NcXHF

PAUL A. MEYERS
Systemic Therapy for Osteosarcoma and Ewing Sarcoma
Paul A. Meyers, MD
OVERVIEW
Curative therapy for both osteosarcoma and Ewing sarcoma requires the combination of effective systemic therapy and local control
of all macroscopic tumors. Systemic therapy for osteosarcoma consists of multiagent chemotherapy. The most common regimen uses
cisplatin, doxorubicin, and high-dose methotrexate. Addition of ifosfamide and etoposide to treatment for patients with poor initial
response to therapy does not improve outcome. Addition of interferon to treatment for patients with favorable initial response does
not improve outcome. Addition of liposomal muramyl tripeptide to chemotherapy may improve overall survival. Systemic therapy for
Ewing sarcoma consists of multiagent chemotherapy including doxorubicin, vincristine, etoposide, and cyclophosphamide and/or
ifosfamide. Increased dose intensity of therapy, either by shortening the intervals between cycles of chemotherapy or by increasing
doses of chemotherapy, improves outcome. Regimens such as irinotecan/temozolomide or cyclophosphamide/topotecan have shown
activity in metastatic recurrent Ewing sarcoma. Trials are ongoing to evaluate the addition of these drugs to existing multiagent
regimens in order to test their ability to improve outcome. High-dose systemic therapy with autologous stem cell reconstitution is being
tested for patients at high risk for recurrence; definitive results await completion of a prospective randomized trial.
Osteosarcoma and Ewing sarcoma are the two most common
primary tumors of the bone seen in children, adolescents,
and young adults. Both diseases almost always present
with systemic metastasis and attempting to cure them by local
measures alone is very unlikely. Successful treatment for both
diseases requires the combination of effective systemic therapy
and local measures directed at all sites of clinically detectable disease.
Substantial progress has been made in the cure rate of these
primary bone sarcomas when they present without clinically detectable
metastatic disease. Curing patients who present with
metastasis is much less likely.
OSTEOSARCOMA
Before the introduction of systemic therapy, cure rates for osteosarcoma
were less than 20%, even among patients who presented
without clinically detectable metastatic disease. 1 The
introduction of multiagent chemotherapy improved the probability
for cure to 60% to 70%. 1 There are only four chemotherapy
agents with evidence of objective responses in osteosarcoma. 2
Anninga et al summarized the results of single-agent phase II
trials of these agents in osteosarcoma, as shown in Table 1.
The reported objective response rates are probably an underestimate
of true response, as osteosarcoma tumors can exhibit
substantial necrosis following chemotherapy without change in
size because of the osteoid matrix produced by the tumor.
Various combinations of the four active agents have
been employed in clinical trials for the treatment of osteosarcoma—some
with the addition of etoposide. Anninga
et al summarized all published cohorts of patients with osteosarcoma.
2 Any trial that employed three of the active
agents had a better outcome than any trial that employed
only two. Trials that used all four active agents did not have
outcomes superior to trials that employed any three.
When osteosarcoma is treated before defınitive surgery,
necrosis in the primary tumor can be assessed at the time of
defınitive surgical resection and strongly correlates with subsequent
event-free survival (EFS) and overall survival. 3 Less
necrosis in the primary tumor is associated with a higher
probability of recurrence and death. Many trials have employed
the strategy of tailoring: altering chemotherapy following
defınitive surgery to intensify therapy for patients
with less necrosis following initial chemotherapy. The European
and American Osteosarcoma Study Group (EURAMOS) performed
the defınitive prospective randomized trial to test the
strategy of tailoring therapy. 4 All patients received initial
therapy with cisplatin, doxorubicin, and high-dose methotrexate
(MAP). Necrosis was assessed in the defınitive surgical
resection after 10 weeks of initial therapy. Patients with
favorable necrosis were randomly selected to receive continuation
of MAP and MAP with the addition of interferon-alfa. Patients
with less necrosis were randomly selected to receive
either continuation of MAP or MAP with the addition of
high-dose ifosfamide and etoposide. Chemotherapy with
MAP continued for 20 weeks following defınitive surgery.
The addition of interferon to MAP did not improve the prob-
From Weill Cornell Medical Center, New York, NY, and Memorial Sloan Kettering Cancer Center, New York, NY.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Paul A. Meyers, MD, Weill Cornell Medical College and Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY, 10065; email: meyersp@mskcc.org.
© 2015 by American Society of Clinical Oncology.
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