Wilms’ tumor

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 recommendation, high quality evidence (retrospective analysis, COG) ⁽¹¹⁾

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 recommendation, high quality evidence (retrospective analysis, COG) ⁽¹²⁾

CT chest is recommended to assess for metastasis.

strong recommendation, high quality evidence (randomized trials, COG) ⁽¹³⁾

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

strong recommendation, high quality evidence (COG randomized trial, COG prospective analysis) ^(14,15)

 

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 recommendation, high quality evidence (systematic review, COG retrospective analysis) ⁽¹⁶⁾

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

strong recommendation, high quality evidence (systematic review, SIOP RTSG) ⁽¹⁷⁾

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 recommendation, high quality evidence (systematic review, SIOP RTSG). (18)

 

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 recommendation, high quality evidence (COG randomized trials). ^(19,20,21)

2. Focal anaplastic WT:

•  Stages I-III: Regimen DD4-A

•   Stage IV: Regimen UH-HR

strong recommendation, high quality evidence (COG report). ⁽²²⁾

3. Diffuse anaplastic WT:

•   Stage I: Regimen DD4A.

•   Stages II-IV:  Regimen UH-HR,

strong recommendation, high quality evidence (COG report, COG prospective analysis). ^(23,24)

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

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

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

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, high quality evidence (COG retrospective analysis, systematic review, SIOP randomized trial). ^(25,26,27)

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.

 

•    Switching to Regimen M for HR favorable histology WT.

strong recommendation, high quality evidence (COG randomized trials). ^(19,20,21)

•    Switching to Regimen I for blastemal predominant histology.

strong recommendation, high quality evidence (SIOP randomized trial). ⁽²⁸⁾

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

strong recommendation, high quality evidence (COG report, COG prospective analysis). ^(23,24)

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

We do not recommend upfront nephrectomy either partial or radical.

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.

We recommend neoadjuvant treatment (VAD) for 6 weeks.

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

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

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.

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

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

strong recommendation, high quality evidence (COG prospective analysis, COG retrospective analysis). ^(29,30)

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.

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.

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

strong recommendation, high quality evidence (COG prospective analysis,). ^(20,30,31)

5. Radiotherapy:

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 recommendation, high quality evidence (COG reports). ^(32,33)

Flank RT (10.8 Gy at 1.8 Gy per fraction) is recommended in both unilateral (either with or without predisposing conditions) and bilateral WT, with:

•   Locally stage III favorable histology WT.

•   Locally stage I-III anaplasia (focal and diffuse).

We do not recommend flank RT in bilateral WT after biopsy alone, however reported surgical tumor spill will require RT.

strong recommendation, high quality evidence (COG reports). ^(33,34.35)

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

•   Diffuse intraoperative spillage (reported by the surgeon)

•   Preoperative rupture

strong recommendation, high quality evidence (COG reports). ⁽³⁷⁾

WLI is not recommended in unilateral favorable histology WT with pulmonary metastasis showing RCR post week 6 (with or without surgical excision of residual metastases).

strong recommendation, high quality evidence (COG reports). ⁽²⁰⁾

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.

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, high quality evidence (COG reports). ^(21,33)

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

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

Standard risk

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

We recommend surgical resection with clear resection margins if feasible

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

strong recommendation, high quality evidence (COG prospective analysis). ⁽³⁸⁾

High and higher risk:

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

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

strong recommendation, high quality evidence (COG prospective analysis, multi-institutional study,). ^(39,40)

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

strong recommendation, high quality evidence (prospective studies). ^(41,42,43)

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.

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 chest CT and abdominal CT or MRI).

strong recommendation, high quality evidence (prospective analysis). ⁽⁴⁴⁾

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, high quality evidence (prospective observational study). ⁽⁴⁵⁾

 

➡️Clinical indicators for monitoring:

·  Contrast enhanced CT abdomen and pelvis with IV contrast or MRI abdomen.

·  CT chest.

·   Upfront surgical resection for unilateral WT, otherwise for preoperative chemotherapy

·  Upfront biopsy is contraindicated in bilateral WT or unilateral WT with predisposition to develop bilateral WT instead preoperative chemotherapy and management according to response

·  Chemotherapy regimens according to histology

·   Radiotherapy referral and start ideally day 10 postoperative no more than 14 days.

➡️Update of this guideline

This guideline will be updated whenever there is new evidence.