The National Wilms Tumor Study (NWTS) was created in 1969 to address the need to study and compare treatments in an efficient period of time.  With only 500 cases of Wilms diagnosed annually, a single institution or several combined institutions could not complete an investigation in a relatively short period of time as they would not have enough patients to make significant comparisons.   Groups of investigators and institutions interested in improving treatment for Wilms tumor agreed to combine their efforts and contribute data to the newly formed NWTS.  Their goal was to combine information on relatively large number of patients so that early answers could be identified to long-standing questions regarding therapy.

In addition to analyzing the results of the initial aims, NWTS researchers identified a variety of elements that at diagnosis would help physicians gauge each patients risk for untoward outcomes.  These “prognostic factors” publications have resulted in better treatment outcomes based upon such factors as tumor stage and histology, surgical and pathology findings, and patient age.

Each study identified objectives which always included the original objectives to improve treatment and outcome and to identify therapies that progressively eliminated or decreased long-term affects on the health of survivors.  Each new study was built on the results of the previous study.  Each new study resulted in improvements in treatments and in the long-term health of patients.  The first protocol in 1969 identified diminishing late effects as a significant purpose of the NWTS.

From the beginning the NWTS overriding principle has been “Cure is not enough.”  In 1991 we received NIH funding for the Late Effects Study to become an activity independent from the clinical trials.  That was the year NWTS co-founder Dr. Audrey Evans published our first comprehensive analyses of finding to date: Late Effects of Treatment for Wilms Tumor: A Report from the National Wilms Tumor Study Group.

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NWTS-1

Aims

• Elimination of radiotherapy for low risk (Group I) patients
• Is treatment with one of two know effective chemotherapy agents better than the other or is treatment improved if they are combined.  These agents were actinomycin and vincristine
• To better diagnose each tumor by extent of spread and by pathology review.  For the first time a study combined the findings of surgeons, pathologists, oncologists and other researchers to obtain a comprehensive assessment of a tumor.
• Can different histologic (microscopic) types be used to assess prognosis.  This would result in more aggressive treatment for “bad” histologies and less aggressive treatment for “good” histologies.
• Implementation of the now longstanding NWTS study of the epidemiology of Wilms tumor

Results

• Radiation therapy will not be given to patient with the low risk Group I diagnosis.
• The treatment combining two drugs is more effective than either one given separately
• .Identification of favorable and unfavorable histologic classifications

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NWTS-2

Aims

• Can the duration of treatment be decreased from 15 months to 6 months for low risk (Group I) patients
• Will outcome (survival) be improved by adding Adriamycin to treatment for Groups II, III and IV patients
• Can current outcome be maintained when reducing chemotherapy dosed by 50% for children under 12 months of age

Results

• Group I patients can safely be treated for 6 months.
• ADR improved outcome for Group II and Group III children
• Babies can safely be treated with a 50% reduction in chemotherapy doses
• Prognosis for children with favorable histology (FH) was very good while children with unfavorable histology (UH) did not fare very well.
• Grouping tumors was redefined and a new staging system was identified.  The major change was that involvement of lymph nodes, formerly a criteria for Group II, was identified as poorer prognostic factor and now is a criteria for a Stage III

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NWTS-3

Aims

• Intensify the study of histology and pathology and compare these to treatment and clinical outcome
• Refine treatment methods according to staging in order to prevent adversities of unnecessary treatment
• Test treatments designed for combinations of specific stages and histologies
• To study the late consequences of successful treatment of Wilms tumor.  The NWTS-3 protocol will include guidelines for studying survivors and formalize forms for data capture

Results

• Patients must be divided into two broad groups based upon histology: Favorable Histology and Unfavorable Histology (now identified as including diffuse and focal anaplasia, clear cell, and rhabdoid.)
• Children with Stage I FH or focal anaplasia may be treated the same and none need be treated with radiotherapy to the flank.
• Children with Stage III FH  are best treated with three drugs (actinomycin D, vincristine and Adriamycin) and radiotherapy
• Children with Stages II-IV anaplastic tumors may be best treated with four drugs (three identified above plus cyclophosphamide)

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NWTS-4

Aims

• The NWTS Committee attempted to simplify, shorten and refine the treatment regimens for all Wilms tumor patients.  It undertook a novel task: lessening the socioeconomic impact of Wilms tumor therapy on the patients, families and society.  The cost of medical care, including direct physician and hospital costs, family expenses due to travel, food, lodging and lost wages was considerable.  The goals were to decrease the number of physician visits and to decrease the number of treatments per course and the number of treatment courses without compromising the efficacy of therapy..
• Implement a separate protocol for the NWTS Late Effects Study which was now separately funded and expanded in scope.

Results

• The new treatment method, “pulse intensive” doses, achieved the same excellent results and also resulted in decrease of toxicities.
• Cost of therapy was also decreased.  The NWTS estimated that at least $790,000/year could be saved if all United States children with stages I-IV FH  Wilms tumor were treated using the “pulse intensive” regimens.

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NWTS-5

Aims

• To increase the survival rate of children with favorable histology (FH) Wilms tumor and other renal tumors of childhood;
• To determine if loss of heterozygosity (LOH) for chromosomes 16q markers in tumor tissue is associated with a poorer prognosis for children with favorable histology Wilms tumor;
• To determine if loss of heterozygosity for chromosome 1P markers in tumor tissue is associated with a poorer prognosis for children with favorable histology Wilms tumor;
• To determine if increased DNA content in tumor cells is associated with a poorer prognosis for children with favorable histology Wilms tumor;
• To decrease the acute and long term morbidity of treatment of children with Wilms tumor by limiting initial therapy and employing a consistent retrieval therapy for patients who relapse after initial treatment;
• To improve the survival and disease-free survival of patients with unfavorable histology tumors including Wilms tumor with diffuse anaplasia and clear cell sarcoma of the kidney by using a new treatment regimen that includes etoposide and cyclophosphamide;
• To study the biology and pathology of patients who present with bilateral Wilms tumor;
• To establish a biological samples bank containing touch preparations, paraffin blocks, frozen tumor, normal kidney tissue, serum and urine that will be available to scientists to evaluate additional potential biological prognostic variables or for the conduct of other research;
• To provide data regarding LOH for chromosomes 11p14, 16q and 1p, age at diagnosis, precursor lesions (perilobar, intralobar nephroblastomatosis), bilaterality, and presence of congenital anomalies required for the completion of A0026 (A Case-Control Study of Risk Factors for Wilms Tumor –Andrew F. Olshan, Ph.D., principal investigator).

Results

• Tumor-specific LOH for either chromosome 1p or 16q is associated with an adverse outcome in favorable histology Wilms tumors, relative to those without LOH. 
• Tumor-specific LOH 1p is associated with a worse outcome for Stage I and II patients but not apparently for Stage III/IV patients.
• The adverse effect on outcome is greatest for tumors classified as LOH for both 1p and 16q.
• Surgery alone may be adequate treatment for a limited group of children younger than 2 years of age at diagnosis with Stage I favorable histology Wilms tumors that weigh less than 550 grams.
• Patients with pulmonary metastases detected only by CT scan but not by chest x-ray may benefit from using doxorubicin in addition to vincristine and dactinomycin and by not receiving whole lung irradiation.
• High telomerase RNA expression level is an adverse prognostic factor for favorable histology Wilms tumor.

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History of the NWTS