C A

C a n c e r

C l i n

1 9 9 6 ; 4 6 : 4 6 - 6 3

Wilms Tumor
Daniel M. Green, MD Giulio J. DAngio, MD J. Bruce Beckwith, MD Norman E. Breslow, PhD Paul E. Grundy, MD Michael L. Ritchey, MD Patrick R.M. Thomas, MD

Introduction
Wilms tumor is the most common primary malignant renal tumor of childhood and is the paradigm for multimodal treatment of a pediatric malignant solid
Dr. Green is the Associate Chief of the Department of Pediatrics at Roswell Park Cancer Institute in Buffalo, New York, and a Professor of Pediatrics in the School of Medicine at the State University of New York at Buffalo in Buffalo, New York. Dr. DAngio is Professor Emeritus in the Department of Radiation Oncology at the Hospital of the University of Pennsylvania in Philadelphia, Pennsylvania. Dr. Beckwith is a Professor in the Department of Pathology and Human Anatomy at Loma Linda University in Loma Linda, California. Dr. Breslow is a Professor in the Department of Biostatistics at the University of Washington in Seattle, Washington. Dr. Grundy is an Assistant Professor in the Departments of Pediatrics and Oncology at the Cross Cancer Institute and the University of Alberta, Edmonton, in Alberta, Canada. Dr. Ritchey is an Associate Professor in the Division of Pediatric Surgery at the University of Texas in Houston, Texas. Dr. Thomas is a Professor in the Department of Radiation Oncology at the Temple University School of Medicine in Philadelphia, Pennsylvania. Supported in part by USPHS Grant CA-42326. The authors thank the investigators of the Pediatric Oncology Group and the Childrens Cancer Group, the many health care professionals who managed the children entered on the National Wilms Tumor Studies, and Mrs. Diane Piacente for preparation of the manuscript.

tumor. Developments in surgical techniques and postoperative care, recognition of the sensitivity of Wilms tumor to irradiation, and the availability of several active chemotherapeutic agents have led to a dramatic change in the prognosis for most patients with this once uniformly lethal malignancy. We will review the progress made in the diagnosis and management of children with Wilms tumor, emphasizing work completed since the last review of Wilms tumor in this journal.1 The late effects of treatment for childhood cancer have been reviewed in this journal2 and elsewhere3 and will not be discussed in detail.

Epidemiology
The incidence rate of Wilms tumor is 8.1 cases per million in white children less than 15 years of age.4 In 1991 Wilms tumor represented ve to six percent of childhood cancers in the United States, where the total incidence was estimated at 460 cases per year.5 The incidence rate is about three times higher for blacks in the United States and Africa than for East Asians, with rates for white populations in Europe and North America intermediate between these extremes.6 Wilms tumor in the United States is slightly less frequent in boys than in girls. The male-to-female ratio for those with a unilateral tumor is 0.92 to 1.00 and for those with bilateral tumors is
CaA cancer Journal for Clinicians

46

C A

C a n c e r

C l i n

1 9 9 6 ; 4 6 : 4 6 - 6 3

0.60 to 1.00.7 The mean age at diagnosis for those with unilateral tumors is 41.5 months for males and 46.9 months for females, compared with 29.5 months for males and 32.6 months for females with bilateral tumors.7 Children with Wilms tumor may have associated anomalies, including aniridia, hemihypertrophy, cryptorchidism, and hypospadias.8 The constellation of Wilms tumor, aniridia, genitourinary malformations, and mental retardation (WAGR syndrome) occurs in association with an interstitial deletion of varying length on chromosome 11 (del(llp13)).9 Children with pseudohermaphroditism and/or renal disease (glomerulonephritis or nephrotic syndrome) who develop Wilms tumor may have the Denys-Drash syndrome, which is associated with mutations within the same chromosomal segment as the WAGR syndrome.10,11 Hemihypertrophy may occur as an isolated abnormality or as a component of the Beckwith-Wiedemann syndrome, which includes macroglossia, omphalocele, and visceromegaly.12 The role of parental environmental exposures in the etiology of Wilms tumor is unknown. No consistent positive ndings have emerged from a series of casecontrol studies. Fabia and Thuy13 reported no excess of fathers of Wilms tumor patients with hydrocarbon-related occupations, but others have identied an excess of fathers of Wilms tumor patients engaged in occupations with signicant lead exposure14; an increased proportional mortality rate among kidney tumor patients whose fathers were employed in hydrocarbon-related industries at the time of the patients death15; and an increased odds ratio for Wilms tumor among the offspring of auto mechanics, machinists, and welders.16,17 Previously reported associations between maternal smoking during pregnancy, tea consumption, and hypertension during pregnancy were not conrmed in a large case-control study.18 Other studies have found no
Vol. 46 No. 1 january/February 1996

correlation between paternal occupation and the occurrence of Wilms tumor.19,20

Genetics
Wilms tumor is an important model for the study of fundamental mechanisms of carcinogenesis. The genetics of Wilms tumor was thought to follow the pattern of retinoblastoma, in which about ten percent of patients with sporadic unilateral tumors and all patients with bilateral tumors are thought to carry a germ line mutation and the tumor arises only when a second event occurs (the second hit).21 This model has been conrmed in detail in patients with retinoblastoma. The rst event may be constitutional, either a new germinal mutation transmitted from the father22,23 or transmitted from a carrier or affected parent,24 or it may be somatic. In either case it results in the loss of function of one of the alleles of the retinoblastoma (RB) gene, located at 13q14. Subsequently, the function of the remaining normal allele is lost by one of several mechanisms, resulting in absence of normal RB gene product within the affected retinal cell.25 The genetics of Wilms tumor, however, are more complex. Analysis of the epidemiologic and clinicopathologic features of patients with Wilms tumor has led investigators in the National Wilms Tumor Study Group (NWTSG) to suggest that some bilateral and multicentric tumors may arise from somatic mosaicism rather than germ line mutation.26,27 They also suggest that the disease comprises at least two pathogenetic entities that are identiable on the basis of distinct precursor lesions.28 The rst evidence that a specic chromosomal locus is associated with Wilms tumor was the demonstration that patients with aniridia and Wilms tumor usually have an interstitial deletion at 11p13.29 Interestingly, the deletion occurs preferentially in the paternal allele,30 as with new germinal mutations at 13q14.22
47

W i l m s

T u m o r

Subsequently, several laboratories reported that about one third of Wilms tumors have undergone tumor-specic loss of heterozygosity for polymorphic DNA markers on 11p13.31,32 Isolation of this Wilms tumor gene (WT1)33,34 allowed the sequence of the normal gene to be determined. Germinal mutations within the WT1 gene have now been identied in patients with Wilms tumor who also have Denys-Drash syndrome35 and in a few patients with bilateral Wilms tumor.36 Strikingly, however, constitutional or even tumor-specic mutations of WT1 have been found in far fewer cases than expected.37,38 Furthermore, in some cases with a tumor-specic WT1 mutation of one allele, the remaining allele is normal.37 A second Wilms tumor locus maps to chromosome 11p15.5, based on tumorspecic loss of heterozygosity restricted to this region.32 Beckwith-Weidemann syndrome, which carries a predisposition to embryonal tumors including Wilms tumor, also maps to this location,32 but it is not yet known whether a single gene is involved. It is of interest that the copy of 11p15 lost in Wilms tumor is invariably derived from the mother.31,39,40 This evidence suggests that the 11p15 Wilms tumor locus is subject to genomic imprinting, resulting in a functional difference between the two alleles. The IGF II gene, which codes for an embryonal growth factor, is a candidate for both Wilms tumor and BeckwithWiedemann syndrome because it maps to 11p15.5,41 it is imprinted such that it is only expressed from the paternal allele,42 and it is highly expressed in Wilms tumors.43 Tumor-specic loss of imprinting at the IGF II locus has been found in many Wilms tumors that have not lost DNA heterozygosity for 11p15,42,44 and constitutional loss of the imprint is associated with both generalized somatic overgrowth and Wilms tumor.45 This epigenetic alteration may result in increased IGF II levels, providing a possible autocrine stimulation pathway. Thus loss of
48

heterozygosity for 11p15, which usually results from mitotic recombination rather than deletion, may not represent loss of a tumor suppressor allele, but rather duplication of the only active IGF II allele. It is not yet known whether a separate Wilms tumor suppressor gene might exist adjacent to IGF II. Finally linkage studies of rare, but large, Wilms tumor pedigrees have excluded linkage to 11p13, 11p15,40,46 and 16q.47 In summary the development of Wilms tumor involves at least two genes on chromosome 11p, an as yet unidentied familial locus, and both genetic and epigenetic mechanisms.

Pathology
The gross appearance of the kidney, distorted by the presence of the tumor, seldom gives external evidence pointing to the underlying histopathology. Tumor multifocality or nephrogenic rests, which may manifest as subcapsular pale pink areas or nodules in the non-tumor-bearing kidney substance, are strongly suggestive of Wilms tumor.28 Extensive research has been conducted by the NWTSG to identify gross and histopathologic patterns that correlate with outcome. These are used both for staging purposes (Table 1) and for tumor type categorization. The classic nephroblastoma is made up of three cell types: blastemal, stromal, and epithelial. However, they are not all present in every case (Fig. 1). When anaplastic nuclear changes as described below are not present, the histology is termed favorable (FH) by the NWTSG Pathology Center because of the generally good outcome for these patients (Table 2).48,71,72,78 The neoplastic elements often reect their renal origin, forming primordial tubules and glomeruli with their associated supporting tissues. Anaplasia is recognized by the presence of gigantic polyploid nuclei within the tumor sample (Fig. 2). The following features should be identied to diagnose anaplasia: (1) nuclei with major diameCaA cancer Journal for Clinicians

C A

C a n c e r

C l i n

1 9 9 6 ; 4 6 : 4 6 - 6 3

Table 1 National Wilms Tumor Study Clinicopathologic Staging System

Stage I - Tumor limited to kidney and completely excised. The surface of the renal capsule is intact. Tumor was not ruptured before or during removal. There is no residual tumor apparent beyond the margins of resection. Stage lI - Tumor extends beyond the kidney, but is completely removed. There is regional extension of the tumor (i.e., penetration through the outer surface of the renal capsule into the perirenal soft tissues). Vessels outside the kidney substance are inltrated or contain tumor thrombus. The tumor may have been biopsied or there has been local spillage of tumor conned to the ank. There is no residual tumor apparent at or beyond the margins of excision. Stage llI - Residual nonhematogenous tumor conned to the abdomen: (1) lymph nodes on biopsy are found to be involved in the hilus, the periaortic chains, or beyond; (2) there has been diffuse peritoneal contamination by tumor, such as spillage of tumor beyond the ank before or during surgery or tumor growth that has penetrated through the peritoneal surface; (3) implants are found on the peritoneal surface; (4) the tumor extends beyond the surgical margins either microscopically or grossly; and/or (5) the tumor is not completely resectable because of local inltration into vital structures. Stage lV - Hematogenous metastases. Deposits beyond stage III (e.g., lung, liver, bone, and/or brain). Stage V - Bilateral renal involvement at diagnosis. An attempt should be made to stage each side according to the above criteria on the basis of the extent of disease before biopsy.

ters at least three times those of adjacent cells and with increased chromatin content and (2) multipolar or otherwise recognizably polyploid mitotic gures. Occasionally, when only a small biopsy is available, the presence of a single, multipolar mitotic gure or an unequivocally gigantic tumor cell nucleus will suffice to diagnose anaplasia. Anaplastic changes may be either focal or diffuse. The criteria distinguishing focal from diffuse anaplasia were modied recently.49 The original denition of focal anaplasia was based on the
Vol. 46 No. 1 january/February 1996

amount of anaplasia present. Anaplastic nuclear changes present in fewer than 10 percent of microscopic elds were originally designated as focal anaplasia. This criterion permitted the inclusion of tumors where anaplasia was present throughout the tumor, albeit at low density, and cases with anaplasia in extrarenal sites or in metastatic deposits. The new denition of focal anaplasia emphasizes distribution by requiring that cells with anaplastic nuclear changes be conned to sharply restricted foci within the primary tumor and not be present in
49

W i l m s

T u m o r

Fig. 1. Triphasic Wilms tumor with well-dened tubules surrounded by dense clusters of blastemal cells and zones of pale-staining stromal differentiation (hematoxylin-eosin, original magnication x100).

any site outside the kidney parenchyma. Diffuse anaplasia is diagnosed when anaplasia is (1) present in any extrarenal site, including vessels of the renal sinus, extracapsular inltrates, or nodal or distant metastases; (2) present in a random biopsy specimen; (3) unequivocally expressed in one region of the tumor, but with extreme nuclear pleomorphism approaching the criteria of anaplasia (extreme nuclear unrest) elsewhere in the lesion; or (4) present in more than one tumor slide, unless (a) it is known that every slide showing anaplasia came from the same region of the tumor or (b) anaplastic foci on the various slides are minute and surrounded on all sides by nonanaplastic tumor. This topographic denition of focal anaplasia makes it mandatory that pathologists carefully document the exact site from which every section is obtained (e.g., on a diagram, specimen photocopy, and/or polaroid photograph of the gross specimen). Although not currently thought to be a variant of Wilms tumor, clear cell sarcoma of the kidney (CCSK) is an important entity to consider. It is associated with a signicantly higher rate of relapse and death than FH Wilms tumor. CCSK also is associated with a distinctively high
50

rate of skeletal metastases. This variant was rst recognized in the literature by Kidd50 in 1970 and was independently identied in 1978 by Marsden et al51 in Britain and the pathologists of the NWTSG.48 The descriptive term CCSK was used by the NWTSG, whereas the British workers referred to bone-metastasizing renal tumour of childhood (BMRTC). CCSK has a much wider distribution of metastases than does FH Wilms tumor, with a strikingly increased number of brain as well as bone metastases.52,53 Most CCSK specimens have a distinct and easily recognized histologic appearance, but a number of variant patterns, such as epithelioid, spindling, myxoid, and cystic, invite confusion with Wilms tumor or other tumor types (Fig. 3).54-57 The reader is referred elsewhere for detailed descriptions and illustrations of both the classic and variant patterns.51,58 Rhabdoid tumor of the kidney (RTK), a distinctive and highly malignant tumor type, was identied for the rst time in 1978 by NWTSG pathologists.48 The tumor, previously confused with Wilms tumor, is monomorphous like CCSK. The cells of RTK, unlike CCSK, characteristically have prominent acidophilic cytoplasm, often resembling that of myoblasts. However, the cytoplasm is negative for ultrastructural or other markers of skeletal muscle (Fig. 4). The cell of origin for this distinctive tumor remains unknown.59,60 It is not a variant of Wilms tumor and will not be encountered as a focal change in a conventional Wilms tumor. Several cases have been reported in which apparently separate primary neuroectodermal tumors of the brain have developed in children with RTK.61

Presentation and Evaluation

Most children with Wilms tumor are brought to medical attention because of abdominal swelling or the presence of an abdominal mass. Usually this is noticed
CaA cancer Journal for Clinicians

C A

C a n c e r

C l i n

1 9 9 6 ; 4 6 : 4 6 - 6 3

Table 2 Pathologic Distribution of Pediatric Renal Tumors

NWTS-1
Favorable Histology Wilms Tumor Anaplastic Wilms Tumor Clear Cell Sarcoma of the Kidney (CCSK) Rhabdoid Tumor of the Kidney (RTK) Total 378 (89.8%) 24 11 31* 8 421 478 56 1,397 2,296

NWTS-2
421 (88.0%) 26

NWTS-3
1,248 (89.3%) 61 32

Total
2,047 (89.2%) 111 (4.8%) 138*

*Combined total for CCSK and RTK. NWTS = National Wilms Tumor Study Data from National Wilms Tumor Studies.71,72,78

by a parent while bathing or dressing the child. Abdominal pain, gross hematuria, and fever are other frequent ndings at diagnosis.62 During the physical examination, it is important to note the location and size of the abdominal mass and its movement with respiration. These ndings help differentiate Wilms tumor from splenomegaly and neuroblastoma, the latter often arising in the celiac axis or extending across the midline because of lymph node involvement. A varicocele secondary to obstruction of the spermatic vein may be associated with the presence of a tumor thrombus in the renal vein or inferior vena cava. Persistence of the varicocele when the child is supine is highly suggestive of venous obstruction. It is also important to note specically any signs of syndromes associated with Wilms tumor, including the presence of aniridia; partial or complete hemihypertrophy; or genitourinary abnormalities, such as hypospadias and cryptorchidism. The laboratory evaluation should inVol. 46 No. 1 january/February 1996

clude a complete blood count; a differential white blood cell count; a platelet count; liver function tests; renal function tests; serum calcium, which may be elevated in patients with RTK and mesoblastic nephroma; and urinalysis. The radiographic evaluation should establish the presence of an intrarenal mass and a normally functioning contralateral kidney, document the patency of the inferior vena cava, and demonstrate the presence or absence of pulmonary metastases.62 The initial study should be an abdominal ultrasound examination. This will demonstrate whether the mass is cystic or solid and will help define the organ from which the tumor originated (Fig. 5). Computed tomography of the abdomen will establish the origin of most abdominal masses (Fig. 6). However a rigorous comparison of the value of computed tomography to that of abdominal ultrasonography in patient management is lacking. Current data suggest that conventional radiographic techniques, including ultra51

W i l m s

T u m o r

Fig. 2. Anaplastic Wilms tumor with a large, darkly stained multipolar mitotic gure near the center and a markedly enlarged interphase nucleus to its left. Nuclei throughout this eld exhibit increased variation in size and shape (hematoxylin-eosin, original magnication x600).

Fig. 3. Clear cell sarcoma of the kidney, classical pattern. Cords and nests of pale-stained tumor cells are separated by a delicate but distinct network of ne vascular septa. Nuclei are vesicular, with poorly stained chromatin and inconspicuous nucleoli (hematoxylin-eosin, original magnication x200).

sonography, provide sufficient information on which to make a decision for laparotomy in most children. The patency of the inferior vena cava can be established with the use of ultrasonography. When tumor is identied within the inferior vena cava, the proximal extent of the thrombus must be established prior to operation. Cardiac extension of such a tumor thrombus may produce few or no signs, but it can, on rare occasions, be responsible for sudden death following manipulation and embolization of the tumor at laparotomy.63,64 Plain chest radiographs, preferably including both oblique views, should be obtained to determine if pulmonary metastases are present. The role of computed tomography of the lungs in the evaluation of children with Wilms tumor is controversial.65 Lesions are rarely identified using computed tomography in patients with a negative plain chest radiograph.66,67 In addition the prognosis for children with densities identified only by computed tomography who are treated according to the stage of their renal tumor is excellent, suggesting that the added information is of limited, if any, value.68
52

A radionuclide bone scan and skeletal survey should be obtained postoperatively on all children with CCSK. A magnetic resonance image of the brain should be obtained on all children with RTK or CCSK.

Surgery
The treatment of children with Wilms tumor begins with abdominal exploration, using the transabdominal approach. The goal of abdominal exploration is radical or modied radical nephrectomy. Upon entering the abdomen, the opposite kidney should be inspected on all its surfaces for evidence of a synchronous bilateral tumor or evidence of nephrogenic rests. These may not be identied on preoperative imaging studies, especially if they are small and/or at. The tumor, kidney, renal hilar structures, and a generous segment of ureter should be dissected free and removed en bloc. The adrenal gland should be included in the resection if the tumor is adherent to the gland or if the tumor originates in the upper pole of the kidney. After the primary tumor has been removed, the liver should be inspected.
CaA cancer Journal for Clinicians

C A

C a n c e r

C l i n

1 9 9 6 ; 4 6 : 4 6 - 6 3

Biopsies should be obtained from areas that are grossly suspicious for tumor. The para-aortic lymph nodes should be inspected. If enlarged nodes are present, these should be biopsied. If all of the para-aortic lymph nodes appear to be normal, then a random biopsy should be obtained. Occasionally at laparotomy the tumor is found to be so large or vital structures are so compromised that tumor excision is not possible without increased surgical morbidity.69 A biopsy should be obtained from the kidney in this situation only if a tumor nodule cannot be identied at some other site, such as the peritoneal surface or the liver. In addition, attempts at primary surgical excision of the tumor and caval extension are associated with increased surgical morbidity.69 Preoperative chemotherapy should be administered to patients who have intracaval and atrial extension of the tumor.70 Tumor shrinkage usually follows, making the standard transabdominal approach feasible.

Fig. 4. Rhabdoid tumor. Most nuclei have a large, single nucleolus, imparting an owls eye appearance to the nucleus. Several cells, including one near the center, have hyaline globular cytoplasmic inclusions. Ultrastructurally the latter inclusions consist of whorled masses of intermediate laments, usually composed of vimentin (hematoxylin-eosin, original magnication x600).

Staging
The staging system used to describe children with Wilms tumor considers several physical features of the tumor that increase the risk of local or distant recurrence and therefore dictate therapeutic modications. The staging system employed by the NWTSG is detailed in Table 1.
Fig. 5. Wilms tumor sonogram. Prone sagittal scan of right renal fossa demonstrates a large, complex, mainly solid intrarenal mass.

Radiation Therapy
Postnephrectomy operative-bed radiation therapy was advocated for every child with Wilms tumor at the time the rst National Wilms Tumor Study (NWTS-1) was initiated in 1969. NWTS-1 and subsequent studies have demonstrated that ank irradiation is not necessary for any child with a stage I or II/FH Wilms tumor, if treatment includes combination chemotherapy with vincristine
Vol. 46 No. 1 january/February 1996

and dactinomycin.71,72 Analyses also indicate that ank irradiation is sufficient for children with tumor spill conned to the ank, but that whole abdomen irradiation is advisable when contamination of the entire peritoneal cavity has occurred.73

Chemotherapy
The use of dactinomycin for the adjuvant treatment of children with Wilms tumor was pioneered by Farber and his
53

W i l m s

T u m o r

Fig. 6. Computed tomography scan of the abdomen showing a right renal tumor and a normal appearing left kidney.

colleagues. These investigators reported that such therapy improved the survival rate of patients compared with that observed when nephrectomy was followed only by abdominal irradiation.74 Others have demonstrated that multiple courses of dactinomycin decrease the frequency of recurrence compared with a single course.75,76 Vincristine was evaluated as singleagent adjuvant chemotherapy by investigators at the MD Anderson Hospital and the Pediatric Division of the Southwest Oncology Group, the NWTSG, and the Medical Research Council. Patients with nonmetastatic, locally advanced tumors in the NWTS-1 trial were randomized to receive dactinomycin, vincristine, or the combination, in addition to postoperative abdominal irradiation. The relapse-free survival rate for children treated with vincristine was 54.4 percent at four years compared with 56.0 percent at four years for children treated with dactinomycin. The relapse-free survival rate for children treated with the combination of vincristine and dactinomycin was 77.5 percent, signicantly better than for either single agent.77,78 In the trial by the Medical Research Council, children were randomized to therapy with multiple courses of
54

dactinomycin or vincristine after receiving a postoperative course of dactinomycin. Thus, children randomized to therapy with vincristine actually received combination chemotherapy. The relapse-free survival rate for children treated with vincristine was 78 percent compared with 54 percent for children treated with dactinomycin.79 In NWTS-2, children with group I tumors were randomized to six or fifteen months of adjuvant chemotherapy with vincristine and dactinomycin. None of these patients received postoperative abdominal irradiation. The relapse-free survival rate after randomization for those children who received six months of chemotherapy was 97.4 percent compared with 91.1 percent for those who were treated for 15 months,71,78 a difference that was not statistically signicant. In NWTS-2, the combination of vincristine and dactinomycin was compared with the same two agents plus doxorubicin in children with stage II to IV, FH or anaplastic Wilms tumor, CCSK, or RTK. All children received local irradiation. Overall there was a statistically signicant improvement in relapse-free survival among those patients randomized to receive the three-drug regimen.78 The relapse-free survival rate following randomization among group II, FH patients treated with two agents was 78.4 percent compared with 87.7 percent for those who received three agents. The relapsefree survival rate following randomization for group III, FH patients treated with two agents was 65.4 percent compared with 88.5 percent for those treated with three agents,71,78 a difference that was statistically signicant. The addition of doxorubicin did not improve the relapse-free survival rate of those patients with an unfavorable histology tumor or group IV disease. The benet reported in NWTS-2 from the addition of doxorubicin may be due to the greater intensity of the threeCaA cancer Journal for Clinicians

C A

C a n c e r

C l i n

1 9 9 6 ; 4 6 : 4 6 - 6 3

Favorable Histology (FH)

DACT + VCR for 10 weeks Stage I (any age) Surgery No radiation therapy DACT + VCR for 6 months No radiation therapy DACT + VCR + DOX for 15 months 2,000 rad Stage II (any age) Surgery No radiation therapy Intensive DACT + VCR for 15 months 2,000 rad

1,000 rad DACT + VCR + DOX for 15 months 2,000 rad Stage III (any age) Surgery 1,000 rad Intensive DACT + VCR for 15 months 2,000 rad

Unfavorable Histology (UH) and All Stage IV

Radiation therapy All UH, any stage All stage IV, FH + UH Surgery Radiation therapy

DACT + VCR +DOX for 15 months

DACT + VCR + DOX + CPM for 15 months

Fig. 7. Treatment randomization for patients entered on National Wilms Tumor Study-3. DACT = dactinomycin; VCR = vincristine; DOX = doxorubicin; CPM = cyclophosphamide.
Vol. 46 No. 1 january/February 1996 55

W i l m s

T u m o r

Table 3 Results of Treatment of Children with Favorable Histology Wilms Tumor on National Wilms Tumor Study3
Four-Year Relapse-Free Survival (Percent)
89.0 87.4 82.0 79.0

Stage
I Il Ill IV

Four-Year Overall Survival (Percent)

95.6 91.1 90.9 80.9

drug regimen, rather than the addition of a third agent. This hypothesis was tested in NWTS-3 (Fig. 7). The results of this trial demonstrated that (1) intensive treatment with vincristine and dactinomycin was equivalent to therapy with these two drugs plus doxorubicin; (2) postoperative abdominal irradiation does not improve the relapse-free survival rate of children with stage II Wilms tumor; and (3) 1,000 and 2,000 cGy are equally effective in controlling microscopic residual disease in children with stage III tumors who were treated with the three-drug regimen (Table 3).72 Early NWTS-3 analyses suggested that patients with stage II to IV, anaplastic Wilms tumor, who all received radiation therapy, beneted from the addition of cyclophosphamide to the combination of dactinomycin, vincristine, and doxorubicin.72 This result for patients with diffuse anaplasia (stages II to IV) has been conrmed with additional patient accrual on NWTS-4.80 There is no benecial effect of adding cyclophosphamide in patients with tumors having only focal anaplasia.
56

All NWTS-3 patients with CCSK received abdominal radiation therapy and were randomized to the same three- versus four-drug comparative regimens. The four-year, relapse-free survival rate for CCSK patients treated with three drugs was 70.6 percent, and the four-year overall survival rate was 74.8 percent. There was no statistically signicant improvement in those given the fourth drug (cyclophosphamide).52 Patients with RTK have responded poorly to all the treatments used in the NWTS. The four-year, relapse-free survival rate for all NWTS-3 patients with RTK randomized according to Figure 7 was about 25 percent, and the overall four-year survival rate was the same.72

Bilateral Wilms Tumor

Wilms tumor occurs simultaneously in both kidneys in about seven percent of cases. Most children with bilateral Wilms tumor are not diagnosed on the basis of the physical examination. In the NWTS-1, only nine of 30 children (30 percent) with bilateral disease had bilateral, palpable
CaA cancer Journal for Clinicians

C A

C a n c e r

C l i n

1 9 9 6 ; 4 6 : 4 6 - 6 3

abdominal masses. Bilateral disease was identied in only 17 of 30 children (56.6 percent) by intravenous urography, and only about 10 percent of those found at laparotomy to have bilateral disease were previously identied using computed tomography.81 These data emphasize the importance of contralateral renal exploration at the time of laparotomy. The treatment of children with bilateral Wilms tumor must be individualized. The goal of therapy is to eradicate all tumor and to preserve as much normal renal tissue as possible, with the hope of decreasing the frequency of chronic renal failure among these children.82-84 The approach presently recommended is initial bilateral renal biopsy with staging of each kidney. Initial treatment is with the combination of vincristine and dactinomycin. A reevaluation is performed to determine if there has been sufficient response of the tumors to allow tumor resection, with preservation of a substantial amount of normal renal tissue. Additional chemotherapeutic agents, such as doxorubicin, with or without radiation therapy, may be necessary for the management of children whose tumors respond poorly to the combination of vincristine and dactinomycin.

received no prior abdominal irradiation, and relapse more than twelve months after diagnosis.

Sequelae of Treatment
The treatment that children receive for Wilms tumor may cause damage to other structures or organs, such as the bones and heart. In addition both chemotherapeutic agents and radiation therapy can induce second malignant neoplasms. CARDIAC COMPLICATIONS Congestive heart failure is a known complication of therapy with an anthracycline.87 The frequency is directly proportional to the cumulative dose of doxorubicin received, with a reported incidence of congestive heart failure of about ve percent in patients who received a cumulative dose of 400 to 500 mg/m2.88 Subclinical effects are observed in up to 57 percent of patients,89 with impairment of diastolic function clearly related to dose.90 Although the initial reports of congestive heart failure were limited to the rst year after completion of therapy,91 reports of cardiac failure and dysrythmias, leading in some cases to sudden death, are now appearing for patients treated four to 20 years earlier92,93 and may be precipitated by a physiologic stress such as pregnancy.94 In a preliminary analysis of the frequency of and risk factors for congestive heart failure in patients entered on NWTS-1, NWTS-2, and NWTS-3, eight cases of congestive heart failure not related to renal failure or pulmonary hypertension were identied in patients who remained continuously free of disease following their initial course of therapy for Wilms tumor. All eight patients received doxorubicin as part of their chemotherapy regimen. The cumulative frequency of congestive heart failure was 1.7 percent among doxorubicin-treated patients. Additional statistically signicant
57

Treatment of Recurrent Disease

Wilms tumor has a tendency to recur in several sites, including lung, liver, opposite kidney, original tumor bed, and other intra-abdominal sites. Bone, brain, and other sites are only occasionally involved. The most frequent site of recurrent disease is the lung.85 Although most rst relapses are diagnosed within the rst two years after nephrectomy, initial relapse has been diagnosed as long as eleven years after diagnosis.86 Those factors that favorably affect the success of further therapy include initial treatment with only vincristine and dactinomycin, relapse to the lungs only, relapse in the abdomen of a patient who
Vol. 46 No. 1 january/February 1996

W i l m s

T u m o r

Table 4 Selection of Imaging Studies for Follow-up of Children with Renal Neoplasms of Proven Histology and Free of Metastases at Diagnosis
Imaging Study Schedule Following Primary Therapy

Tumor Type
Wilms Tumor FH, any stage and anaplastic stage I

Chest lms

6 weeks and 3 months postoperatively; then every 3 months x 5, every 6 months x 3, yearly x 2 Yearly to full growth, then every 5 years indenitely Yearly x 3 As for chest lms Every 3 months x 8, every 6 months x 6; yearly x 5 As for FH Every 3 months x 8; every 6 months x 6

Irradiated patients, any stage Bony structure* (e.g., spine +/- pelvis) Without NR, stages I & I I Without NR, stage III With NR, any stage Stage II and III anaplastic Abdominal US Abdominal US Abdominal US Chest lms Abdominal US

Clear Cell Sarcoma of the Kidney (CCSK)

Brain MRI &/or opacied CT, Skeletal survey & bone scan Chest lms

When CCSK is established; then every 6 months x 10

As for FH

Rhabdoid Tumor of the Kidney (RTK)

Brain MRI &/or opacied CT Chest lms

As for CCSK As for FH

*To include any irradiated osseous structures. To detect second neoplasms, benign (osteochondromas) or malignant. FH = favorable histology; US = ultrasonography; MRI = magnetic resonance imaging; CT = computed tomography NR = nephrogenic rests in one or both kidneys Adapted with permission from DAngio et al.85

58

CaA cancer Journal for Clinicians

C A

C a n c e r

C l i n

1 9 9 6 ; 4 6 : 4 6 - 6 3

risk factors included prior whole lung irradiation and concurrent therapy with cyclophosphamide.95 Others have reported congestive heart failure in Wilms tumor patients who received doxorubicin and left ventricular irradiation from the abdominal radiation therapy treatment portal.96,97 Further follow-up of the NWTSG cohort is needed to dene more accurately the magnitude of the risk for late congestive heart failure.95 ABNORMAL TRUNK DEVELOPMENT The late effects of trunk irradiation scoliosis and soft tissue underdevelopmentare still being seen since the advent of megavoltage irradiation.98-101 Heaston et al100 reported the frequency of spinal abnormalities in patients treated with megavoltage irradiation following nephrectomy. Scoliosis was diagnosed in six of 16 patients (38 percent) who had entered the adolescent growth spurt, but no patient had a curve that exceeded 25 degrees. Eight patients (50 percent) had kyphosis, including ve who did not have scoliosis.100 Other investigators identied scoliosis in seven of 12 patients (58 percent)99 and 35 of 57 patients (61 percent)102 treated with megavoltage irradiation following nephrectomy. These data suggest that the frequency of spinal deformity may not decrease with the use of megavoltage radiation sources. Longer follow-up is necessary to conrm the observation by Heaston et al100 that the severity of deformities is less than observed following orthovoltage irradiation. One would expect the least deformity in nonirradiated patients. That expectation has been documented by the NWTSG, which recorded 66 instances of musculoskeletal difficulties (not otherwise defined) among 88 irradiated stage I children followed for five or more years versus seven in 93 nonirradiated children.102
Vol. 46 No. 1 january/February 1996

SECOND MALIGNANT NEOPLASMS Second malignant neoplasms can develop in Wilms tumor survivors.103-105 Most of these, such as bone,106 breast,107 and thyroid cancers,108 have occurred in irradiated areas. The most signicant risk factor for the occurrence of a second malignant neoplasm in the NWTSG cohort was treatment with radiation therapy. Initial treatment that included doxorubicin increased this risk. Signicantly, even those patients whose therapy included only dactinomycin and vincristine, without radiation therapy, had an increased risk of cancer compared with the US population.104 It is obvious that Wilms tumor survivors must be followed carefully for life so that late adverse effects of therapy can be detected early, should they occur, and not vitiate what has been gained from so many years of successful clinical research.

Follow-up
Children who have been treated for Wilms tumor should be examined regularly by a physician who is familiar with the natural history of this tumor and the complications of therapy. Careful palpation of the abdomen is essential to detect local tumor recurrence or tumor growth in the liver or contralateral kidney. The indicated radiographic examinations depend upon the original stage of the tumor. Local tumor recurrence and recurrence at other intra-abdominal sites is very uncommon among children with stage I or II Wilms tumor. The rst site of disease recurrence in these patients is most frequently the lung. Children who have gross residual abdominal disease (stage III and stage IV) have a greater risk of local tumor recurrence. These patients should have frequent, careful palpation of the abdomen. Suspicious ndings on physical examination may be clarified using abdominal ultrasonography or computed tomography (Table 4).85
59

W i l m s

T u m o r

Patients who present with hematogenous metastases (lung, brain, bone, and/or liver) require regular evaluation of these sites. The brain is most easily evaluated using magnetic resonance imaging. The liver should be palpated at each follow-up visit. Evidence on physical examination of enlargement and/or nodularity of the liver should be conrmed with computed tomography. Bones known to be involved with tumor and areas of bone

pain in patients predisposed to bone metastases (CCSK) should be evaluated with plain radiographs. A radionuclide bone scan should be obtained when the plain radiographs are negative and the symptoms are highly suggestive of a bone metastasis. The tumor bed of patients who present with hematogenous metastases and patients without metastases CA should be evaluated (Table 4).85

References 1. Belasco J, DAngio GJ: Wilms tumor. CA Cancer J Clin 1981;31:258-270. 2. DeLaat CA, Lampkin BC: Long-term survivors of childhood cancer: Evaluation and identication of sequelae of treatment. CA Cancer J Clin 1992; 42:263-282. 3. Green DM: Long Term Complications of Therapy for Cancer in Childhood and Adolescence. Baltimore, Johns Hopkins University Press, 1989. 4. Breslow N, Olshan A, Beckwith JB, et al: Ethnic variation in the incidence, diagnosis, prognosis and follow-up of children with Wilms tumor. J Natl Cancer Inst 1994;86:49-51. 5. Crist WM, Kun LE: Common solid tumors of childhood. N Engl J Med 1991;324:461-471. 6. Stiller CA, Parkin DM: International variations in the incidence of childhood renal tumours. Br J Cancer 1990;62:1026-1030. 7. Breslow N, Olshan A, Beckwith JB, Green DM: Epidemiology of Wilms tumor. Med Pediatr Oncol 1993;21:172-181. 8. Miller RW, Fraumeni JF Jr, Manning MD: Association of Wilmss tumor with aniridia, hemihypertrophy and other congenital malformations. N Engl J Med 1964;270:922-927. 9. Riccardi VM, Hittner HM, Francke U, et al: The aniridia-Wilms tumor association: The critical role of chromosome band 11p13. Cancer Genet Cytogenet 1980;2:131-137. 10. Coppes MJ, Huff V, Pelletier J: Denys-Drash syndrome: Relating a clinical disorder to genetic alterations in the tumor suppressor gene WT1. J Pediatr 1993;123:673-678. 11. Eddy AA, Mauer SM: Pseudohermaphroditism, glomerulopathy, and Wilms tumor (Drash syndrome): Frequency in end-stage renal failure. J Pediatr 1985;106:584-587. 12. Beckwith JB: Macroglossia, omphalocele, adrenal cytomegaly, gigantism, and hyperplastic visceromegaly, in Bergsma D, McKusick VA, Hall JG, Scott CI (eds): Birth Defects: Original Article Series, Vol 5. New York, The National FoundationMarch of Dimes, 1969, pp 188-196.

13. Fabia J, Thuy TD: Occupation of father at time of birth of children dying of malignant diseases. Br J Prev Soc Med 1974;28:98-100. 14. Kantor AF, Curnen MG, Meigs JW, Flannery JT: Occupations of fathers of patients with Wilmss tumour. J Epidemiol Community Health 1979; 33:253-256. 15. Sanders BM, White GC, Draper GJ: Occupations of fathers of children dying from neoplasms. J Epidemiol Community Health 1981;35: 245-250. 16. Olshan AF, Breslow NE, Daling JR, et al: Wilms tumor and paternal occupation. Cancer Res 1990;50:3212-3217. 17. Bunin GR, Nass CC, Kramer S, Meadows AT: Parental occupation and Wilms tumor: Results of a case-control study. Cancer Res 1989;49:725-729. 18. Olshan AF, Breslow NE, Falletta JM, et al: Risk factors for Wilms tumor: Report from the National Wilms Tumor Study. Cancer 1993;72:938-944. 19. Zack M, Cannon S, Loyd D, et al: Cancer in children of parents exposed to hydrocarbon-related industries and occupations. Am J Epidemiol 1980;111:329-336. 20. Hicks N, Zack M, Caldwell GG, et al: Childhood cancer and occupational radiation exposure in parents. Cancer 1984;53:1637-1643. 21. Knudson AG: Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68:820-823. 22. Dryja TP, Mukai S, Petersen R, et al: Parental origin of mutations of the retinoblastoma gene. Nature 1989;339:556-558. 23. Ejima Y, Sasaki MS, Kaneko A, Tanooka H: Types, rates, origin and expressivity of chromosome mutations involving 13q14 in retinoblastoma patients. Hum Genet 1988;79:118-123. 24. Wiggs J, Nordenskjold M, Yandell D, et al: Prediction of the risk of hereditary retinoblastoma, using DNA polymorphisms within the retinoblastoma gene. N Engl J Med 1988;318:151-157. 25. Cavenee WK, Dryja TP, Phillips RA, et al: Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 1983;305:

60

CaA cancer Journal for Clinicians

C A

C a n c e r

C l i n

1 9 9 6 ; 4 6 : 4 6 - 6 3

779-784. 26. Breslow NE, Beckwith JB: Epidemiological features of Wilms tumor: Results of the National Wilms Tumor Study. J Natl Cancer Inst 1982; 68:429-436. 27. Breslow NE, Beckwith JB, Ciol M, Sharples K: Age distribution of Wilms tumor: Report from the National Wilms Tumor Study. Cancer Res 1988; 48:1653-1657. 28. Beckwith JB, Kiviat NB, Bonadio JF: Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms tumor. Pediatr Pathol 1990; 10:1-36. 29. Riccardi VM, Sujansky E, Smith AC, Francke U: Chromosomal imbalance in the Aniridia-Wilms tumor association: 11p interstitial deletion. Pediatrics 1978;61:604-610. 30. Huff V, Meadows A, Riccardi VM, et al: Parental origin of de novo constitutional deletions of chromosomal band 11p13. Am J Hum Genet 1990;47:155-160. 31. Mannens M, Slater RM, Heyting C, et al: Molecular nature of genetic changes resulting in loss of heterozygosity of chromosome 11 in Wilms tumors. Hum Genet 1988;81:41-48. 32. Koufos A, Grundy P, Morgan K, et al: Familial Wiedemann-Beckwith syndrome and a second Wilms tumor locus both map to 11p15.5. Am J Hum Genet 1989;44:711-719. 33. Call KM, Glaser T, Ito CY, et al: Isolation and characterization of a zinc nger polypeptide gene at the human chromosome 11 Wilms tumor locus. Cell 1990;60:509-520. 34. Gessler M, Poustka A, Cavenee W, et al: Homozygous deletion in Wilms tumours of a zincnger gene identied by chromosome jumping. Nature 1990;343:774-778. 35. Pelletier J, Bruening W, Kashtan CE, et al: Germline mutations in the Wilms tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 1991;67:437-447. 36. Huff V, Miwa H, Haber DA, et al: Evidence for WT1 as a Wilms tumor (WT) gene: Intragenic germinal deletion in bilateral WT. Am J Hum Genet 1991;48:997-1003. 37. Haber DA, Buckler AJ, Glaser T, et al: An internal deletion within an 11p13 zinc nger gene contributes to the development of Wilms tumor. Cell 1990;61:1257-1269. 38. Varanasi R, Bardeesy N, Ghahremani M, et al: Fine structure analysis of the WT1 gene in sporadic Wilms tumors. Proc Natl Acad Sci USA 1994; 91:3554-3558. 39. Schroeder WT, Chao LY, Dao DD, et al: Nonrandom loss of maternal chromosome 11 alleles in Wilms tumors. Am J Hum Genet 1987;40:413420. 40. Grundy P, Koufos A, Morgan K, et al: Familial predisposition to Wilms tumour does not map to the short arm of chromosome 11. Nature 1988; 336:374-376. 41. Tricoli JV, Rall LB, Scott J, et al: Localization of

insulin-like growth factor genes to human chromosomes 11 and 12. Nature 1984;310:784-786. 42. Rainier S, Johnson LA, Dobry CJ, et al: Relaxation of imprinted genes in human cancer. Nature 1993;362:747-749. 43. Reeve AE, Eccles MR, Wilkins RJ, et al: Expression of insulin-like growth factor-II transcripts in Wilms tumour. Nature 1985;317:258-260. 44. Ogawa O, Eccles MR, Szeto J, et al: Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms tumor. Nature 1993;362:749751. 45. Ogawa O, Becroft DM, Morison IM, et al: Constitutional relaxation of insulin-like growth factor II gene imprinting associated with Wilms tumour and gigantism. Nat Genet 1993;5:408-412. 46. Huff V, Compton DA, Chao LY, et al: Lack of linkage of familial Wilms tumour to chromosomal band 11p13. Nature 1988;336:377-378. 47. Huff V, Reeve AE, Leppert M, et al: Nonlinkage of 16q markers to familial predisposition to Wilms tumor. Cancer Res 1992;52:61176120. 48. Beckwith JB, Palmer NF: Histopathology and prognosis of Wilms tumors: Results from the First National Wilms Tumor Study. Cancer 1978;41: 1937-1948. 49. Faria P, Beckwith JB: A new denition of focal anaplasia (FA) in Wilms tumor (WT) identies cases with good outcome: A report from the National Wilms Tumor Study (Abstract). Mod Pathol 1993;6:3p. 50. Kidd JM: Exclusion of certain renal neoplasms from the category of Wilms tumor (Abstract). Am J Pathol 1970;59:16a. 51. Marsden HB, Lawler W, Kumar PM: Bone metastasizing renal tumor of childhood: Morphological and clinical features and differences from Wilms tumor. Cancer 1978;42:1922-1928. 52. Green DM, Breslow NE, Beckwith JB, et al: Treatment of children with clear-cell sarcoma of the kidney: A report from the National Wilms Tumor Study Group. J Clin Oncol 1994;12:2132-2137. 53. Beckwith JB, Larson E, Case T: Clear cell sarcoma of kidney. Pediatr Pathol 1989;9:211-218. 54. Haas JE, Bonadio JF, Beckwith JB: Clear cell sarcoma of the kidney with emphasis on ultrastructural studies. Cancer 1984;54:2978-2987. 55. Schmidt D, Harms D, Evers KG, et al: Bone metastasizing renal tumor (clear cell sarcoma) of childhood with epithelioid elements. Cancer 1985; 56:609-613. 56. Lamego CM, Zerbini MC: Bone-metastasizing primary renal tumors in children. Radiology 1983;147:449-454. 57. Marsden HB, Lawler W: Bone metastasizing renal tumour of childhood: Histopathological and clinical review of 38 cases. Virchows Arch [Pathol Anat] 1980;387:341-351. 58. Beckwith JB: Wilms tumor and other renal tumors of childhood: A selective review from the National Wilms Tumor Study Pathology Center. Hum Pathol 1983;14:481-492.

Vol. 46 No. 1 january/February 1996

61

W i l m s

T u m o r

59. Haas JE, Palmer NF, Weinberg AG, Beckwith JB: Ultrastructure of malignant rhabdoid tumor of the kidney: A distinctive renal tumor of children. Hum Pathol 1981;12:646-657. 60. Weeks DA, Beckwith JB, Mierau GW, Luckey DW: Rhabdoid tumor of kidney: A report of 111 cases from the National Wilms Tumor Study Pathology Center. Am J Surg Pathol 1989;13:439458. 61. Bonnin JM, Rubinstein LJ, Palmer NF, Beckwith JB: The association of embryonal tumors originating in the kidney and in the brain. Cancer 1984;54:2137-2146. 62. Green DM: Diagnosis and Management of Malignant Solid Tumors in Infants and Children. Boston, Martinus Nijhoff Publishing, 1985, pp. 129186. 63. Akyon MG, Arslan G: Pulmonary embolism during surgery for a Wilms tumor (nephroblastoma). Br J Anaesth 1981;53:903-905. 64. Shurin SB, Gauderer MWL, Dahms BB, Conrad WG: Fatal intraoperative pulmonary embolization of Wilms tumor. J Pediatr 1982; 101:559-562. 65. Cohen M, Provisor A, Smith WL, Weetman R: Efficacy of whole lung tomography in diagnosing metastases from solid tumors in children. Radiology 1981;141:375-378. 66. Wilimas JA, Douglass EC, Magill HL, et al: Signicance of pulmonary computed tomography at diagnosis in Wilms tumor. J Clin Oncol 1988; 6:1144-1146. 67. Riggs JM, Wooton SL, Ihrke H, et al: Computed tomography versus chest radiography in the detection of pulmonary metastases in Wilms tumor (Abstract). Clin Res 1994;42:30A. 68. Green DM, Fernbach DJ, Norkool P, et al: The treatment of Wilms tumor patients with pulmonary metastases detected only with computed tomography: A report from the National Wilms Tumor Study. J Clin Oncol 1991;9:1776-1781. 69. Ritchey ML, Kelalis PP, Breslow N, et al: Surgical complications after nephrectomy for Wilms tumor. Surg Gynecol Obstet 1992;175:507514. 70. Ritchey ML, Kelalis PP, Haase GM, et al: Preoperative therapy for intracaval and atrial extension of Wilms tumor. Cancer 1993;71:41044110. 71. DAngio GJ, Evans A, Breslow N, et al: The treatment of Wilms tumor: Results of the Second National Wilms Tumor Study. Cancer 1981;47: 2302-2311. 72. DAngio GJ, Breslow N, Beckwith JB, et al: Treatment of Wilms tumor: Results of the Third National Wilms Tumor Study. Cancer 1989;64:349360. 73. Tefft M, DAngio GJ, Grant W 3rd: Postoperative radiation therapy for residual Wilms tumor: Review of Group III patients in the National Wilms Tumor Study. Cancer 1976;37:2768-2772. 74. Farber S: Chemotherapy in the treatment of leukemia and Wilms tumor. JAMA 1966;198:826-

836. 75. Wolff JA, DAngio G, Hartmann J, et al: Longterm evaluation of single versus multiple courses of actinomycin D therapy of Wilms tumor. N Engl J Med 1974;290:84-86. 76. Wolff JA, Newton WA Jr, Krivit W, DAngio GJ: Single versus multiple dose dactinomycin therapy of Wilmss tumor. N Engl J Med 1968;279:290294. 77. DAngio GJ, Beckwith JB, Breslow NE, et al: Wilms tumor: An update. Cancer 1980;45:17911798. 78. DAngio GJ, Evans AE, Breslow N, et al: The treatment of Wilms tumor: Results of the National Wilms Tumor Study. Cancer 1976;38:633-646. 79. Medical Research Councils Working Party on Embryonal Tumours in Childhood: Management of nephroblastoma in childhood: Clinical study of two forms for maintenance therapy. Arch Dis Child 1978;53:112-119. 80. Green DM, Beckwith JB, Breslow NE, et al: The treatment of children with stages II to IV anaplastic Wilms tumor: A report from the National Wilms Tumor Study Group. J Clin Oncol 1994;12:2126-2131. 81. Ritchey ML, Green DM, Breslow N, et al: Accuracy of current imaging modalities in the diagnosis of synchronous bilateral Wilms tumor. J Urol 1994;151:329A. 82. Blute ML, Kelalis PP, Breslow N, et al: Bilateral Wilms tumor. J Urol 1987;138:968-973. 83. Bishop HC, Tefft M, Evans AE, DAngio GJ: Survival in bilateral Wilms tumor: Review of 30 National Wilms Tumor Study cases. J Pediatr Surg 1977;12:631-638. 84. Montgomery BT, Kelalis PP, Blute ML, et al: Extended followup of bilateral Wilms tumor: Results of the National Wilms Tumor Study. J Urol 1991;146:514-518. 85. DAngio GJ, Rosenberg H, Sharples K, et al: Position paper: Imaging methods for primary renal tumors of childhood: Costs versus benets. Med Pediatr Oncol 1993;21:205-212. 86. Clausen N: Late recurrence of Wilms tumor. Med Pediatr Oncol 1982;10:557-561. 87. Gilladoga AC, Manuel C, Tan CT, et al: The cardiotoxicity of adriamcyin and daunomycin in children. Cancer 1976;37:1070-1078. 88. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91:710-717. 89. Lipshultz SE, Colan SD, Gelber RD, et al: Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991;324:808-815. 90. Hausdorf G, Morf G, Beron G, et al: Long term doxorubicin cardiotoxicity in childhood: Non-invasive evaluation of the contractile state and diastolic lling. Br Heart J 1988;60:309-315. 91. Goorin AM, Borow KM, Goldman A, et al: Congestive heart failure due to adriamycin cardiotoxicity: Its natural history in children. Cancer 1981;47:2810-2816.

62

CaA cancer Journal for Clinicians

C A

C a n c e r

C l i n

1 9 9 6 ; 4 6 : 4 6 - 6 3

92. Steinherz LJ, Steinherz PG, Tan CT, et al: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 1991;266:1672-1677. 93. Goorin AM, Chauvenet AR, Perez-Atayde AR, et al: Initial congestive heart failure, six to ten years after doxorubicin chemotherapy for childhood cancer. J Pediatr 1990;116:144-147. 94. Davis LE, Brown CE: Peripartum heart failure in a patient treated previously with doxorubicin. Obstet Gynecol 1988;71:506-508. 95. Green DM, Breslow NE, Moksness J, DAngio GJ: Congestive heart failure following initial therapy for Wilms tumor: A report from the National Wilms Tumor Study. (Abstract). Pediatr Res 1994;35:161A. 96. Bhanot P, Cushing B, Philipart A, et al: Hepatic irradiation and adriamycin cardiotoxicity. J Pediatr 1979;95:561-563. 97. Pinkel D, Camitta B, Kun L, et al: Doxorubicin cardiomyopathy in children with left-sided Wilms tumor. Med Pediatr Oncol 1982;10:483-488. 98. Probert JC, Parker BR, Kaplan HS: Growth retardation in children after megavoltage irradiation of the spine. Cancer 1973;32:634-639. 99. Oliver JH, Gluck G, Gledhill RB, et al: Musculoskeletal deformities following treatment of Wilms tumor. Can Med Assoc J 1978;119:459-464. 100. Heaston DK, Libshitz HI, Chan RC: Skeletal effects of megavoltage irradiation in survivors of Wilms tumor. AJR Am J Roentgenol 1979;133: 389-395.

101. Wallace WH, Shalet SM, Morris-Jones PH, et al: Effect of abdominal irradiation on growth in boys treated for a Wilms tumor. Med Pediatr Oncol 1990;18:441-446. 102. Evans AE, Norkool P, Evans I, et al: Late effects of treatment for Wilms tumor: A report from the National Wilms Tumor Study Group. Cancer 1991;67:331-336. 103. Breslow NE, Norkool PA, Olshan A, et al: Second malignant neoplasms in survivors of Wilms tumor: A report from the National Wilms Tumor Study. J Natl Cancer Inst 1988;80:592-595. 104. Breslow NE, Takashima JR, Whitton JA, et al: Second malignant neoplasms following treatment for Wilms tumor: A report from the National Wilms Tumor Study Group. J Clin Oncol 1995;13:1851-1859. 105. Li FP, Yan JC, Sallan S, et al: Second neoplasms after Wilms tumor in childhood. J Natl Cancer Inst 1983;71:1205-1209. 106. Tucker MA, DAngio GJ, Boice JD Jr, et al: Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 1987;317:588-593. 107. Hancock SL, Tucker MA, Hoppe RT: Breast cancer after treatment of Hodgkins disease. J Natl Cancer Inst 1993;85:25-31. 108. Tucker MA, Jones PH, Boice JD Jr, et al: Therapeutic radiation at a young age is linked to secondary thyroid cancer. Cancer Res 1991;51: 2885-2888.

American Association for Cancer Research 1996 Research Fellowships

The purpose of the AACRs 1996 Research Fellowship in Clinical Translational Research, sponsored by Amgen, Inc., and its 1996 Research Fellowship in Basic Research is to foster meritorious clinical/ translational or basic research in the US or Canada by a young scientist currently at the postdoctoral or clinical research fellow level. Candidates must have been a fellow for at least two years but no more than ve years prior to the beginning of the award year (July 1996). Academic faculty holding the rank of assistant professor or higher, graduate or medical students, government employees, and employees of private industry are not eligible. Both fellowships provide a one-year grant of $30,000. Candidates must be nominated by a member of the AACR and submit a detailed application. The deadline is February 15. For application information, contact Jenny Anne Horst-Martz, American Association for Cancer Research, Public Ledger Building, Suite 816, 150 South Independence Mall West, Philadelphia, PA 191063483; telephone 215-440-9300; fax 215-440-9313.

Vol. 46 No. 1 january/February 1996

63