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NCCN Flash Updates: NCCN Guidelines for Wilms Tumor (Nephroblastoma)

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), NCCN Radiation Therapy Compendium™, NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™), and the NCCN Drugs and Biologics Compendium (NCCN Compendium^®) for Wilms Tumor (Nephroblastoma). These NCCN Guidelines^® are currently available as Version 1.2022.

Link directly to the Updates section of the NCCN Guidelines: Wilms Tumor (Nephroblastoma)

General: Terminologies modified to be more inclusive of all sexual and gender identities.

INTRO-1

• Introduction to Wilms Tumor, modified: All patients with suspected Wilms tumor (WT) should be managed by a multidisciplinary team with experience in managing renal tumors led by a pediatric oncologist; consulting a pediatric oncologist is strongly encouraged.
• Introduction to Wilms Tumor, added: NCCN recommendations have been developed to be inclusive of individuals of all sexual and gender identities to the greatest extent possible. On this page, the terms male and female refer to sex assigned at birth.

INTRO-2

• Content has been split from previous page. (INTRO-1)
• Treatment, 2nd bullet added: Consult pediatric oncologic surgeon or urologist when renal tumor is discovered. Second opinion consultations and referral to tertiary care centers should be considered for complex surgeries.
• Treatment, 3rd bullet added: Imaging studies, pathology, and tumor genetic testing results that are used to determine stage and risk group should be performed by experienced specialists.
• Treatment, 4th bullet modified: Consulting a radiation oncologist is recommended at time of suspected or confirmed diagnosis of WT.
• Treatment, 7th bullet modified: Referral tofor Cancer Predisposition Consultation is appropriate for all patients with WT and strongly encouraged for patients with multifocal or bilateral WT.

WILMS-1

• Presentation, added: Renal tumor discovered by imaging
• Initial Evaluation, 3rd bullet, 1st sub-bullet added: PT/PTT and, if abnormal, screen for acquired von Willebrand disease.
• Findings: Bilateral renal tumors and Unilateral renal tumors have been moved to the top of the algorithm.
• Findings, Renal malignant tumor unlikely, modified: Renal malignant Malignant renal tumor unlikely
• Findings, Non-renal malignant tumor likely, modified: Malignant Non-renal malignant tumor likely

WILMS-2

• Initial Treatment, Tumor not resectable, modified: Tumor biopsy when possible (preferred)
• Initial Treatment, Tumor not resectable, removed: Tumor biopsy not possible
• Footnote l modified: Biopsy is strongly recommended (preferred) for diagnosis and so that molecular biomarker testing can be done earlier and used for treatment decisions.
• Footnote m modified: Biopsy is not indicated for patients with bilateral Wilms and/or predisposing syndromecondition.

WILMS-4

• Initial Risk Group, Extrapulmonary ± Lung Metastases: Algorithm has been split to a new page. (WILMS-4A)
• Molecular/Imaging Results (Week 6), added: No LOH at both 1p and 16q, 1q gain positive, and CR of lung metastases at week 6
  • Adjuvant Chemotherapy, added: Continue Regimen DD4A or Switch to Regimen M
  • Radiation Therapy, 1st bullet added: Flank or whole abdomen for local stage III
  • Radiation Therapy, 2nd bullet added: Whole lung
• Molecular/Imaging Results, modified: LOH 1p and 16q positive or 1q gain positive, or slow incomplete response (SIR) of lung metastases at week 6
• Footnote was removed: If feasible, resect metastatic tumors at the time of primary nephrectomy. (Also on WILMS-4A, WILMS-5, WILMS-5A, and WILMS-7)
• Footnote was removed: Patients with extrapulmonary metastases were switched to Regimen M on AREN0533, but results have not been published.
• Footnote u has been divided into new footnote v: Patients with 1q gain, no LOH, and CR of lung metastases at week 6 should continue on Regimen DD4A but should have whole lung irradiation (WLI). Omission of WLI for patients with CR of lung metastases at week 6 and 1q gain is not recommended because of lower event-free survival (EFS; 57%). Intensification of therapy chemotherapy for this group has not been studied, but can be considered. (Also on WILMS-4A and WILMS-5)
• Footnote v added: Intensification of chemotherapy for this group has not been studied, but can be considered. (Also on WILMS-5)

WILMS-4A

• New page has been divided from previous page. (WILMS-4)
• Initial Risk Group, added: Lung-only metastases (re-image week 6)
• Molecular/Imaging Results (Week 6), added: LOH 1p and 16q negative.
  • Adjuvant chemotherapy, added: Continue Regimen DD4A
• Molecular/Imaging Results (Week 6), added: LOH 1p and 16q positive
  • Adjuvant chemotherapy, added: Continue Regimen DD4A or Switch to Regimen M

WILMS-5

• Resectable, Extrapulmonary ± Lung Metastases: Algorithm has been split to a new page (WILMS-5A)
• Findings, modified: Unilateral FHWT renal tumor, initially unresectable, no predisposing condition
• Lung-only metastases, Molecular/Imaging Results, added: No combined LOH at 1p and 16q, and 1q gain positive, and CR of lung metastases
  • Adjuvant Chemotherapy, added: Continue Regimen DD4A
  • Radiation Therapy, 1st bullet added: Post-op: Flank or whole abdomen for local stage III
  • Radiation Therapy, 2nd bullet added: Whole lung
• Lung-only metastases, Molecular/Imaging Results, modified: LOH 1p and 16q positive or 1q gain positive or SIR of lung metastases at week 6
• Footnote z was modified: In patients who only have metastases in the lungs, assess response of lung metastases after 6 weeks of chemotherapy to determine need for WLI.
• Footnote was removed: If response is WILMS-6 , WILMS-7)

WILMS-5A

• Extrapulmonary ± Lung metastases: Algorithm has been split from previous page. (WILMS-5)
• Molecular/Imaging Results, added: If LOH 1p and 16q negative
  • Adjuvant Chemotherapy, added: Continue Regimen DD4A
• Molecular/Imaging Results, added: If LOH 1p and 16q positive
  • Adjuvant Chemotherapy, modified: Continue Regimen DD4A or Switch to Regimen M
• Footnote w was added: Patients with extrapulmonary metastases were switched to Regimen M on AREN0533, but results have not been published.

WILMS-6

• Neoadjuvant Therapy, Regimen EE4A, added new branch to algorithm: Complete response
  • Adjuvant Chemotherapy, added: Continue Regimen EE4A
  • Radiation Therapy, added: None
• Neoadjuvant Therapy, Regimen EE4A, Resectable by partial nephrectomy week 6, modified: Partial, when feasible, or total nephrectomy...
• Neoadjuvant Therapy, Regimen EE4A, modified: Unresectable Not resectable by partial nephrectomy
  • Not resectable by partial nephrectomy, added: Less than a partial response or progression
  • Not resectable by partial nephrectomy, added: Partial response
    • Added: Complete response (at week 12)
• Footnote ff was added: Indications for total nephrectomy for unilateral WT are described in Principles of Surgery. (Also on WILMS-7)
• Footnote ee modified: Switch to Regimen VAD if biopsy was performed up front. If patient had biopsy upfront (not recommended), start with Regimen VAD.
• Footnote was removed: No surgery if there is a CR on reimaging. (Also on WILMS-7, WILMS-8, WILMS-8A, WILMS-9, and WILMS-9A)
• Footnote was removed: AREN0534 specified a total nephrectomy for less than a PR at week 6. Consider open biopsy for less than a PR or progression at week 6. (Also on WILMS-7, WILMS-8A, and WILMS-9A)
• Footnote ii was modified: Molecular biomarkers were not used to direct therapy on AREN0534. (Also on WILMS-7, WILMS-8, WILMS-8A, and WILMS-9)
• Footnote nn was added: Refer to Complete response pathway at the top for treatment recommendations. (Also on WILMS-7)

WILMS-7

• Neoadjuvant Therapy, Regimen VAD, added new branch to algorithm: Complete response
  • Adjuvant Chemotherapy, added: Switch to Regimen DD4A
    • Radiation Therapy, 1st bullet added: No flank radiation
    • Radiation Therapy, 2nd bullet added: Whole lung for lung metastases and/or
    • Radiation Therapy, 3rd bullet added: Other sites (eg. LNs)
• Neoadjuvant Therapy, Regimen VAD, Resectable by partial nephrectomy at 6 weeks, modified: Partial, when feasible, or total nephrectomy...
• Neoadjuvant Therapy, Regimen VAD, modified: Unresectable Not resectable by partial nephrectomy
  • Not resectable by partial nephrectomy, added: Less than a partial response or progression
  • Not resectable by partial nephrectomy, added: Partial response
    • Partial response, modified: Continue Regimen VAD EE4A (reimage week 12)
      • Added: Complete response (at week 12)

WILMS-8

• Neoadjuvant Therapy, Regimen VAD, Not resectable by partial nephrectomy moved to a new page (WILMS-8A)
• Neoadjuvant Therapy, Regimen VAD, added new branch to algorithm: Complete response
  • Adjuvant Chemotherapy, added: Switch to Regimen EE4A
    • Radiation Therapy, added: None
• Neoadjuvant Therapy, Regimen VAD, Resectable by partial nephrectomy at 6 weeks, modified: Partial...when feasible...or total nephrectomy...
• Neoadjuvant Therapy, Regimen VAD, modified: Unresectable Not resectable by partial nephrectomy
• Footnote oo was added: Total nephrectomy is indicated in patients with bilateral WT if partial nephrectomy is not feasible after 12 weeks of chemotherapy. (Also on WILMS-8A, WILMS-9, WILMS-9A)

WILMS-8A

• Neoadjuvant Therapy, Regimen VAD, Not resectable by bilateral partial nephrectomy: Algorithm has been split from previous page. (WILMS-8)
• Neoadjuvant Therapy, Regimen VAD, Resectable by partial nephrectomy at 6 weeks, modified: Partial...when feasible...or total nephrectomy...
• Neoadjuvant Therapy, Regimen VAD, modified: Unresectable Not resectable by partial nephrectomy
  • Not resectable by partial nephrectomy, added: Less than a partial response or progression
    • Added: Bilateral open biopsies recommended
      • Added: Adjust chemotherapy based on histology (see WILMS-8), (re-image at week 12)
        • Added: See WILMS-8 (Surgery)
  • Not resectable by partial nephrectomy, added: Partial response
    • Added: Complete response (at week 12)
      • Added: Switch to Regimen DD4A
        • Added: None
    • Added: Less than a complete response

WILMS-9

• Neoadjuvant Therapy, Regimen VAD, Not resectable by partial nephrectomy moved to a new page (WILMS-9A)
• Neoadjuvant Therapy, Regimen VAD, added a new branch to the algorithm: Complete response
  • Adjuvant Chemotherapy, added: Switch to Regimen DD4A
    • Radiation, 1st bullet added: No flank radiation
    • Radiation, 2nd bullet added: Whole lung for lung metastases and/or
    • Radiation, 3rd bullet added: Other sites (eg, LNs)
• Neoadjuvant Therapy, Regimen VAD, Resectable by partial nephrectomy at 6 weeks, modified: Partial...when feasible...or total nephrectomy...
• Neoadjuvant Therapy, Regimen VAD, modified: Unresectable Not resectable by partial nephrectomy
• Footnote was removed: Reimage primary and metastatic sites. Repeat imaging of lungs before general anesthesia.
  (Also on WILMS-9A)

WILMS-9A

• Neoadjuvant Therapy, Regimen VAD, Not resectable by partial nephrectomy: Algorithm has been split from previous page. (WILMS-9)
• Neoadjuvant Therapy, Regimen VAD, modified: Unresectable Not resectable by partial nephrectomy
  • Not resectable by partial nephrectomy, added: Less than a partial response or progression
    • Added: Bilateral open biopsies recommended
      • Added: Adjust chemotherapy based on histology (see WILMS-9), (re-image at week 12)
        • Added: See WILMS-9 (surgery)
  • Not resectable by partial nephrectomy, added: Partial response
    • Continue Regimen VAD, added: Complete response (at week 12)
      • Added: Switch to Regimen DD4A
        • Added: No flank radiation
        • Added: Whole lung for lung metastases and/or
        • Added: Other sites (eg LNs)
    • Continue Regimen VAD, added: Less than a complete response

WILMS-A

• Differential Diagnosis, Benign Conditions, 3rd bullet added: Complex renal cysts from pyelonephritis

WILMS-B

• Imaging: CT/MRI, 7th bullet modified: CT of the chest is also recommended to assess for pulmonary metastases. If concerned with mediastinal/thoracic hilar involvement, contrast may be helpful. While CT and MRI are equivalent for the abdomen, chest CT is superior to chest MRI for evaluation of lung metastases. Perform chest CT prior to anesthesia to avoid atelectasis.

WILMS-D 1 of 4

• General Principles:
  • 1st bullet, 5th sub-bullet added: Assess for ureteral involvement by imaging, palpation; consider cystoscopy if gross hematuria on presentation, or for suspicious findings on preoperative imaging, such as hydronephrosis or nonfunctioning kidney.
  • 2nd bullet modified: Evaluation of resectability prior to surgery by imaging
  • 2nd bullet, 3rd sub-bullet modified: Evaluate whether the patient is at risk for pulmonary compromise secondary to pulmonary metastases or tumor embolus.
  • 2nd bullet, 5th sub-bullet modified: Patients at risk for long-term renal failure, including patients with a predisposition syndrome, may benefit from a nephron-sparing surgery(NSS) approach.
  • 3rd bullet modified: Transabdominal or a thoracoabdominal exposure with transperitoneal approach (preferred surgical approaches) and abdominal exploration, unilateral radical ureteronephrectomy with LN sampling. LN sampling MUST be performed for adequate staging; recommend obtaining minimum >5 (nodes) Adequate LN sampling is necessary for staging. Although there is no consensus about the minimal number of LNs to obtain from these different locations, a suggested minimum is 5 nodes from areas in the renal hilum, pericaval, and para-aortic regions, which are anatomically expected to represent nodes associated with kidney. Palpate ureter prior to transecting to assess for ureteral tumor extension.
  • 5th bullet modified: Preoperative disruption of the tumor capsule intraoperatively across the tumor is a tumor spillage. A preoperative disruption of the tumor capsule is termed preoperative rupture; any intraoperative cut across the tumor is termed spillage.
• Contraindications to Primary Resection
  • 2nd bullet, 1st sub-bullet modified: Massive pulmonary disease or tumor embolus
  • 5th bullet modified: IVC tumor thrombus above the level of the hepatic veins is an absolute contraindication; extension of thrombus to the retrohepatic cava is a relative contraindication.
  • 6th bullet added: Bilateral tumors or unilateral disease in patients with a predisposing condition.
• Goals of Surgery for Unilateral WT
  • 4th bullet modified: Resection without rupture of the tumor spillage

WILMS-D 2 of 4

• Surgical Management: Abdominal Cavity
  • 3rd bullet added: Palpate ureter prior to transection
  • 6th bullet modified: LN sampling from renal hilum, pericaval/para-aortic regions. Additionally, regional LNs should be sampled from the renal hilum and paracaval and para-aortic regions. Involved or suspicious LNs should be removed, but a formal LN dissection is not necessary.
• Surgical Management: Pulmonary Nodules
  • 1st bullet modified: Consideration Consider assessing at diagnosis for confirmation of metastatic disease.
  • 2nd bullet added: After 6 weeks of chemotherapy, consider resection of persistent, surgically accessible, pulmonary lesions to guide decisions about adjuvant therapy, such as need for intensification and/or need for whole lung irradiation (WLI).
  • 3rd bullet and 3 sub-bullets added:
    • A surgeon may be needed for managing pulmonary metastases:
      • At presentation: If there are concerns about whether the pulmonary lesions are metastases, they should be biopsied. As many as 33% of small lesions may not be metastases.
      • At the end of 2 cycles or 6 weeks of chemotherapy: If concerns remain about the pulmonary lesion(s), a biopsy should be performed prior to proceeding with pulmonary radiation.
  • 4th bullet removed: If surgically resectable without significant morbidity, resect persistent pulmonary lesions following 6 weeks of chemotherapy
• New section added: Summary of Surgical Approach in Unilateral Tumors in Patients with Predisposing Conditions.

WILMS-D 3 of 4

• Summary of Surgical Approach to Bilateral WT
  • 3rd bullet, 2nd sub-bullet modified: For less than a partial response to chemotherapy, consider bilateral open biopsy biopsies to assess reasons for non-responsiveness, such as anaplasia for presence of anaplasiaor rhabdomyomatous differentiation.
  • 4th bullet, 3rd sub-bullet added: Total nephrectomy is indicated for patients with bilateral WT if partial nephrectomy is not feasible after 12 weeks of chemotherapy.

WILMS-D 4 of 4

• References added:
  • Ritchey M, Daley S, Shamberger RC, Ehrlich P, et al. Ureteral extension in Wilms' tumor: a report from the National Wilms' Tumor Study Group (NWTSG). J Pediatr Surg 2008;43:1625-1629.
  • Kuusk T, De Bruijn R, Brouwer OR, et al. Lymphatic drainage from renal tumors in vivo: A prospective sentinel node study using SPECT/CT imaging. J Urol 2018;199:1426-1432.
  • Scott RH, Stiller CA, Walker L, Rahman N. Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour. J Med Genet 2006;43:705-715.
  • Ehrlich PF, Chi YY, Chintagumpala MM, et al. Results of treatment for patients with multicentric or bilaterally predisposed unilateral Wilms tumor (AREN0534): A report from the Children's Oncology Group. Cancer 2020;126:3516-3525.

WILMS-E

• 2nd bullet modified: The only situation in which a pre-treatment biopsy is recommended a biopsy is recommended is when the tumor...

WILMS-F

• Prognostic Factors, this section and the following bullets have been removed:
  • Prognostic Factors
    • Stage (See ST-1)
    • Histology (favorable or unfavorable/anaplastic)
    • Patient age at diagnosis
    • Tumor weight
    • Completeness of lung nodule response to therapy at week 6
    • LOH of chromosomes 1p, 11p15, and 16q LOI of 11p15 LOH
    • Chromosome 1q gain

WILMS-G 1 of 2

• Reference 5 added: Dix DB, Fernandez CV, Chi YY, et al. Augmentation of Therapy for Combined Loss of Heterozygosity 1p and 16q in Favorable Histology Wilms Tumor: A Children's Oncology Group AREN0532 and AREN0533 Study Report. J Clin Oncol 2019;37:2769-2777.

WILMS-G 2 of 2

• Supportive Care, 1st bullet added: The addition of dexrazoxane can be considered for children receiving doxorubicin.

WILMS-H 1 of 3

• Flank Radiation, 2nd bullet modified: Target volume: Contour the preoperative tumor on presentation imaging (either CT or MRI). Add a 1-cm clinical target volume (CTV) expansion while respecting anatomical barriers...
• Whole Abdominal Irradiation (WAI)
  • 1st bullet modified: Indications: Cytology-positive ascites; preoperative tumor rupture including retroperitoneal; peritoneal seeding; and diffuse surgical spillage...
  • 2nd bullet modified: Target volume: The treatment field design The CTV shall encompass the entire peritoneal cavity that includes the dome of the diaphragm superiorly and extends inferiorly to the pelvic diaphragm. A 4DCT should be used to determine diaphragm motion. Final PTV expansion should be similar to the traditional field borders listed below. (consider 4D-CT to evaluate extent of CTV motion and excursion)
  • 3rd bullet modified: Traditional Field Borders
• Footnote a was added: Recommend fertility counseling for female patients receiving flank RT and/or WAI.

WILMS-H 2 of 3

• Whole Lung Irradiation, 1st bullet modified: Indications: Lung metastases. WLI can be delayed to week 6 in select patients with FHWT and 1q gain positive but with no LOH at both 1p and 16q who only have metastases in the lungs. If there is a CR to chemotherapy and the tumor did not have the unfavorable biomarkers, 1q gain or LOH at 1p and 16q, then whole lung irradiation can be omitted.
• Radiation Doses, 2nd bullet, sub-bullets have been removed:
  • Tumor rupture
  • Surgical spill
  • Peritoneal implants

WILMS-I 1 of 3

• Somatic Genetic Variants:
  • 2nd bullet, 1st sub-bullet modified: REST, TRIM28, FBXW7, NYNRIN, KDM3B, XPO5, CHEK2, and PALB2, and DICER1
  • 3rd bullet, 3rd sub-bullet modified: Beckwith-Wiedemann syndrome: Inheritance complex: AD, uniparental disomy, epimutations involving locus such as CDKNIC 11p15.5 Characterized by gigantism, omphalocele, macroglossia, genitourinary abnormalities, ear pits and creases, hypoglycemia, and hemihyperplasia; present in about 5% of children with WT.
  • 3rd bullet, 4th sub-bullet modified: Contiguous gene deletion syndrome or WAGR/WAGR syndrome with obesity (WAGRO) Gene WT1 gene; locus 11p13 Characterized by aniridia, genitourinary abnormalities, obesity, and hemihyperplasia intellectual disability

 

 

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