Data for this Review were identified by searches of Medline and PubMed, using the search terms “Ewing (and Ewing's) sarcoma”, “PNET”, and “pediatric sarcoma”; as well as references from relevant articles. We searched the same databases for articles written by leading investigators in the field. Initially we searched from 1997 onwards, but went back further to research specific areas. Abstracts and reports from meetings were included only when they related to previously published work.
ReviewEwing's sarcoma
Introduction
Some time in the future a teenager with a destructive bone lesion will be referred to a paediatric oncology centre, where he will have metabolic and anatomical imaging (perhaps a PET or CT and MRI, but perhaps more sophisticated) revealing the precise location and anatomical relation of the tumour and any metastases. A needle biopsy of the most metabolically active part of the tumour will provide tissue for histological and molecular diagnosis, and amplification techniques will provide abundant material for research. A multidisciplinary team will begin treatment using sophisticated algorithms and a combination of cytotoxic chemotherapy and agents directed against the biological features of the tumour. After one cycle, new imaging will reveal the tumour's response (figure), and the physicians will adjust therapy appropriately. After completing systemic and local therapy with only mild acute and late side-effects, the patient will enjoy almost assured survival.
Although such management is partly fantasy now, our deepening understanding of Ewing's sarcoma biology and increasingly sophisticated tools might herald rapid changes. We review the current state of Ewing's sarcoma diagnosis and therapy, what new approaches are in development, and how we might get from the present to the future.
The Ewing's sarcoma family of tumours (ESFT) is an aggressive form of childhood cancer, which include classic Ewing's sarcoma, Askin tumour, and peripheral primitive neuroectodermal tumour. While significant progress has been made in the diagnosis and treatment of localised disease over the past 30 years, there is much room for improvement. Before chemotherapy was introduced, about 10% of patients with Ewing's sarcoma survived.1 Progress since then has been dramatic, with 75% of patients with localised tumours now surviving. However, we calculate that only 55% of patients are receiving therapy that is appropriate (panel). The others are either receiving therapy that is ineffective or unnecessary. Current approaches also have many short-term toxicities, and leave survivors at risk for serious late effects.
Section snippets
Epidemiology
Primary bone tumours account for 5% of all child and adolescent cancers, and ESFT is the second most common primary bone tumour. Between 1973 and 2004, the incidence of Ewing's sarcoma in the US was 2·93 per 1 000 000.2 Ewing's sarcoma is much more common in white populations, and has a slight male predominance.3 About a quarter of Ewing's sarcomas arise in soft tissues rather than bone, and about a quarter of patients have detectable metastases at diagnosis. The lungs are the most common site
Diagnosis, imaging, and staging
Most patients with Ewing's sarcoma present with tumour-related symptoms, such as pain or a mass. The first step in the assessment phase should be imaging of the suspected tumour, preferably by MRI, encompassing the entire involved bone or compartment, and before the occurrence of bleeding and oedema from biopsy. If possible, the surgeon who will do the local control surgery should do or participate in the biopsy. This enables expert placement of the biopsy tract and maintenance of tissue
Molecular diagnosis and staging
Identification of the characteristic t(11;22) chromosomal translocation and resulting EWS–FLI1 gene fusion5 has had a considerable effect on diagnosis. The EWS gene on chromosome 22 encodes a widely-expressed and highly-conserved RNA-binding protein. In 85% of ESFTs, the amino terminus of EWS is fused with the DNA-binding domain of FLI1, a member of the ETS (erythroblastalis transforming-virus-1) family of transcription factors, which are involved in cellular proliferation, development, and
Imaging
FDG-PET, whole body MRI, and spiral CT are widely used, and their effect on patient classification and prognosis will take time to assess. MRI is the current standard of care for primary tumour assessment. Spiral CT is more sensitive than traditional thin cut CT for the detection of metastases.12 Whole body MRI is sensitive for the detection of metastases, although its use has been limited (particularly in paediatrics) by the time required. A small pilot study showed that rapid whole-body MRI
Risk groups
There is currently no internationally recognised risk classification scheme for patients with Ewing's sarcoma. The first clinical trials did not classify them, since the prognosis was uniformly poor. Early chemotherapy trials found that patients with pelvic primary sites or metastases at diagnosis had a higher risk of relapse and death than others. Cooperative group and single-institution studies have also identified patient sex and age, tumour size (with varied criteria), site, fever, serum
Cytotoxic chemotherapy
The use of chemotherapy has greatly improved survival rates for patients with localised ESFT, from about 10% to 70–80%. Unfortunately, it has had much less effect on the survival of patients with metastases at diagnosis.
Chemotherapy for Ewing's sarcoma began in the 1960s, with single-agent cyclophosphamide, dactinomycin, doxorubicin, vincristine, and carmustine, followed by single-arm multi-agent adjuvant chemotherapy trials using vincristine–actinomycin–cyclophosphamide (VAC) or VAC plus
Metastatic disease and megatherapy
There has not been similar progress in the treatment of patients with metastases. The addition of ifosfamide–etoposide to vincristine–doxorubicin–cyclophosphamide in the INT-0091 study did not improve the outcome for patients with metastases.18 Increasing the doses of doxorubicin, cyclophosphamide, and ifosfamide by 20%, 83%, and 56%, respectively, in regimen C of the same protocol also produced no improvement, and greatly increased acute toxicity and the incidence of secondary leukaemia and
Primary tumour treatment
Though Ewing's sarcomas are considered radiation-sensitive, the proportion of patients whose primary tumours are treated with radiation alone has steadily declined over the past 30 years. This is because of advances in orthopaedic surgery and a growing awareness of the late effects of radiation in children, particularly second malignancies and growth disturbances. Patients whose primary tumours are excised might survive more often, although the prognostic influences of site and size complicate
Biologically based approaches to treatment
Convential cytotoxic chemotherapy is ineffective in a quarter of patients with localised tumours, and three-quarters of patients with metastases. The growing understanding of Ewing's sarcoma biology raises the hope that new more selective, effective, and less toxic agents will be developed. We will consider new and potential approaches beginning with the EWS-ETS fusion, then moving to the cell surface and working toward the nucleus, finishing with angiogenesis.
From here to there
Bringing new diagnostic and therapeutic approaches to bear on Ewing's sarcoma will be neither easy nor neat. Progress in pathology and imaging have rarely waited for randomised controlled trials. Indeed, current techniques (radionuclide bone scans and chest CT scans) have never been re-assessed as their sensitivity has increased. That is unlikely to change, so we need to collect data and specimens carefully for retrospective assessment of new techniques.
Individual anti-cancer agents have been,
Conclusion
Our rapidly growing understanding of ESFT biology will lead to a growing arsenal of diagnostic and staging technologies and medicines; the challenge for clinical trials will be integrating them into our current protocols for assessment and treatment. Since the number of patients with Ewings' sarcoma is limited, such integration will require new statistical and study design strategies to be adopted, careful further use of international studies, further collaboration between industry and clinical
Search strategy and selection criteria
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