Introduction and Some
We are going to try to describe what Ewing’s
Sarcoma is, its unique characteristics, how it is treated
and where research is headed. Our goal of this section is
to explain Ewing’s sarcoma thoroughly, but in the simplest
language we can without leaving anything out. Please, if you
do not understand some terminology, search in google the word
to find its defintion because this section will make much
more sense. Much of this information was taken from uptodate.com
and a few other sources. The amount of research they have
put together into a very reliable information source is astonishing.
Remember none of this should be substituted for the advice
of a medical physician. Our hope is that you might come out
of this with a better understanding of the disease and feel
more comfortable with this topic or discussing it with whomever
is affected by Ewing’s sarcoma in your life.
Ewing’s sarcoma (ES) is a rare cancer
that presents itself as a primary bone tumor, but also less
commonly it arises in soft tissue, known as extraosseous Ewing’s
Sarcoma (EES). Both are part of a spectrum disease known as
the Ewing’s sarcoma family (EFT) of tumors, which also
includes primitive neuroectodermal tumor (PNET), which means
a tumor arising from the portion of the ectoderm of the early
embryo called the neuroectoderm, which gives rise to the central
and peripheral nervous systems, including some glial cells.
This tumor can also arise in bone or soft tissue. All these
tumors are thought to have the same origin due to its histological
and immunohistochemical characteristics and unique chromosomal
translocation. These characteristics will be discussed later.
In addition to their immunohistochemical and
cytogenetic similarities, the EFT share important clinical
features. These include a peak incidence between the age of
10 and 20 (70 percent of affected patients are under the age
of 20), a tendency towards rapid spread to lungs, bone, and
bone marrow, and responsiveness to the same chemotherapeutic
regimens and radiotherapy. As with osteosarcoma (the other
major sarcoma affecting bone), advances in multidisciplinary
management over the past 30 years have resulted in a marked
improvement in long-term survival. In data derived from the
Surveillance, Epidemiology, and End Results (SEER) program
of the National Cancer Institute, five-year survival rates
for patients with Ewing's sarcoma rose from 36 to 56 percent
during the periods 1975 to 1984 and 1985 to 1994.
Primary bone tumors are responsible for 5 percent
of all childhood cancers. Although rare, the EFT represent
the second most common primary bone malignancy affecting children
and adolescents. Despite this, EFT is responsible for only
3.5 percent of cancers in American children 10 to 14 years
old, and 2.3 percent of those arising among 15 to 19 year
olds. A similar incidence 2.8 percent of all tumors in children
aged 15 to 19 years old is described in adolescents in England.
In the United States, 650 to 700 children and adolescents
younger than 20 years old are diagnosed with bone tumors every
year, of which only 200 are EFT and the remainder osteosarcomas.
The peak incidence is between 10 to 15 years of age; children
less than 10, and those over the age of 20 account for 30
percent of the cases. As with many pediatric tumors, there
is a slight male predominance.
You might wonder where the name Ewing’s
sarcoma came from. ES was described by James Ewing in 1921
as an undifferentiated tumor involving the shaft of long bones
that, in contrast to osteosarcoma, was radiation-sensitive.
The Ewing’s sarcoma family of tumors (EFT) can develop
in almost any bone or soft tissue, but the most common site
is in a flat or long bone, and patients typically present
with localized pain and swelling. Although overt metastatic
disease is found in fewer than 25 percent at the time of diagnosis,
subclinical metastatic disease is assumed to be present in
nearly all patients because of the 80 to 90 percent relapse
rate in patients undergoing local therapy alone. As a result,
systemic chemotherapy has evolved as an important component
Racial and ethnic factors are of epidemiologic
importance. For unclear reasons, EFT affects mainly Caucasians
and is extremely uncommon among blacks (both in the United
States and Africa) and Asians. The reason for this striking
ethnic distribution is not known, although interethnic differences
exist for certain alleles, or variations of the Ewing's sarcoma
(EWS) gene, which is consistently disrupted in these tumors.
Despite the fact that fewer than 25 percent
of patients have overt metastases at the time of diagnosis,
EFT is a systemic disease. Because of the high relapse rate
in patients undergoing local therapy alone, it is surmised
that the majority of patients have subclinical metastatic
disease at the time of diagnosis, even in the absence of overt
metastases. Chemotherapy can successfully eradicate these
deposits, and modern treatment plans all include chemotherapy,
usually administered prior to and following local treatment.
For patients with localized disease, the addition of several
months of intensive multiagent chemotherapy to local therapy
has had a dramatic impact on survival, and reported 5 and
10 year survival rates are now approximately 70 and 50 percent,
Modern treatment plans utilize initial chemotherapy
followed by local treatment and more chemotherapy. Through
this process reduction of tumor mass is accomplished in the
majority of patients and can be followed by surgical resection.
This is very important in regard to limb-sparing procedures
for extremity tumors.
Chemotherapy has greatly improved in the last
decade do to many cooperative groups:
In the first Intergroup Ewing's Sarcoma Study
(IESS-I) the combination of vincristine, doxorubicin, cyclophosphamide
and actinomycin D (VDCA) was associated with a significantly
better five- year relapse-free survival than vincristine,
actinomycin D, and cyclophosphamide (VAC) alone or VAC plus
adjuvant bilateral pulmonary irradiation.
Increasing the doxorubicin dose intensity during
the early months of therapy further improved response, and
in the second intergroup study (IESS-II), the five-year relapse-free
survival rates using intermittent high dose four drug therapy
improved to 73 percent for non-pelvic lesions. Because of
concerns about limiting the dose intensity of doxorubicin
in regimens containing actinomycin D, actinomycin D was omitted
from most trials thereafter, with no adverse impact on long-term
Adding alternating cycles of ifosfamide (I)
and etoposide (E) to a VDC backbone provides further benefit.
In the randomized IESS-III study, the addition of I/E to VDCA
was associated with significantly better five-year relapse-free
survival compared to VDCA alone (69 versus 54 percent, respectively)
in patients with nonmetastatic, but not metastatic EFT or
PNET. A similar outcome was shown with a slightly different
IE/VDC regimen at Memorial Sloan Kettering (four-year event-free
survival 82 percent), and with ifosfamide plus VDCA by the
Orthopedic Institute from Rizzoli (five- year event-free survival
79 percent). Earlier trials from the Rizzoli group had suggested
no additional benefit (five-year event-free survival rates
54 and 50 percent for VDCA plus I/E, and for VDCA alone in
two consecutive phase II trials).
From this and other research the standard chemotherapy
for EFT in the United States includes vincristine, doxorubicin,
and cyclophosphamide alternating with ifosfamide and etoposide.
Typically, four to six cycles of chemotherapy are given before
local therapy. So long as there is any sign of response to
preoperative chemotherapy, additional cycles of the same treatments
are given post-operatively, and the total duration of therapy
is approximately 48 weeks. Relief of pain, decrease in tumor
size, fall in LDH level, radiologic improvement, or evidence
of necrosis in the resected specimen all argue for continued
chemotherapy for those who can tolerate its sometimes considerable
Local treatment usually consists of surgery,
radiation, or both. Depending on the trade off of a positive
result and the risk of secondary malignancy due to radiation
and other radiation induced side effects. If a patient does
not have a respectable tumor than radiation would mostly be
recommended; however, if a patients has a respectable tumor,
such as a tumor residing on the rib, than surgery would probably
be the best recommended option. Surgery avoids risk of secondary
radiation-induced sarcomas, the degree of necrosis in the
excised tumor can be analyzed and the side effect of bone
deformity and lack of growth due to radiation can be avoided
(very important in the younger population with EFT).
Because of the complexity and the variability
of how to manage metastatic patients, we are not going to
go into depth on this topic. Treament for advanced disease
becomes much more complicated due to the variability of the
site of metastatic disease. However, aggressive multimodality
therapy can relieve pain, prolong the progression free duration
and cure some patients of disease.
Summary of Disease and Treatment
Patients with Ewing’s sarcoma or
another sarcoma part of the Ewing’s sarcoma family need
referral to a center that has a team of sarcoma specialists.
This disease requires strong coordination between the oncologist,
surgeon and radiation therapist.