Combination Chemotherapy and Surgery in Treating Young Patients With Wilms Tumor

OBJECTIVES:

I. To improve 4-year event-free survival (EFS) to 73% for young patients with bilateral Wilms tumor (BWT).

II. To prevent complete removal of at least one kidney in 50% of patients with BWT by using prenephrectomy 3-drug chemotherapy induction with vincristine (vincristine sulfate), dactinomycin, and doxorubicin (doxorubicin hydrochloride).

III. To evaluate the efficacy of chemotherapy in preserving renal units in children with diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) and preventing Wilms tumor development.

IV. To facilitate partial nephrectomy in lieu of nephrectomy in 25% of children with unilateral tumors and aniridia, Beckwith-Wiedemann syndrome (BWS), hemihypertrophy or other overgrowth syndromes, by using prenephrectomy 2-drug chemotherapy induction with vincristine and dactinomycin.

V. To have 75% of patients with BWT undergo definitive surgical treatment by 12 weeks after initiation of chemotherapy.

OUTLINE: Patients are assigned to 1 of 3 arms.

ARM 1 (Bilateral Wilms Tumors): Patients start with three drug chemotherapy (Regimen VAD; vincristine, dactinomycin and doxorubicin) and are evaluated and six and 12 weeks for feasibility of undergoing a partial nephrectomy/renal sparing surgery. At week 12 definitive surgery takes place followed by chemotherapy and radiation therapy based on histology and stage. Treatment continues for 25 or 31 weeks depending on histology. Patients are followed for up to 10 years following end of therapy.

ARM 2 (Unilateral High Risk tumors bilaterally predisposed): Patients start with either 2 drug or three drug chemotherapy (Regimen VA, VAD) and are evaluated a 6 and 12 weeks for feasibility of undergoing a partial nephrectomy. At week 12 definitive surgery takes place followed by chemotherapy.

ARM 3 (DHPLN): Patients with this rare disease are diagnosed based on cross-sectional imaging characteristics and undergo 2 drug chemotherapy (Regimen;VA). Patients are reassessed at 6 weeks and 12 weeks. If disease has responded or stayed stable chemotherapy is completed for 19 weeks (Regimen EE4A). If disease has progress a biopsy is performed to assess histology and adjust therapy based on the biopsy. This therapy may include, nephrectomy, chemotherapy or radiation therapy.

VAD REGIMEN: Patients receive vincristine sulfate intravenously (IV) over 1 minute on days 1, 8, 15, 22, 29, and 36 (weeks 1-6) and dactinomycin IV and doxorubicin hydrochloride IV over 15-120 minutes on days 1 and 22 (weeks 1 and 4).

EE4A REGIMEN: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, 15, 22, 29, and 36 (weeks 1-6) and dactinomycin IV over 1-5 minutes on days 1 and 22 (weeks 1 and 4).

After completion of study treatment, patients are followed up periodically for 10 years.

• Dactinomycin (Biological), also known as Actinomycin A IV, Actinomycin C1, Actinomycin D, Actinomycin I1, Actinomycin IV, Actinomycin X 1, Actinomycin-[thr-val-pro-sar-meval], Cosmegen, DACT, Dactinomycine, Lyovac Cosmegen, Meractinomycin: Given IV
• Doxorubicin Hydrochloride (Drug), also known as 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin HCl, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, FI106, hydroxydaunorubicin, Rubex: Given IV
• Radiation Therapy (Radiation), also known as Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation: Undergo radiation therapy
• Therapeutic Conventional Surgery (Procedure): Undergo surgical resection
• Vincristine Sulfate (Drug), also known as Kyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfate: Given IV

Primary outcomes

• Event-Free Survival (EFS) [4 years from study enrollment]: Probability of no relapse, secondary malignancy, or death whichever occurs first
• Kidney Preservation After Preoperative Chemotherapy [12 weeks from study entry]: Prevention of complete removal of at least one kidney in 50% of patients with bilateral Wilms tumor (BWT).
• Number of Patients Without Complete Removal of at Least One Kidney [12 weeks from the study entry]: To evaluate the efficacy of chemotherapy in preserving renal units in children with diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) and preventing Wilms tumor development.
• Percentage of Patients Who Experienced Partial Nephrectomy After Preoperative Chemotherapy [12 weeks from study entry]: Percentage of patients who experienced partial nephrectomy in lieu of nephrectomy in 25% of children with unilateral tumors and aniridia, Beckwith-Wiedemann syndrome (BWS), hemihypertrophy or other overgrowth syndromes, by using prenephrectomy 2-drug chemotherapy induction with vincristine and dactinomycin.
• Percentage of Patients Who Had Definitive Surgical Treatment [12 weeks from study entry]: Percentage of Bilateral Wilms Tumor (BWT) patients who undergo definitive surgery by week 12 after initiation of chemotherapy.

Sex: All, ages: any to 29 Years

Inclusion Criteria:

* The patient must have one of the following conditions to be eligible:

  * Synchronous bilateral Wilms tumors**; or
  * Unilateral Wilms tumor and aniridia, Beckwith-Wiedemann Syndrome, idiopathic hemihypertrophy, Simpson-Golabi-Behmel-Syndrome, Denys-Drash Syndrome or other associated genitourinary anomalies associated with bilateral Wilms tumor, such as hypospadias and undescended testis (to be eligible, these patients must not undergo any nephrectomy at diagnosis; note-horseshoe kidney is not associated with bilateral Wilms tumor and these patients should go on the appropriate unilateral Wilms tumor study); or
  * Multicentric Wilms tumor (any age) (to be eligible, these patients must not undergo any nephrectomy at diagnosis); or
  * Unilateral Wilms tumor with contralateral nephrogenic rest(s) (any size) in a child under one year of age (to be eligible, these patients must not undergo any nephrectomy at diagnosis); or
  * Diffuse hyperplastic perilobar nephroblastomatosis (unilateral or bilateral) defined by central radiological review; or
  * Wilms tumor arising in a solitary kidney (patients with metachronous Wilms tumor are not eligible)

    * The AREN0534 study uses the guideline that Wilms tumor with a single lesion 1 cm or greater in the contralateral kidney or multiple lesions (of any size) in the contralateral kidney should be treated on the synchronous bilateral Wilms tumor stratum; patients with an isolated lesion less than 1 cm in the contralateral kidney should be treated on the appropriate study for unilateral Wilms tumor OR on the unilateral Wilms tumor/contralateral nephrogenic rest stratum of this study if they have not undergone nephrectomy and are under one year of age
  * Loss of heterozygosity (LOH) results-which are used in the unilateral Wilms tumor studies-are not a requirement for enrollment on AREN0534; blood samples can be submitted but will not be used to direct AREN0534 therapy
* Specimens/materials must be submitted for central review by day 7; for enrollment on AREN0534, unless a biopsy was done, the submission requirements at enrollment on AREN03B2 refer to imaging studies; tissue samples are only required if a surgical procedure (biopsy or nephrectomy) was performed at the time of enrollment on AREN03B2
* Patients must begin protocol therapy on AREN0534 by day 14 following surgery or diagnosis by initial computed tomography (CT)/magnetic resonance imaging (MRI), unless medically contraindicated
* Karnofsky performance status must be >= 50% for patients > 16 years of age and Lansky performance status must be >= 50% (for patients =< 16 years of age
* Patients must not have received systemic chemotherapy or radiation therapy prior to treatment on this study
* Patients with unilateral Wilms tumor and aniridia, Beckwith-Wiedemann Syndrome, idiopathic hemihypertrophy, Simpson-Golabi-Behmel-Syndrome, Denys-Drash Syndrome or other associated genitourinary anomalies; or multicentric or unilateral Wilms tumor with contralateral nephrogenic rest(s) (any size) in a child under 1 year of age who undergo a nephrectomy at diagnosis are not eligible for this study and should be directed to a unilateral Wilms tumor study
* Total bilirubin =< 1.5 times upper limit of normal (ULN) for age
* Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) < 2.5 times upper limit of normal (ULN) for age
* Shortening fraction >= 27% by echocardiogram, OR ejection fraction >= 50% by radionuclide angiogram

  * (Cardiac function does not need to be assessed in patients who will not receive doxorubicin as part of their initial therapy on this study \[i.e., patients who start on regimen EE-4A\])
* Female patients of childbearing age must have a negative pregnancy test
* Female patients who are lactating must agree to stop breastfeeding
* Sexually active patients of childbearing potential must agree to use effective contraception
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
* No concurrent aprepitant

Participant flow

Outcome results

• Event-Free Survival (EFS) (Primary), Mean, Probability: Arm 1 (Bilateral Wilms Tumors) 0.82 (0.74 to 0.91)
• Kidney Preservation After Preoperative Chemotherapy (Primary), Number, Percentage of patients: Arm 1 (Bilateral Wilms Tumors) 39 (31 to 47)
• Number of Patients Without Complete Removal of at Least One Kidney (Primary), Count of participants, Participants: Arm 3 (DHPLN) 7
• Percentage of Patients Who Experienced Partial Nephrectomy After Preoperative Chemotherapy (Primary), Number, percentage of patients: Arm 2 (Unilateral High Risk Tumors Bilaterally Predisposed) 57 (37 to 77)
• Percentage of Patients Who Had Definitive Surgical Treatment (Primary), Number, percentage of participants: Arm 1 (Bilateral Wilms Tumors) 85 (80 to 90)

Adverse events

Time frame: From enrollment to up to 10 years of follow-up

Serious adverse events by term

Other adverse events by term

69 more sites not listed.

• Results publication: Ehrlich PF, Tornwall B, Chintagumpala MM, Chi YY, Hoffer FA, Perlman EJ, Kalapurakal JA, Warwick A, Shamberger RC, Khanna G, Hamilton TE, Gow KW, Paulino AC, Gratias EJ, Mullen EA, Geller JI, Fernandez CV, Dome JS. Kidney Preservation and Wilms Tumor Development in Children with Diffuse Hyperplastic Perilobar Nephroblastomatosis: A Report from the Children's Oncology Group Study AREN0534. Ann Surg Oncol. 2022 May;29(5):3252-3261. doi: 10.1245/s10434-021-11266-6. Epub 2022 Jan 24. PMID 35072864

• Peter F Ehrlich, Principal investigator, Children's Oncology Group

NIH grants: U10CA098543, U10CA180886