Vincristine, Dactinomycin, and Doxorubicin With or Without Radiation Therapy or Observation Only in Treating Younger Patients Who Are Undergoing Surgery for Newly Diagnosed Stage I, Stage II, or Stage III Wilms' Tumor

Study Overview
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Brief Summary
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This phase III trial is studying vincristine, dactinomycin, and doxorubicin with or without radiation therapy or observation only to see how well they work in treating patients undergoing surgery for newly diagnosed stage I, stage II, or stage III Wilms' tumor. Drugs used in chemotherapy, such as vincristine, dactinomycin, and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving these treatments after surgery may kill any tumor cells that remain after surgery. Sometimes, after surgery, the tumor may not need additional treatment until it progresses. In this case, observation may be sufficient.

Detailed Description
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PRIMARY OBJECTIVES: I. Evaluate the overall and event-free survival of younger patients with newly diagnosed stage I favorable histology Wilms' tumor (< 2 years of age and < 550gms) treated with nephrectomy only (very low risk), or with newly diagnosed stage III favorable histology Wilms tumor with possible nephrectomy followed by vincristine, dactinomycin, doxorubicin hydrochloride, and radiotherapy (standard risk). SECONDARY OBJECTIVES: I. Determine the effects of adding doxorubicin hydrochloride to the regimen for patients with stage I or II favorable histology found to have a high-risk biological marker. II. Determine whether the omission of adjuvant therapy increases the incidence of contralateral kidney lesions in patients with very low-risk disease treated by nephrectomy and observation only. III. Determine whether the omission of adjuvant therapy increases the incidence of renal failure in patients with very low-risk disease who have metachronous relapse. IV. Correlate study outcomes in patients with standard-risk disease with biological data from tissue collections on protocol study COG-AREN03B2. OUTLINE: This is a multicenter study. Patients are stratified according to clinical and biological risk factors (very low risk vs standard risk). STRATUM I: (very low-risk disease) Patients undergo nephrectomy only. If they meet criteria, they are then observed periodically for 5 years. Patients with recurrent disease undergo surgery (immediate or delayed) and receive chemotherapy as in stratum III. Patients with no metachronous renal disease receive radiotherapy. Patients with metachronous disease undergo renal-sparing surgery and chemotherapy as in stratum III, but no radiotherapy. Treatment continues for up to 25 weeks. STRATUM II: (standard-risk, stage I or II disease with adverse biological marker) Patients undergo nephrectomy. Between 9 and 14 days post-nephrectomy, patients receive vincristine IV beginning on day 1, every week for 10 weeks then every 3 weeks for a total of 15 doses. Patients receive dactinomycin IV beginning day 1, alternating every 3 weeks with doxorubicin hydrochloride IV for a total of 5 doses of dactinomycin and 4 doses of doxorubicin. Treatment continues for up to 25 weeks. STRATUM III: (standard-risk, stage III disease) Patients undergo nephrectomy, if feasible, or biopsy. For patients who undergo biopsy only, definitive surgery is undertaken at week 7 or 13. Between 9 and 14 days post-nephrectomy, patients receive vincristine IV beginning on day 1 every week for 10 weeks then every 3 weeks for a total of 15 doses. Patients receive dactinomycin IV beginning day 1, alternating every 3 weeks with doxorubicin hydrochloride IV for a total of 5 doses of dactinomycin and 4 dose of doxorubicin hydrochloride. Patients undergo radiotherapy over 5-7 days after nephrectomy. Treatment continues for up to 25 weeks. After completion of study treatment, patients are followed periodically for up to 8 years.

Official Title
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Treatment for Very Low and Standard Risk Favorable Histology Wilms Tumor

Conditions
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Stage I Kidney Wilms Tumor, Stage II Kidney Wilms Tumor, Stage III Kidney Wilms Tumor

Intervention / Treatment
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* Radiation: 3-Dimensional Conformal Radiation Therapy
* Biological: Dactinomycin
* Drug: Doxorubicin Hydrochloride
* Procedure: Therapeutic Conventional Surgery
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed Wilms' tumor Newly diagnosed stage I-III disease Favorable histology No moderate- or high-risk Wilms' predisposition syndromes Must meet 1 of the following disease stratification categories: Very low-risk disease Stage I disease Age < 2 years Tumor weight < 550 g Regional lymph nodes histologically negative (must have been sampled) No pulmonary metastases on CT scan of chest No synchronous bilateral Wilms tumors (Stage V) Not predisposed to develop bilateral Wilms tumors, defined as unilateral Wilms tumor and any of the following: Aniridia Beckwith-Wiedemann syndrome Simpson-Golabi-Behmel syndrome Denys-Drash syndrome or other associated genito-urinary anomalies Multicentric WT or unilateral WT with contralateral nephrogenic rest(s) in a child < 1 year of age Diffuse hyperplastic perilobar nephroblastomatosis Standard-risk disease meeting 1 of the following criteria: Disease does not require radiotherapy LOH at chromosomes 1p and 16q for stage I or II Stage I disease meeting 1 of the following criteria: Age ≥ 2 years to age < 30 years Tumor weight ≥ 500 g Stage II disease Age < 30 years Any tumor weight Disease requires radiotherapy No LOH at chromosomes 1p and 16q* Stage III disease Must be enrolled on protocol COG-AREN03B2 Karnofsky performance status (PS) 50-100% for patients > 16 years old Lansky PS 50-100% for patients ≤ 16 years old Bilirubin (direct) ≤ 1.5 times upper limit of normal (ULN) AST or ALT < 2.5 times ULN Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram (standard-risk disease) Not pregnant or nursing Negative pregnancy test Fertile patient must use effective contraception No prior tumor-directed chemotherapy or radiotherapy Patients transferring from AREN03B2 with LOH 1p and 16q allowed

Ages Eligible for Study
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Maximum Age: 29 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stratum I (very low-risk disease)<br>Patients undergo nephrectomy only. If they meet criteria, they are then observed periodically for 5 years. Patients with recurrent disease undergo surgery (immediate or delayed) and receive chemotherapy as in stratum III. Patients with no metachronous renal disease receive radiotherapy. Patients with metachronous disease undergo renal-sparing surgery and chemotherapy as in stratum III, but no radiotherapy. Treatment continues for up to 25 weeks. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Patients undergo radiotherapy<br>* Other names: Radiation, 3D Conformal;Biological: Dactinomycin<br>* Given IV<br>* Other names: Meractinomycin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Stratum II (standard-risk, stage I or II)<br>Patients undergo nephrectomy. Between 9 and 14 days post-nephrectomy, patients receive vincristine IV beginning on day 1, every week for 10 weeks then every 3 weeks for a total of 15 doses. Patients receive dactinomycin IV beginning day 1, alternating every 3 weeks with doxorubicin hydrochloride IV for a total of 5 doses of dactinomycin and 4 doses of doxorubicin. Treatment continues for up to 25 weeks. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Patients undergo radiotherapy<br>* Other names: Radiation, 3D Conformal;Biological: Dactinomycin<br>* Given IV<br>* Other names: Meractinomycin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Stratum III (standard-risk, stage III)<br>Patients undergo nephrectomy, if feasible, or biopsy. For patients who undergo biopsy only, definitive surgery is undertaken at week 7 or 13. Between 9 and 14 days post-nephrectomy, patients receive vincristine IV beginning on day 1 every week for 10 weeks then every 3 weeks for a total of 15 doses. Patients receive dactinomycin IV beginning day 1, alternating every 3 weeks with doxorubicin hydrochloride IV for a total of 5 doses of dactinomycin and 4 dose of doxorubicin hydrochloride. Patients undergo radiotherapy over 5-7 days after nephrectomy. Treatment continues for up to 25 weeks. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Patients undergo radiotherapy<br>* Other names: Radiation, 3D Conformal;Biological: Dactinomycin<br>* Given IV<br>* Other names: Meractinomycin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival Probability | Probability of no relapse, secondary malignancy, or death after 4 year in the study. | 4 years | 
| Overall Survival (OS) Probability | Probability of being alive after 4 years in the study. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Contralateral Kidney Lesions | Number of contralateral kidney lesions during follow-up. | During follow-up | 
| Incidence of Renal Failure | Number of renal failures defined as requiring dialysis or renal transplant as determined by low GFR during follow-up | During follow-up |