did not equal the
MSKCC in dose intensity over the duration of treatment. In a
subsequent trial, COG studied dose intensifıcation by shortening
the interval between cycles of chemotherapy. 14 Administration
of the usual fıve-drug combination every 2 weeks for
28 weeks achieved EFS (p 0.048), which was statistically
superior to the EFS observed with the fıve-drug combination
administered every 3 weeks for 42 weeks. Increasing dose intensifıcation
by either increasing the dose of alkylating agents
or by shortening the intervals between cycles of chemotherapy
has been associated with improved outcome in the treatment
of Ewing sarcoma (Table 2).
The demonstration of improved outcome with increased
dose intensifıcation for patients with localized Ewing sarcoma
led to the concept that even further dose intensifıcation
of therapy might improve outcome for patients at higher risk
for failure. A very dose-intensive regimen including higher
doses of doxorubicin was tried with patients with Ewing sarcoma
metastatic at initial presentation. 16 The regimen failed
to improve EFS and was associated with a very high rate of
secondary leukemia. Administration of chemotherapy in
myeloablative doses followed by autologous stem cell reconstitution
has been used for patients with Ewing sarcoma metastatic
at initial presentation and for patients following
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e645