EWING SARCOMA

Union for International Cancer Control

2014 Review of Cancer Medicines on the WHO List of Essential Medicines
 

EWING SARCOMA

Executive Summary

Ewing sarcoma family of tumors (ESFT) form a group of highly malignant diseases that peak in
incidence in adolescence and early adult life. These tumors arise in either bone or soft tissue and
the term ESFT includes the ASKIN tumor of the chest wall and peripheral primitive
neuroectodermal tumors (pPNET) that are related closely to medulloblastoma and intracranial
PNET, reflecting the neural differentiating potential of these tumors1. The ESFT are much more
common in Caucasians than in Africans and Asians, for which a genetic explanation has been
proposed2. The hallmark of ESFT is a translocation between chromosomes 11 and 22 resulting
in a fusion protein referred to commonly as EWS-FLI13.

Prior to the introduction of chemotherapy more than 90% of patients died from tumor spread4.
Now at least 70% of those presenting with apparently localized disease are cured by multi-modal
treatment5, 6, though the outlook for those who have evident metastases at diagnosis remains poor
with five year survival rates of 25-30%7. Other adverse prognostic features include the location
(especially in the pelvis) and size (>8cm) of the tumor8. The outcomes may be better for patients
with extra-osseous primary tumors9.

Pre-treatment evaluation should include plain radiographs of the primary tumor, CT scans of that
site and of the chest (to screen for metastases), MRI of the primary site (especially to clarify
surgical options), radioisotopic bone scan and possibly PET scan (both to detect metastatic
disease). Bone marrow biopsies appear to be unnecessary in patients who have seemingly
localized disease after comprehensive radiological assessment10.

At the core of chemotherapeutic strategies is the combination of vincristine, doxorubicin and

cyclophosphamide (VDC); both in North America and Western Europe. The addition of
ifosfamide and etoposide (IE) was pioneered by the Rizzoli Orthopedic Institute in Bologna,
Italy8. The combination of VDC-IE is now standard of care in the United States and forms the
basis of various protocols in Europe8. Studies by the Children’s Oncology Group demonstrated
no advantage to dose intenstification6 that came with a predictably greater burden of toxicity, but
survival benefit with interval compression, gained without adding to toxicity11, in patients with
localized disease. For patients with relapsed disease the combination of irinotecan and
temozolamide may be useful12.

Public Health Relevance

Primary bone tumors account for 5% of all cancers in childhood and Ewing sarcoma is the
second most common bone tumor in this age group. The incidence of ESFT in the US between
1973 and 2004 was estimated to be approximately 3 per 1,000,000.

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 EWING SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
 
Requirements for diagnosis, treatment, and monitoring

Diagnostics:
A definitive diagnosis is made almost always on biopsied material. This should be obtained
incisionally rather than by needle core in order to provide sufficient material for pathologic
interpretation and for biologic studies. Frozen sections may be used to determine whether the
biopsy has provided lesional tissue but should not be the basis for a final diagnosis. It is strongly
preferred that the biopsy be obtained by the orthopedic surgeon who will perform the operation
to achieve local tumor control, adhering to the principles of surgical oncology13. At the time of
tumor resection a histological response to neo-adjuvant chemotherapy has prognostic
implications14.

Testing:
Determination of the extent of disease is critical to selection of appropriate therapy and initial
assessment of prognosis. Plain radiographs of the primary site are complemented by CT scans
(including the chest to look for pulmonary metastases), MRI (particularly of the primary site) to
provide anatomical detail of value to both the radiation and surgical oncologists, radio-isotopic
bone scan to detect osseous metastases and PET scan to confirm these findings and identify other
sites of occult disease15. PET scans are also of value in assessing response to therapy16.

Institutions caring for patients with ESFT should be able to detect the EWS-FLI1 related
translocation by one of various techniques or CD 99 by immunohistochemistry. However,
although CD 99 expression is a highly sensitive marker for ESFT it has low specificity, being
found in other “small round blue cell” tumors of childhood. Standard blood tests to assess organ
function and a baseline echocardiogram are required. For those with very large tumor volumes
biochemical monitoring for tumor lysis syndrome is valuable. Serum lactate dehydrogenase is a
surrogate matter of tumor volume13.

Administration and Care of Patients:

Chemotherapy for ESFT is given by the IV route and consists of multiple agents. This requires
careful management of fluid and electrolyte balance as well as prophylactic anti-emetic therapy
and other supportive care measures e.g. mesna to offset bladder toxicity from cyclophosphamide
and ifosfamide. All of this is accomplished usually through a central venous catheter and so
should be undertaken only in a specialized cancer centre.

Likewise, control of local disease demands careful consideration of and planning for
radiotherapy and surgery, which may involve limb conservation procedures; all requiring
attention to health-related quality of life17.

Management of the side effects of chemotherapy in the short term include nausea, vomiting,
anorexia, mucositis, pancytopenia, electrolyte imbalance, peripheral neuropathy and hematuria.
In the long-term, survivors are at risk for infertility (notably from cyclophosphamide),
cardiomyopathy (especially from doxorubicin) and second cancers (particularly leukemia from
etoposide and solid tumors in the radiation fields).

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 EWING SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
 
Overview of Regimens

The following tables include basic information on administration and dosing for AEWS 1031
and EURO-W.W.I.N.G. 99, and exclude ancillary medications pertaining to the management of
side effects. For the therapeutic regimens considered AEWS 1031: 11 cycles and EURO-
W.W.I.N.G. 99: 6 cycles of therapy is recommended, respectively.

Standard Regimens (of equivalent efficacy)

AEWS 1031: 11 cycles
Vincristine IV push 1.5 mg/m2 (max 2mg/m2)
Approximately weekly intervals x 18 doses
Doxorubicin IV infusion 37.5 mg/m2
Approximately monthly intervals x 5 doses
Cyclophosphamide IV infusion 1200 mg/m2
Approximately monthly intervals x 9 doses
Ifosfamide* IV infusion 1800 mg/m2
Approximately monthly intervals x 8 doses
Etoposide IV infusion 100 mg/m2
Approximately monthly intervals x 8 doses
 
EURO-E.W.I.N.G. 99 : 6 cycles**
Vincristine IV push 1.5 mg/m2 (max 2mg/m2)
Weekly intervals x 6 doses
Ifosfamide* IV infusion 3000 mg/m2
Daily x 3 days per cycle = 18 doses
Doxorubicin IV infusion 20 mg/m2
Daily x 3 days per cycle = 18 doses
Etoposide IV infusion 150 mg/m2
Daily x 3 days per cycle = 18 doses

*Administration of ifosfamide requires the accompanying drug, mesna.

**Patients with localized disease are then randomized to Vincristine, Actinomycin, Ifosfamide
(VAI) for one cycle then 7 cycles of Vincristine, Actinomycin, Cyclophosphamide OR VAI for 8
cycles.

Advanced Regimen
There are no protocols of notable efficacy in patients with metastatic disease. The Children’s
Oncology Group has joined with EURO-E.W.I.N.G. in the treatment of these patients. Myelo-
ablative therapy with autologous hematopoietic stem cell rescue has not been shown consistently
to be of benefit.

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 EWING SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
 
Review of Benefits and Harms

Survival Benefits

For patients with localized disease the strategy of neo-adjuvant multi-agent chemotherapy
followed by local control (surgery/radiotherapy) then further chemotherapy has achieved 5 year
survival rates of approximately 70%. Treatment of relapsed and metastatic disease achieves
survival rates that seldom exceed 20%.

Harms and Toxicity Considerations

Vincristine commonly causes neurotoxicity, including sensory and motor neuropathies, which is
typically dose-related. Neurotoxicity is usually reversible, though recovery may be gradual.
Vincristine also causes constipation which can be severe and patients should receive
prophylaxis.18

Anthracyclines including doxorubicin are associated with a risk of cardiotoxicity. Development

of severe heart failure is uncommon, however myocardial dysfunction may appear in long-term
follow up. In pediatric patients, the risk of heart failure and pericardial disease increases with
cumulative doses ≥250mg/m2.19

Patients treated with cyclophosphamide have a high risk of bladder toxicity and potentially
hemorrhagic cystitis due to the accumulation of active metabolites in urine. Patients need to be
suprahydrated (at least 2L/m2/day), need to void frequently and/or receive mesna prophylaxis to
reduce the incidence of hemorrhagic cystitis.20 The drug also commonly causes alopecia,
mucositis, stomatitis, and may result in infertility.21

Ifosfamide can also cause bladder toxicity and administration should be managed as with
cyclophosphamide. Ifosfamide also causes alopecia and myelosuppression in most patients.

The most frequent dose-limiting toxicity for etoposide is myelosuppression, primarily

leukopenia which can be grade 3-4 in >10% of patients. A small percentage (up to 2%) of
patients receiving intravenous etoposide experience hypersensitivity reactions, which may
include angioedema, bronchospasm, and/or chest discomfort.22 Etoposide also causes reversible
alopecia in up to 60% of patients.23 The use of etoposide has been associated with an increased
risk of a second cancer.

Patients treated for ESFT have a risk of developing a second malignancy. In one long term
follow up study this risk was as high as 9% and appears to be highest among patients receiving
radiation.24

Systematic Reviews

Cote GM, Choy E. Update in treatment and targets in Ewing sarcoma. Hematol Oncol Clin N
Am 2013; 27: 1007-1019.

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 EWING SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
 
Key Points: The improvement in outcome for patients with localized and metastatic Ewing
sarcoma since the development of cytotoxic chemotherapy remains one of the most profound
advances in oncology. Vincristine, doxorubicin, and cyclophosphamide alternating with
ifosfamide and etoposide (VDC/IE) remains the chemotherapeutic backbone of Ewing
sarcoma therapy, and the addition of other cytotoxic agents to this regimen is unlikely to
produce significant benefits. Identification of molecular targets for new treatments has
become an intense area within Ewing sarcoma research. The development of improved
preclinical Ewing sarcoma models and advanced molecular techniques, including high-
throughput sequencing, will build on knowledge of EWS/FLI1 function, EWS/FLI1
transcription targets, and the other critical driver events in these tumors.

Moore DD, Haydon RC. Ewing’s sarcoma of bone. Cancer Treat Res 2014; 162: 93-115.
Abstract: Ewing's sarcoma of bone is a primary bone sarcoma found predominantly in
patients during their second decade of life. It is a high-grade aggressive small round blue cell
tumor that is part of the Ewing's family of tumors. Its exact eitiology is unknown but it
commonly demonstrates reproducible staining of CD99 and translocations of the EWS gene.
Historically, this diagnosis was associated with near certain metastasis and subsequent
mortality. However, current management consists of extensive chemotherapy in addition to
local control with surgical resection and/or radiation. As a result, survival has improved to
the 55–75% range in those patients who present without known metastases. Current research
aims to continue this improvement by looking further into the assocated gene abnormalities
and possibly targeted therapies.

Hawkins DS, Bolling T, Dubois S et al. Ewing sarcoma. In-Principles and Practice of Pediatric
Oncology, 6th edition – PA Pizzo and DG Poplack, eds. Philadelphia, Lippincott Williams and
Wilkins 2007 pp. 987-1014.

Recommendations
 
The reviewers recommend the incorporation of ESFT cancer treatment options into the WHO
Model List of Essential Medicines, and recommend specifically that ifosfamide and etoposide be
added for pediatric indications in the core Essential Medicines List.

Medicines proposed for Section 8.2 of the Child EML

Ifosfamide (already on adult EML)

Etoposide (already on adult EML)

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 EWING SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
 
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2014 Sept 24. Epub ahead of print.

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 EWING SARCOMA
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
 
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Pediatric Oncology, 6th edition. PA Pizzo and DG Poplack, eds. Philadelphia, Lippincott
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