Ewing Sarcoma

- Acknowledgment

We would like to acknowledge the Guidelines Development Group (GDG) of Paediatric Oncology for adapting this Guideline.

• Chair of the Committee:

Prof Alaa El-Haddad (Professor of Paediatric Oncology and Former Dean of the National Cancer Institute - Cairo University, Head of the Paediatric Oncology Department and the Bone Marrow Transplant Unit at the Children’s Cancer Hospital Cairo, Egypt).

 • The Scientific Committee Members:

Prof Iman Sidhom (Professor and Head of Department of Paediatric Oncology - National Cancer Institute - Cairo University).

Prof Emad Ebied (Deputy Director, National Cancer Institute and Professor of Paediatric Oncology - National Cancer Institute - Cairo University).

Prof Mahmoud Hammad (Committee Rapporteur and Professor of Paediatric Oncology - National Cancer Institute - Cairo University - and Director of the Oncology and Nuclear Medicine Centre at Nasser Institute Hospital).

Prof Youssef Madney (Professor of Paediatric Oncology - National Cancer Institute - Cairo University - and Consultant of Paediatric Oncology at Dar Al Salam Cancer Hospital Harmal).

Dr Ahmed Mustafa (Lecturer of Paediatric Oncology - National Cancer Institute - Cairo University - and Assistant Head of the Specialized Medical Centres Secretariat for Oncology Affairs).

Dr Zaki Ahmed Zaki (Consultant and Director, Haematology Unit at Sheikh Zayed Specialized Hospital).

Dr Amal Ahmed Zein (Paediatric Oncology Consultant at Al-Sahel Teaching Hospital- and at Oncology Centre of Nasser Institute Hospital).

Prof Shady Fadel (Assistant Professor, Faculty of Medicine, Alexandria University - Director and Head, Paediatric Oncology Department, Borg El Arab Hospital).

Dr Mahmoud Motaz (Lecturer, South Egypt Oncology Institute, Assiut University, Medical Director and Head of the Paediatric Oncology Department at Shifa Al Orman Oncology Centre).

Dr Ebtehal Mahmoud Ali (Assistant lecturer of Paediatric Oncology at National Cancer Institute – Cairo University).

Dr Mai Mamdouh (Clinical Pharmacist, Paediatric Oncology, Dar El Salam Cancer Hospital Harmal).

- Abbreviations

AYA (Adolescent and Young Adult)

BM (bone marrow)

COG (Children’s Oncology Group)

CT (computed tomography)

FDG (fluorodeoxyglucose F18)

GCSF (granulocyte colony stimulating factor)

IHC (immunohistochemistry)

MRI (magnetic resonance imaging)

NCCN (National Comprehensive Cancer Network)

PET (positron emission tomography)

RT (radiation therapy)

- Glossary

Negative surgical margins: Minimal distance between the tumour and surgical margins is more than 2 mm. ⁽¹⁾

Positive surgical margins: Minimal distance between the tumour and surgical margins is 2 mm or less. ⁽¹⁾

- Executive Summary

This guidance provides a data-supported approach to the diagnosis, treatment, and follow up of paediatric patients diagnosed with Ewing sarcoma.

- Introduction

Ewing sarcoma is the second most common primary bone tumour in paediatric population, accounting for about 1% of all childhood cancers. This malignancy typically originates in the bones or the surrounding soft tissues and most frequently affects AYAs, with a common age range at diagnosis between 10 and 20 years. The incidence of Ewing sarcoma is notably higher among individuals of European and North African/Middle Eastern ancestry, making it a significant concern in these populations. Despite its rarity, Ewing sarcoma is known for its aggressive nature and the challenges it presents in treatment and management. ⁽²⁾⁽³⁾

- Scope of the Guideline

These guidelines are developed to improve the quality of care for Ewing Sarcoma cancer patients Via providing a uniform standard of care across the country to help in early diagnosis and treatment for Ewing Sarcoma, with improved clinical outcomes. These guidelines cover primary diagnosis, treatment and follow-up of Ewing Sarcoma patients.

Target audience

Clinicians who are involved in the care and treatment of patients with Ewing Sarcoma, including paediatric oncologists, radiation oncologists, surgeons, radiologists, pathologists, and palliative care specialists.

- Methodology

 A comprehensive search for guidelines was undertaken to identify the most

relevant guidelines to consider for adaptation. 

 inclusion/exclusion criteria followed in the search and retrieval of

guidelines to be adapted:

- Selecting only evidence-based guidelines (guideline must include a

 report on systematic literature searches and explicit links between

 individual recommendations and their supporting evidence).

- Selecting only national and/or international guidelines.

- Specific range of dates for publication (using Guidelines published or

 updated 2015 and later).

- Selecting peer reviewed publications only.

- Selecting guidelines written in English language.

- Excluding guidelines written by a single author not on behalf of an

 organization in order to be valid and comprehensive, a guideline

 ideally requires multidisciplinary input.

- Excluding guidelines published without references as the panel needs

 to know whether a thorough literature review was conducted and

 whether current evidence was used in the preparation of the

 recommendations.

 All retrieved Guidelines were screened and appraised using AGREE II

instrument (www.agreetrust.org) by at least two members. the panel decided

a cut-off points or rank the guidelines (any guideline scoring above 50% on

the rigour dimension was retained)

The NCCN guidelines are the main source used while formulating the national guidelines for Ewing Sarcoma.

 Evidence assessment

According to WHO handbook for Guidelines we used the GRADE (Grading

of Recommendations, Assessment, Development and Evaluation) approach

to assess the quality of a body of evidence, develop and report

recommendations. GRADE methods are used by WHO because these

represent internationally agreed standards for making transparent

recommendations. Detailed information on GRADE is available through the

on the following sites:

. GRADE working group: http://www.gradeworkingroup.org

 . GRADE online training modules: http://cebgrade.mcmaster.ca/

 . GRADE profile software: http://ims.cochrane.org/revman/gradepro

 Table 1: Quality of evidence in GRADE

The strength of the recommendation

The strength of a recommendation communicates the importance of adherence to the recommendation:

Strong recommendations

With strong recommendations, the guideline communicates the message that

the desirable effects of adherence to the recommendation outweigh the

undesirable effects. This means that in most situations the recommendation

can be adopted as policy.

Conditional recommendations

These are made when there is greater uncertainty about the four factors

above or if local adaptation must account for a greater variety in values and

preferences, or when resource use makes the intervention suitable for some,

but not for other locations. This means that there is a need for substantial

debate and involvement of stakeholders before this recommendation can be

adopted as policy.

 When not to make recommendations.

When there is lack of evidence on the effectiveness of an intervention, it may

be appropriate not to make a recommendation.

- Recommendations

1-Work up for newly diagnosed Ewing Sarcoma

Image guided biopsy with IHC is recommended.

strong recommendation, high quality level of evidence (systematic review and meta-analysis, comparative trial) ⁽⁴⁾⁽⁵⁾

Molecular studies are recommended as needed guided by expert opinion.

Conditional recommendation, low quality level of evidence (retrospective analysis) ⁽⁶⁾

Contrast enhanced MRI of the primary site is recommended.

strong recommendation, high quality level of evidence (comparative trial) ⁽⁵⁾

We recommend PET/CT if available or CT chest and bone scan if PET/CT is unavailable.

strong recommendation, high quality level of evidence (systematic review and

meta-analysis) ⁽⁴⁾

Bone marrow biopsy is recommended if PET/CT is unavailable or positive uptake of bone marrow in PET/CT.

strong recommendation, high quality evidence (systematic review) ⁽⁷⁾

2- First line therapy for non-metastatic primary tumour

(neoadjuvant/adjuvant)

Multiagent chemotherapy for at least 9 weeks prior to local therapy is recommended (interval compressed chemotherapy).

strong recommendation, high quality level of evidence (randomised trials) ^(8-13)

All patients are recommended to continue adjuvant chemotherapy after local control till 28 weeks.

strong recommendation, high quality level of evidence (randomised trials) ^(8-13)

Preferred regimen

VDC/IE (Vincristine, doxorubicin and cyclophosphamide) alternating with (ifosfamide and etoposide) every 2 weeks with GCSF for a total of 14 cycles.

strong recommendation, high quality level of evidence (randomised trial) ⁽¹³⁾

Restage after neoadjuvant therapy before local control

CT chest and contrast enhanced MRI of primary site are recommended.

strong recommendation, high quality level of evidence (COG report, randomised trial) ^(14)(15)

Local Control Therapy for stable/improved disease following neoadjuvant therapy

We recommend wide surgical excision and adjuvant chemotherapy. Radiotherapy is recommended if positive surgical margins.

strong recommendation, high quality level of evidence (retrospective analysis, COG report, prospective study) ^(16)(17)(18)

strong recommendation, high quality level of evidence (retrospective analysis, COG report, prospective study) ^(16)(17)(18)

3- First line therapy for metastatic disease at initial presentation

Multiagent chemotherapy for at least 9 weeks prior to local therapy is recommended (interval compressed chemotherapy).

Preferred Regimen

VDC/IE (Vincristine, doxorubicin and cyclophosphamide) alternating with (ifosfamide and etoposide) every 2 weeks with GCSF for a total of 14 cycles.

All patients are recommended to continue adjuvant chemotherapy after local control till 28 weeks.

strong recommendation, high quality level of evidence (randomised trial) ^(8-13)

Local control for metastatic disease

We recommend wide surgical excision and adjuvant chemotherapy. Radiotherapy is recommended if positive surgical margins.

strong recommendation, high quality level of evidence (retrospective analysis of clinical trial, retrospective analysis of clinical trial) ^(19)(20)

Definitive radiotherapy and adjuvant chemotherapy are recommended for irresectable tumours.

strong recommendation, high quality level of evidence (retrospective analysis of clinical trial, retrospective analysis of clinical trial) ^(19)(20)

Management of metastases

For lung only metastases with partial response to neoadjuvant treatment, resection and whole lung irradiation are recommended.

Strong recommendation, high quality level of evidence (retrospective analysis, Prospective multicentre trial) ^(21)(22)

For lung only metastases with complete response to neoadjuvant treatment, whole lung irradiation is recommended.

Strong recommendation, high quality level of evidence (retrospective analysis, Prospective multicentre trial) ^(21)(22)

For bone metastases it is recommended to give radiotherapy to metastatic sites.

(retrospective analysis) ⁽²³⁾

4- Radiotherapy

Timing of RT

For patients receiving radiation therapy only it is recommended to be delivered at the beginning of week 13 concurrently with chemotherapy.

strong recommendation, high quality level of evidence (systematic review, Prospective trial) ^(24)(25)

If post-operative radiotherapy is recommended, consider starting at week 15 concurrently with chemotherapy starting on day 1 of the cycle as soon as possible after surgery.

strong recommendation, high quality level of evidence (systematic review, Prospective trial) ^(24)(25)

Patients with recent cord compression are recommended to start emergency concurrent radiotherapy and chemotherapy starting from day 1 first cycle.

strong recommendation, high quality level of evidence (systematic review, Prospective trial) ^(24)(25)

Concurrent chemotherapeutic agents

Ifosfamide, etoposide, cyclophosphamide and vincristine should be given with radiotherapy. It is recommended to withhold doxorubicin with radiotherapy and re-institute after completion of radiation.

strong recommendation, high quality level of evidence (Randomised trial, systematic review) ^(13)(26)

5- Treatment of recurrent/relapsed Ewing Sarcoma

Chemotherapy

Recommended chemotherapy combination

·  Irinotecan and temozolomide in 21-day interval cycles, Or

·  Ifosfamide, carboplatin and etoposide (if > 6 months).

strong recommendation, high quality level of evidence (prospective clinical trials) ^(27-28)

Surgery

Surgical resection of both local and metastatic sites (especially pulmonary) if feasible is recommended.

strong recommendation, high quality level of evidence (prospective observational study, retrospective analysis) ^(29)(30)

Radiotherapy

Radiation is recommended either definitive or postoperative.

strong recommendation, high quality level of evidence (meta-analysis) ⁽³⁰⁾

6- Surveillance – Follow up - for Ewing Sarcoma patients

X-ray of the primary site is recommended every 4 months for the first 2 years and as clinically warranted.

strong recommendation, high quality level of evidence (prospective observational study, retrospective analysis) ⁽³¹⁾

CT chest every 4 months is the recommended chest imaging in the first 2 years. Chest X-ray is recommended for chest imaging in later years.

strong recommendation, high quality level of evidence (prospective observational study, retrospective analysis) ⁽³¹⁾

It is recommended to increase intervals of imaging of primary site and chest after 24 months and annually after 5 years (indefinitely).

strong recommendation, high quality level of evidence (prospective observational study, retrospective analysis) ⁽³¹⁾

^{Clinical indicators for monitoring}

·  Contrast enhanced MRI of primary site.

·  CT chest.

^{This guideline will be updated whenever there is new evidence.}

- References

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