Recommendations

Strength Of recommendation

1-Work up for newly diagnosed Ewing Sarcoma

Image guided biopsy with IHC is recommended.

Strong recommendation

Molecular studies are recommended as needed guided by expert opinion.

Conditional recommendation

Contrast enhanced MRI of the primary site is recommended.

Strong recommendation

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

Strong recommendation

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

Strong recommendation

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).

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

Strong recommendation

Strong recommendation

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

Restage after neoadjuvant therapy before local control

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

Strong recommendation

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

Definitive radiotherapy and adjuvant chemotherapy are recommended for irresectable tumours.

Strong recommendation

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

Local control for metastatic disease

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

Strong recommendation

Definitive radiotherapy and adjuvant chemotherapy are recommended for irresectable tumours.

Strong recommendation

Management of metastases

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

Strong recommendation

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

Strong recommendation

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

Strong recommendation

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

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

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

Strong recommendation

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

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

Surgery

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

Strong recommendation

Radiotherapy

Radiation is recommended either definitive or postoperative.

Strong recommendation

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

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

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

Strong recommendation

Recommendations

Level Of Recommendations

1–Work up for newly diagnosed Wilms’ tumor

We recommend complete assessment for signs of associated syndromes including blood pressure measurement and urine analysis.

Strong Recommendations

Contrast enhanced CT abdomen and pelvis or MRI is recommended (to assess bilaterality, evidence of tumor rupture and evidence of tumor thrombus extension into the renal vein or inferior vena cava, nephrogenic rests)

Strong Recommendations

CT chest is recommended to assess for metastasis.

Strong Recommendations

For stage IV WT, we recommend local staging to determine local therapy.

Strong Recommendations

2-Treatment of unilateral WT with no predisposition to develop bilateral WT

We recommend primary nephrectomy with regional LN sampling (5-10 nodes) for all patients, followed by adjuvant treatment according to stage and histology.

Strong Recommendations

If initially unresectable or resection is contraindicated, we recommend proceeding to chemotherapy without biopsy (either image guided core needle biopsy or open).

Strong Recommendations

We recommend either image guided core needle biopsies, or open biopsy to confirm WT pathology in the following conditions:

·   Age < 1year or older than 10 years

·   Uncertain renal origin

·   Atypical metastases: bones (any age), central nervous system (any age), isolated pulmonary nodules < 2years.

·  Elevated LDH > 3-4 folds

·   Hypercalcaemia and age<4 years.

Strong recommendations

Management of initially resected WT with no predisposition to develop bilateral WT

We recommend the following adjuvant treatment:

1. Favorable histology WT:

·  Regimen EE-4A for LR patients

· Regimen DD-4A for SR patients

·   Regimen M for HR patients.

Strong Recommendations

2. Focal anaplastic WT:

·  Stages I-III: Regimen DD4-A

·  Stage IV: Regimen UH-HR

Strong Recommendations

3. Diffuse anaplastic WT:

·   Stage I: Regimen DD4A.

·   Stages III-IV:  Regimen UH-HR

Strong Recommendations

Management of initially unresectable WT with no predisposition to develop bilateral WT

We recommend neoadjuvant treatment, regimen (DD-4A) for initially unresectable tumors.

Strong Recommendations

We recommend reassessment at week 6 by contrast enhanced CT chest, abdomen and pelvis.

Strong Recommendations

We recommend total nephrectomy and LN sampling at week 6, if feasible. If not feasible, we recommend continuing (DD-4A) till week 12, followed by reassessment and surgery.

Strong Recommendations

We recommend the following postoperative adjuvant treatment for initially unresectable WT:

·  Continuing Regimen DD-4A for SR favorable histology WT, stages I-III focal anaplastic WT and stage I diffuse anaplastic WT.

Strong Recommendations

·  Switching to Regimen M for HR favorable histology WT.

·  Switching to Regimen I for blastemal predominant histology.

·  Switching to Regimen UH-HR for stage IV focal anaplastic WT and stages II-IV diffuse anaplastic WT.

3. Treatment of bilateral WT and unilateral WT with predisposition to develop bilateral WT:

We do not recommend upfront nephrectomy either partial or radical.

Strong Recommendations

We do not recommend upfront biopsy (either needle or open).  If biopsied, a tumor is stage III for determination of chemotherapy regimen, but biopsy alone does not upstage a tumor to stage III for determining whether to give radiation.

Strong Recommendations

We recommend neoadjuvant treatment (VAD) for 6 weeks.

Strong Recommendations

We recommend reassessment with contrast enhanced CT chest, abdomen and pelvis at week (6) VAD.

Strong Recommendations

We recommend bilateral partial nephrectomy (one or both sides) at week 6, if feasible.

Strong Recommendations

If bilateral partial nephrectomy at week 6 is not feasible, assess for response:

·       Partial response in both kidneys, we recommend continuing VAD regimen till week 12 then reassess for bilateral partial nephrectomy or total nephrectomy with LN sampling followed by adjuvant treatment based on higher risk histology.

·  Less than partial response (<50% reduction of tumor size) in either kidney, we recommend either immediate surgery or bilateral open biopsies followed by adjuvant treatment based on higher risk histology, reimage at week 12 for definitive surgery.

Strong Recommendations

We recommend the following adjuvant treatment after surgery or biopsy in bilateral WT determined by the highest assigned stage/histology of either kidney:

Strong Recommendations

EE-4A regimen is recommended for

·     Stage I – CR with no lesion detectable on imaging after preoperative chemotherapy at week 6, or

·   Stage I-II favorable histology WT after complete resection or completely necrotic.

DD-4A regimen is recommended for

· Stage III-IV favorable histology WT, or

·  Stage III-IV completely necrotic, or

·  Stage I favorable histology WT with blastemal predominant histology, or

·  Stage I-III focal anaplastic WT, or

·  Stage I diffuse anaplastic WT

Regimen I is recommended for

· Stage II-IV favorable histology WT with blastemal predominant histology.

Regimen UH (start week 1) is recommended for

·  Stage IV focal anaplastic WT, or

·  Stages II-IV diffuse anaplastic WT

4. Management of extrapulmonary metastasis stage IV WT

·  We recommend upgrading to regimen M in stage IV favorable histology WT and irradiation to all metastatic sites post nephrectomy.

Strong recommendation

·  We do not recommend liver irradiation in the following condition only:

Solitary liver metastasis, at presentation (before chemotherapy) completely resected and negative margins with nephrectomy.

Strong recommendation

·  We recommend regimen UH for stage IV anaplastic histology (focal or diffuse) and irradiation to all metastatic sites

Strong recommendation

5. Radiotherapy (RT):

Timing of RT

Post nephrectomy (either upfront or delayed), RT should begin close to chemotherapy, preferably by Day 10 (surgery is Day 0), but no later than Day 14.

Strong Recommendations

Flank RT (10.8 Gy at 1.8 Gy per fraction) is recommended in unilateral WT, bilateral WT and unilateral WT with predisposition to develop WT under the following conditions:

· Locally stage III favorable histology WT.

·  Locally stage I-III focal anaplasia

·  Locally stage I-II diffuse anaplasia

Strong Recommendations

Flank RT (19.8 Gy at 1.8 Gy per fraction) is recommended in unilateral WT, bilateral WT and unilateral WT with predisposition to develop WT under the following conditions:

· Locally stage III diffuse anaplastic histology WT.

Strong Recommendation

For bilateral WT and unilateral WT with predisposition to develop WT, we do not recommend flank RT in these conditions:

·  Biopsy alone, however reported surgical tumor spill will require RT.

·  Complete resection with negative surgical margins/nodes.

Strong Recommendations

Whole abdomen RT (10.5 Gy at 1.5 Gy per fraction) is recommended in all patients with:

· Cytology positive ascites

· Preoperative rupture

·  Diffuse abdominal surgical spillage (reported by surgeon)

·  Peritoneal seeding, in case of diffuse peritoneal implants (21Gy in 1.5 fractions)

Strong Recommendations

WLI is not recommended in unilateral favorable histology WT with pulmonary metastasis showing RCR post week 6

Strong Recommendations

WLI (at week 7) (12 Gy at 1.5 Gy per fraction or 10.5 Gy at 1.5 Gy per fraction if <12 months) is recommended in patients with:

·   Unilateral favorable histology WT with pulmonary metastasis showing slow incomplete response at week 6 (with or without surgical excision of residual metastases).

·   Metastatic bilateral and unilateral WT with predisposition to develop bilateral WT.

·   Pulmonary metastasis and other extra-thoracic metastases (such as liver, bone, or brain).

·  LN metastases in the hilum and/or mediastinum, or cytology-positive pleural effusion regardless of response to chemotherapy.

Strong Recommendations

We recommend dactinomycin and doxorubicin reduction by 50% during or within 6 weeks of completing a course of whole lung or abdominal RT.

Strong recommendation

6-Treatment of relapse or refractory disease

We recommend complete evaluation for both local and metastatic sites at relapse with contrast enhanced CT chest, abdomen and pelvis

Strong Recommendations

We recommend biopsy from site of recurrence to confirm WT relapse.

Strong recommendation

Standard risk

We recommend 2^nd line chemotherapy as first treatment using four drugs (combinations of alternating courses of doxorubicin and cyclophosphamide and carboplatin and etoposide)

Strong Recommendations

We recommend surgical resection with clear resection margins if feasible

Strong recommendation

We recommend flank RT or whole abdomen irradiation in case of peritoneal extension or ascites.

Strong recommendation

High and higher risk:

Strong recommendation

We recommend combination chemotherapy (ICE/CCE) alternating with topotecan/cyclophosphamide up to 10 cycles if feasible

Strong Recommendations

We recommend surgical resection and consolidation with RT if feasible for local and metastatic sites.

Strong Recommendations

Autologous bone marrow transplantation is recommended for patients with chemo-sensitive relapse who are not candidates for RT consolidation.

Strong Recommendations

7- End of treatment evaluation

We recommend end of treatment evaluation by contrast enhanced CT chest, abdomen and pelvis to confirm CR before starting follow up.

Strong Recommendations

8- Surveillance (follow up after end of treatment)

We recommend clinical examination together with chest and abdominal imaging every 3 months for 2 years, then every 6 months for 5 years.

(Chest x-ray and abdominal US may be used in place of cross-sectional imaging with CT chest and abdomen with IV contrast or MRI).

Strong recommendation

9- Screening recommendations predisposed patients to develop bilateral WT

We recommend renal US every 3 months until 7 years (ie, all of year 6).

Strong recommendation

Recommendations

Level Of recommendation

1–Work up for newly diagnosed retinoblastoma

We recommend bilateral examination under anaesthesia and full ophthalmology assessment for all patients suspected to have retinoblastoma.

Strong Recommendation

We recommend MRI of brain and orbits with IV contrast prior to therapy in all patients.

Strong Recommendation

For all tumors stage II and above – according to IRSS-  we recommend metastatic work up: Bilateral bone marrow biopsies, bone scan, CSF cytology and whole spine MRI

Strong recommendation

Pathology is not recommended for initial confirmation of diagnosis prior to therapy.

Strong Recommendation

We recommend family counseling for all children with RB.

Strong recommendation

2- Treatment of Unilateral Intraocular Retinoblastoma

Surgery  

We recommend enucleation for:

·  IIRC Group E

·  Failed eye salvage with local treatment and systemic chemotherapy in groups C and D

· Unilateral advanced intraocular group D disease with no hope of useful vision.

Strong Recommendation

Optic nerve resection margin is recommended to be at least 10 mm

Strong Recommendation

Histopathological assessment and staging of the enucleated eye is recommended for all patients.

Strong Recommendation

Treatment of Group A

We recommend local treatment for all group A eyes.

Strong Recommendation

Treatment of Group B

We recommend both local treatment and systemic IV three drug chemotherapy (Vincristine-Carboplatin-Etoposide) for a total of 6 cycles with 21-28 days interval in between cycles.

Strong Recommendation

Treatment of Groups C and D 

We recommend both local treatment and systemic IV three drug chemotherapy (Vincristine-Carboplatin-Etoposide) for a total of 6 cycles with 21-28 days interval in between cycles.         

Strong Recommendation

We recommend routine EUA with every 1 cycle and if progressive disease we recommend enucleation and histopathology examination.

Strong Recommendation

If NO high risk features in pathology, we do not recommend further treatment after enucleation.

Strong Recommendation

If  high risk features are present in pathology, we recommend giving total 6 cycles of systemic IV three drug chemotherapy (Vincristine-Carboplatin-Etoposide) with 21-28 days interval in between cycles.

Strong Recommendation

We recommend starting systemic chemotherapy whithin 35 days of enucleation for high risk features.

Strong Recommendation

Treatment of Group E

We recommend enucleation upfront for all group E eyes

Strong recommendation

If NO high risk features in pathology, we do not recommend further treatment after enucleation

Strong recommendation

If  high risk features are present in pathology, we recommend giving total 6 cycles of systemic IV three drug chemotherapy (Vincristine-Carboplatin-Etoposide) with 21-28 days interval in between cycles.

Strong Recommendation

We recommend starting systemic chemotherapy whithin 35 days of enucleation for high risk histology.

Strong Recommendation

3-Treatment of Bilateral Intraocular Retinoblastoma

We recommend dictating treatment protocol by the most advanced eye.

Strong Recommendation

We recommend upfront enucleation of the most advanced eye followed by histopathology. If the better eye is group A, B or C, we recommend enucleation of group D eyes.

If both eyes are group D we recommend chemoreduction and focal therapy for both eyes.

Strong Recommendation

We recommend chemoreduction for groups B, C and D eyes as well as local therapy similar to unilateral intraocular treatment protocols.

Strong Recommendation

4- Treatment of Extraocular Retinoblastoma  

We recommend systemic chemotherapy followed by radiation therapy for IRSS stages II-III orbital and regional lymph node involvement.

Strong Recommendation

For stage IV metastatic eyes, we recommend systemic chemotherapy, followed by high dose chemotherapy and stem cell rescue.

Strong Recommendation

Recommended systemic chemotherapy regimen includes 4 cycles of 4 drug regimen (VCR-CDDP-CPM-ETOP)

Strong Recommendation

5- Surveillance

We recommend EUA every 3-4 weeks for patients receiving active anti-tumor treatment till the end of therapy.

Strong Recommendation

We recommend 1-2 months EUA starting at the end of therapy and continuing for 24 months thereafter for patients who present with unilateral disease and are younger than 2 years of age at presentation or bilateral disease of any age.

Strong Recommendation

We recommend life long follow up and counseling for bilateral RB patients and patients with positive family history of RB as well as sibling screening.

Strong Recommendation

For sibling screening we recommend EUA at intervals:

•  Every 2 weeks since birth till 8 weeks of age,

•  then monthly till 1 year of age,

•  then every 3 months till 3 years of age,

•  then every 6 months till 7 years of age

Strong recommendation

For unilateral retinoblastoma patients who are older than 2 years of age we recommend extending ophthalmology examination intervals post therapy, reaching 6 monthly by age of 5 and annually thereafter.

Strong recommendation

We recommend that RB survivors treated with chemotherapy or EBRT , follow up at oncology clinic every 3 months then for longer intervals as clinically warranted.

Strong Recommendation