Introduction and Some Epidemiology

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 of treatment.

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.

Treatment

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, respectively.

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 Evolution

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 outcome.

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 side effects.

Local Treatment

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).

Advanced Disease

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.

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