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.

·  Confirmed Pathology.

·  2 weeks interval between cycles.

·  local control after 9 weeks of chemotherapy.

·  Radiotherapy referral.

Research Gaps

Comparison of outcome in terms  of recurrence and toxicity between local

 control modalities in Egyptian patients.

Update of this guideline

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