2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Role of Doxorubicin in Rhabdomyosarcoma:
Is the Answer Knowable?
Overview: The role of doxorubicin in treatment of rhabdomyosarcoma
(RMS) has been controversial for 30 years. Despite
its known activity in RMS, because of its risk of
cardiotoxicity, its use is not justified in low-risk patients who
have an excellent chance of cure with vincristine, actinomycin
with or without cyclophosphamide, and primary tumor treatment.
For patients with intermediate and high risks, the
risk/benefit ratio must be carefully considered. In addition, the
peak incidence of RMS is in toddlers, with whom the risk of
THE ROLE of doxorubicin in the treatment of rhabdomyosarcoma
has been controversial for over three decades.
The first report of its activity in rhabdomyosarcoma
was by Massimo and colleagues in 1969, 1 followed by an
early phase II study in children by Tan, which showed that
doxorubicin was active against both newly diagnosed and
previously treated rhabdomyosarcoma. 2
However, one of the major disadvantages of doxorubicin
is its cardiotoxicity, which was recognized early in its use. 3
Risk factors for cardiotoxicity include young age at
administration, higher cumulative dose, and radiation fields
including the heart. With the peak incidence of rhabdomyosarcoma
being in toddlers, and the majority of patients being
under age 10 at diagnosis, cardiotoxicity is a factor in the
risk/benefit calculation. Low-risk patients (low stage and
clinical group, favorable histology) have excellent outcomes—
with survival rates of 80% to 90% with VAC (vincristine,
actinomycin, cyclophosphamide) or VA (vincristine, actinomycin)
and primary tumor treatment alone; in them, the use
of doxorubicin with its potential for long-term cardiotoxicity
cannot be justified.
The goal of this discussion is to review the historic data
on use of doxorubicin in rhabdomyosarcoma, as well as to
discuss ongoing clinical studies utilizing it.
Historical Perspectives
North American Experience. Patients with group III and
group IV rhabdomyosarcoma were randomly assigned in Intergroup
Rhabdomyosarcoma Study (IRS) to receive therapy
with VAC and radiation, with or without doxorubicin. The
dose of doxorubicin was 60 mg/m 2 , given at 10 to 12 week
intervals (alternating with actinomycin) either alone or with
continuous daily oral cyclophosphamide. There was no difference
in outcome between regimens and the conclusion was
that doxorubicin did not improve the outcome of patients
with group III or IV disease. 4 It should be noted that the
intervals between treatment cycles were much longer in the
early RMS studies than treatment intervals are in the current
era, and much of the cyclophosphamide was given orally.
IRS II, conducted between 1978 and 1984, again evaluated
the role of doxorubicin in patients with group III and IV
rhabdomyosarcoma, but this time given along with vincristine
and intravenous cyclophosphamide as “pulsed” therapy.
Patients were randomly assigned between repetitive pulse
VAC or repetitive pulse VAC/VDC (D � doxorubicin). 5 Once
again, there was no difference in outcomes between the two
regimens.
By Carola A. S. Arndt, MD
cardiotoxicity of anthracyclines is higher. A number of trials
both in North America and Europe, which are reviewed in this
article, have investigated the role of doxorubicin in RMS, with
no conclusive outcomes. In addition, differences in riskgroup
assignment on two sides of the Atlantic further complicate
comparisons and analyses. The current European EpSSG
2005 study for high-risk RMS (by the European definition) may
come closest to giving an answer to the role of doxorubicin in
RMS.
IRS III, conducted between 1984 and 1991, had a very
complex study design. 5 For patients with group II tumors,
the major objective was to see whether the addition of
doxorubicin to VA and radiation therapy (RT) improved the
outcome of favorable histology tumors. Patients were randomly
assigned to treatment with VA or VA plus doxorubicin
(with RT in both cases). The outcome was better for the
patients treated with VA plus doxorubicin (89% vs. 54%
5 years survival, p � 0.03). However, when historic controls
from IRS II treated with VA and RT were included, the
statistical significance disappeared. Moreover, the VA regimen
had a worse outcome on IRS III than the identical
therapy on IRS II, further confounding the results. Nevertheless,
the paper stated, “In this randomized comparison,
there was suggestive statistical evidence that the addition of
doxorubicin (30 mg/m 2 /d IV X 2 during weeks 3, 6, 12, 15, 21,
and 24) to a basic VA regimen improved clinical outcome.”
Patients with group III and group IV tumors were treated
with doxorubicin containing regimens that also included
other agents in addition to VAC, making the individual
contribution of doxorubicin impossible to determine. Patients
with clinical group I and II unfavorable histology
tumors received pulsed VDC and VAC plus cisplatin, and
showed significant improvement in 5-year progression free
survival and survival rates compared with similar patients
treated less intensively on IRS II (71% � 6% and 80% � 6%
versus 59% � 5% and 71% � 5%, respectively; p � 0.002 and
0.01, respectively). However, the regimens were quite complex,
making the individual contribution of doxorubicin
impossible to determine.
In a series of “phase II window” studies for high-risk
patients with metastatic disease conducted by the Children’s
Oncology Group (COG) between 1988 and 2000,
the combination of doxorubicin/ifosfamide and etoposide/
ifosfamide had the highest response rates, although there
was no survival difference. 6 So once again, the role of
doxorubicin was not able to be determined conclusively.
A pilot study utilizing VDC alternating with ifosfamide/
From the Department of Pediatric and Adolescent Medicine, Mayo Clinic Children’s
Center, Rochester, MN.
Author’s disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Carola A. S. Arndt, MD, Mayo Clinic, Mayo Clinic Children’s
Center, Department of Pediatric and Adolescent Medicine, 200 First Street SW, Rochester,
MN; email: carndt@mayo.edu.
© 2012 by American Society of Clinical Oncology.
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