Wilms' tumor

Wilms' tumor

TABLE OF CONTENTS

GENERAL INFORMATION 
CELLULAR CLASSIFICATION
STAGE INFORMATION 
   Stage I (43% of patients) 
   Stage II (23% of patients) 
   Stage III (23% of patients) 
   Stage IV (10% of patients) 
   Stage V (5% of patients) 
TREATMENT OPTION OVERVIEW 
STAGE I WILMS' TUMOR 
STAGE II WILMS' TUMOR 
STAGE III WILMS' TUMOR 
STAGE IV WILMS' TUMOR 
STAGE V WILMS' TUMOR 
RECURRENT WILMS' TUMOR

GENERAL INFORMATION
This state-of-the-art statement on Wilms' tumor is an overview of prognosis, diagnosis, classification, and treatment. The National Cancer Institute created the PDQ database to increase the availability of new treatment information and its use in treating patients. Information and references from the most recently published literature are included after review by pediatric oncology specialists.

Cancer in children is rare. A team approach that incorporates the skills of the local physician, pediatric surgeon, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, and social workers is imperative to ensure that patients receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. For advances to be made in treating these patients, therapy should be delivered in the context of a clinical trial at a major medical center that has expertise in treating children. Only through entry of all eligible children into appropriate, well-designed clinical trials will progress be made against these diseases. Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[1]

Wilms' tumor is a curable disease in the majority of affected children. More than 90% of patients survive 4 years after diagnosis.[2] The prognosis is related not only to the stage of disease at diagnosis, the histopathologic features of the tumor, patient age, and tumor size but also to the team approach to each patient by the pediatric surgeon, radiotherapist, and pediatric oncologist.[2-4] Previous clinical trials have, in part, evaluated whether reduced therapy is sufficient to control disease in patients with early-stage, favorable-histology Wilms' tumor with some success.[5] Ongoing clinical trials are addressing duration and refinement of therapy.[2]

Wilms' tumor (hereditary or sporadic) appears to result from changes in one or more of several genes. Specific germ-line mutations in one of these genes (Wilms' tumor gene-1, WT1), located on the short arm of chromosome 11 (band 11p13), are not only associated with Wilms' tumor but also cause the rare Denys-Drash syndrome. A gene that causes aniridia is located near the WT1 gene on chromosome 11p13, and deletions encompassing the WT1 and aniridia genes may explain the association between aniridia and Wilms' tumor. Patients with aniridia or hemihypertrophy should be screened with ultrasound every 3 months until they are 6 years of age.[6] There appears to be a second Wilms' tumor gene at or near the Beckwith-Wiedemann gene locus on chromosome 11p15, and children with Beckwith-Wiedemann syndrome are at increased risk for developing Wilms' tumor. It is recommended that patients with Beckwith-Wiedemann disorder be screened with ultrasound every 3 months until they have reached 7 years of age.[7] Approximately one third of Wilms' tumors have loss of genetic material in the tumor cells from the short arm of chromosome 11, encompassing one or both of the Wilms' tumor gene regions on this chromosome. Genes on other chromosomes may also have an etiologic role in Wilms' tumor, and loss of genetic material from chromosome 16 and/or trisomy of chromosome 1q occurs in some tumors.[8]

Despite the number of genes that appear to be involved in the development of Wilms' tumor, hereditary Wilms' tumor (either bilateral tumors or a family history of the neoplasm) is uncommon, with 4%-5% of patients having bilateral tumors and 1%-2% of patients having a positive family history for Wilms' tumor.[9,10] The risk of Wilms' tumor among offspring of persons who have had unilateral (i.e., sporadic) tumors is quite low (less than 2%).[11] Siblings of children with Wilms' tumor have a low likelihood of developing Wilms' tumor.[9]

References:
1.Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99(1): 139-141, 1997.

2.National Wilms' Tumor Study Committee: Wilms' tumor: status report, 1990. Journal of Clinical Oncology 9(5): 877-887, 1991.

3.Ritchey ML, Haase GM, Shochat S: Current management of Wilms' tumor. Seminars in Surgical Oncology 9(6): 502-509, 1993.

4.Breslow N, Sharples K, Beckwith JB, et al.: Prognostic factors in nonmetastatic, favorable histology Wilms' tumor: results of the Third National Wilms' Tumor Study. Cancer 68(1): 345-2353, 1991.

5.D'Angio GJ, Breslow N, Beckwith JB, et al.: Treatment of Wilms' tumor: results of the third National Wilms' Tumor Study. Cancer 64(2): 349-360, 1989.

6.Green DM, Breslow NE, Beckwith JB, et al.: Screening of children with hemihypertrophy, aniridia, and Beckwith-Wiedemann syndrome in patients with Wilms tumor: a report from the National Wilms Tumor Study. Medical and Pediatric Oncology 21(3): 188-192, 1993.

7.Clericuzio CL, D'Angio GJ, Duncan M, et al.: Summary and recommendations of the workshop held at the First International Conference on Molecular and Clinical Genetics of Childhood Renal Tumors, Albuquerque, New Mexico, May 14-16, 1992. Medical and Pediatric Oncology 21(3): 233-236, 1993.

8.Coppes MJ, Haber DA, Grundy PE, et al.: Genetic events in the development of Wilms tumor. New England Journal of Medicine 331(9): 586-590, 1994.

9.Bonaiti-Pellie C, Chompret A, Tournade MF, et al.: Genetics and epidemiology of Wilms' tumor: the French Wilms' Tumor Study. Medical and Pediatric Oncology 20:(4): 284-291, 1992.

10.Breslow NE, Beckwith JB: Epidemiological features of Wilms' tumor: results of the National Wilms' Tumor Study. Journal of the National Cancer Institute 68(3): 429-436, 1982.

11.Li FP, Williams WR, Gimbrere K, et al.: Heritable fraction of unilateral Wilms tumor. Pediatrics 81(1): 147-149, 1988.

CELLULAR CLASSIFICATION

Although most patients with a histologic diagnosis of Wilms' tumor fare well with current treatment, approximately 10% of patients have histopathologic features that are associated with a poorer prognosis, and, in some types, with a high incidence of relapse and death. There are two general patterns of unfavorable histology:

anaplastic (extreme cellular pleomorphism and atypia, diffuse).[1]

Focal anaplasia may not confer nearly as poor a diagnosis as diffuse

anaplasia.[2]

sarcomatous (includes clear cell sarcoma of the kidney and malignant rhabdoid tumor of the kidney).[3-5] These sarcomatous tumors are separate entities rather than variants of Wilms' tumor.

Except for patients with diffuse anaplastic stage I tumors, the presence of unfavorable histology indicates a poorer prognosis in each clinical stage when compared with favorable histology.[6,7] More aggressive therapy may be used for treatment of these patients.[8]

The addition of doxorubicin to the combination of vincristine, dactinomycin, and radiation therapy probably resulted in an improvement in disease-free survival for patients with clear cell sarcoma of the kidney in the Third National Wilms' Tumor Study. The further addition of cyclophosphamide did not improve survival.[2] In contrast, patients with stages II-IV diffuse anaplastic histology clearly benefit from the further addition of cyclophosphamide to vincristine, dactinomycin, and doxorubicin. Patients with malignant rhabdoid tumor of the kidney continue to have a poor prognosis despite three- or four-drug regimens.

References:
1.Zuppan CW, Beckwith JB, Luckey DW: Anaplasia in unilateral Wilms' tumor: a report from the National Wilms' Tumor Study Pathology Center. Human Pathology 19(10): 1199-1209, 1988.

2.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. Journal of Clinical Oncology 12(10): 2132-2137, 1994.

3.Haas JE, Bonadio JF, Beckwith JB: Clear cell sarcoma of the kidney with emphasis on ultrastructural studies. Cancer 54(12): 2978-2987, 1984.

4.Palmer NF, Sutow W: Clinical aspects of the rhabdoid tumor of the kidney: a report of the National Wilms' Tumor Study Group. Medical and Pediatric Oncology 11(4): 242-245, 1983.

5.Weeks DA, Beckwith JB, Mierau GW, et al.: Rhabdoid tumor of kidney: a report of 111 cases from the National Wilms' Tumor Study Pathology Center. American Journal of Surgical Pathology 13(6): 439-458, 1989.

6.Ritchey ML, Haase GM, Shochat S: Current management of Wilms' tumor. Seminars in Surgical Oncology 9(6): 502-509, 1993.

7.Breslow NE, Palmer NF, Hill LR, et al.: Wilms' tumor: prognostic factors for patients without metastases at diagnosis: results of the National Wilms' Tumor Study. Cancer 41(4): 1577-1589, 1978.

8.Green DM, Beckwith JB, Breslow NE, et al.: Treatment of children with stages II to IV anaplastic Wilms' Tumor: a report from the National Wilms' Tumor Study Group. Journal of Clinical Oncology 12(10): 2126-2131, 1994.

STAGE INFORMATION
A clinicopathologic staging system has been devised by the National Wilms' Tumor Study Group. The clinical stage is determined by the pediatric surgeon in the operating room and is confirmed by the pathologist. Staging, which is based on the degree of gross and microscopic tumor extension, is the same for tumors with favorable or unfavorable histologic features. Thus, patients should be characterized by a statement of both criteria (for example, stage II, favorable histology or stage II, unfavorable histology).[1,2]

Patients with unfavorable histology form a heterogenous group, including those with stage I anaplastic tumors who have an excellent prognosis, those with clear cell sarcoma of the kidney, and those with rhabdoid tumor of the kidney.[1,2] A description of the staging system is given below, with data for 4-year survival rates from the Third National Wilms' Tumor Study.[2]

Stage I (43% of patients)
Stage I Wilms' tumor is defined as tumor limited to the kidney and completely excised. The surface of the renal capsule is intact. The tumor is not ruptured before or during removal. The vessels of the renal sinus are not involved. There is no residual tumor apparent beyond the margins of excision.

Stage II (23% of patients)
Stage II Wilms' tumor is defined as tumor that extends beyond the kidney but is completely excised. No residual tumor is apparent at or beyond the margins of excision. Any of the following conditions may exist:

Regional extension of the tumor, i.e., penetration through the outer surface of the renal capsule into the perirenal soft tissue or more than 1-2 mm of tumor invasion into the renal sinus.
Vessels outside the kidney are infiltrated or contain tumor thrombus
The tumor was biopsied or there was local spillage of tumor confined to the flank.

Stage III (23% of patients)
Stage III Wilms' is defined as residual tumor confined to the abdomen. One or more of the following conditions may exist:

Lymph nodes in the renal hilus, the periaortic chains, or beyond are found to contain tumor on biopsy. Lymph node involvement in the thorax or other extra-abdominal sites would be a criterion for stage IV.
There has been diffuse peritoneal contamination by the tumor, such as by spillage of tumor beyond the flank before or during surgery or by tumor growth that has penetrated through the peritoneal surface.
Implants are found on the peritoneal surfaces.
Tumor extends beyond the surgical margins either microscopically or grossly.
Tumor is not completely resectable because of local infiltration into vital structures.

Stage IV (10% of patients)
Stage IV Wilms' tumor is defined as the presence of hematogenous metastases. There are metastatic deposits beyond stage III, e.g., to the lung, liver, bone, or brain or to a combination of these sites.

Stage V (5% of patients)
Stage V Wilms' tumor is defined as bilateral renal involvement at the time of initial diagnosis.

An attempt should be made to stage each side according to the above criteria on the basis of extent of disease prior to biopsy. The 3-year survival was 92% for those patients whose most advanced lesion was stage I; it was 75% for those whose most advanced lesion was stage III if the lesion's histology was favorable.[3]

References:
1.National Wilms' Tumor Study Committee: Wilms' tumor: status report, 1990. Journal of Clinical Oncology 9(5): 877-887, 1991.

2.D'Angio GJ, Breslow N, Beckwith JB, et al.: Treatment of Wilms' tumor: results of the third National Wilms' Tumor Study. Cancer 64(2): 349-360, 1989.

3.Blute ML, Kelalis PP, Offord KP, et al.: Bilateral Wilms' tumor. Journal of Urology 138(4, Part 2): 968-973, 1987.

TREATMENT OPTION OVERVIEW
Because of the relative rarity of this tumor, all patients with Wilms' tumor should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) with experience treating Wilms' tumor is required to determine and implement optimum treatment.

For the vast majority of patients, therapy consists of surgery followed by chemotherapy and, in some patients, radiotherapy.[1,2] Pulmonary nodules not detected on chest radiographs but visible on computed tomography of the chest do not mandate treatment with whole-lung irradiation. The results of the first two National Wilms' Tumor Studies (NWTS-1 and NWTS-2) demonstrate that radiotherapy can be safely omitted in the postoperative management of stage I patients provided adequate chemotherapy with vincristine and dactinomycin is administered.[3,4] Results from the NWTS-3 demonstrate that abdominal radiotherapy does not provide significant clinical benefit for patients with stage II, favorable histology disease receiving vincristine and dactinomycin.[5] For stage III patients with favorable histology disease, results of the NWTS-3 suggest benefit from doxorubicin added to vincristine and dactinomycin and reduced-dose abdominal irradiation.[5] In certain cases, as described in the treatment options for stage III disease, initial surgical resection may be deemed xcessively risky (e.g., patients with right atrial extension of tumor), and preoperative chemotherapy following biopsy (which may be performed percutaneously) may be appropriate.[6-11] In other situations, preoperative chemotherapy is generally avoided because it limits the ability to accurately determine the extent of disease prior to therapy and to tailor therapy accordingly.[12] In the NWTS-3, patients selected for preoperative treatment had a slightly less favorable prognosis, stage for stage, but an ultimate 93% complete resection rate.[13] In Europe, however, preoperative chemotherapy has been more widely used.[7] The NWTS-4 evaluated pulse- intensive regimens for the treatment of children with Wilms' tumor. The pulse- intensive regimens produced less hematologic toxicity and delivered higher drug dose intensity than the standard regimen.[14] Major economic benefits will accrue if all children with stages I-IV favorable histology are treated using the pulse-intensive regimens.

The National Wilms' Tumor Study Committee has reported serious toxicity in patients younger than 12 months of age when treated with full doses of vincristine and dactinomycin.[15] The doses for such patients should be reduced by 50%.[16] This reduction diminishes toxicity while maintaining an excellent overall outcome. A report from NWTS-4 indicates that hepatic toxicity is no more common in the pulse-intensive regimen than in the standard regimen despite a significantly increased dose intensity.[14,17] Hepatic toxicity (in association with thrombocytopenia) attributed to dactinomycin has also been noted in United Kingdom Wilms' tumor trials.[18] Careful attention should be given to tests of liver function in children with Wilms' tumor, especially during the early course of therapy, and dactinomycin should not be administered during radiotherapy. Children treated for Wilms' tumor are at increased risk for developing second malignant neoplasms. This risk depends on the intensity of their therapy, including the use of radiation and doxorubicin, and on possible genetic factors.[19] Efforts, therefore, have been aimed toward reducing the intensity of therapy where possible.

Except for patients with diffuse anaplastic stage I tumors, the presence of unfavorable histology indicates a poorer prognosis in each clinical stage when compared with favorable histology.[20,21] More aggressive therapy may be used for treatment of these patients.[22]

The addition of doxorubicin to the combination of vincristine, dactinomycin, and radiation therapy probably resulted in an improvement in disease-free survival for patients with clear cell sarcoma of the kidney in the Third National Wilms' Tumor Study. The further addition of cyclophosphamide did not improve survival.[23] In contrast, patients with stages II-IV diffuse anaplastic histology clearly benefit from the further addition of cyclophosphamide to vincristine, dactinomycin, and doxorubicin. Patients with malignant rhabdoid tumor of the kidney continue to have a poor prognosis despite three- or four-drug regimens.

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

References:
1.D'Angio GJ, Breslow N, Beckwith JB, et al.: Treatment of Wilms' tumor: results of the third National Wilms' Tumor Study. Cancer 64(2): 349-360, 1989.

2.Jereb B, Burgers JM, Tournade MF, et al.: Radiotherapy in the SIOP (International Society of Pediatric Oncology) nephroblastoma studies: a review. Medical and Pediatric Oncology 22(4): 221-227, 1994.

3.D'Angio GJ, Evans AE, Breslow N, et al.: The treatment of Wilms' tumor: results of the National Wilms' Tumor Study. Cancer 38(2): 633-646, 1976.

4.D'Angio GJ, Evans A, Breslow N, et al.: The treatment of Wilms' tumor: results of the Second National Wilms' Tumor Study. Cancer 47(9): 2302-2311, 1981.

5.Thomas PR, Tefft M, Compaan PJ, et al.: Results of two radiation therapy randomizations in the Third National Wilms' Tumor Study. Cancer 68(8): 1703-1707, 1991.

6.Burger D, Moorman-Voestermans CG, Mildenberger H, et al.: The advantages of preoperative therapy in Wilms' tumor: a summarised report on clinical trials conducted by the International Society of Paediatric Oncology (SIOP). Zeitschrift Fur Kinderchirurgie 40(3): 170-175, 1985.

7.Tournade MF, Com-Nougue C, Voute PA, et al.: Results of the Sixth International Society of Pediatric Oncology Wilms' Tumor Trial and Study: a risk-adapted therapeutic approach in Wilms' tumor. Journal of Clinical Oncology 11(6): 1014-1023, 1993.

8.Oberholzer HF, Falkson G, De Jager LC: Successful management of inferior vena cava and right atrial nephroblastoma tumor thrombus with preoperative chemotherapy. Medical and Pediatric Oncology 20(1): 61-63, 1992.

9.Saarinen UM, Wikstrom S, Koskimies O, et al.: Percutaneous needle biopsy preceding preoperative chemotherapy in the management of massive renal tumors in children. Journal of Clinical Oncology 9(3): 406-415, 1991.

10.Dykes EH, Marwaha RK, Dicks-Mireaux C, et al.: Risks and benefits of percutaneous biopsy and primary chemotherapy in advanced Wilms' tumour. Journal of Pediatric Surgery 26(5): 610-612, 1991.

11.Thompson WR, Newman K, Seibel N, et al.: A strategy for resection of Wilms' tumor with vena cava or atrial extension. Journal of Pediatric Surgery 27(7): 912-915, 1992.

12.Zuppan CW, Beckwith JB, Weeks DA, et al.: The effect of preoperative therapy on the histologic features of Wilms' tumor: an analysis of cases from the Third National Wilms' Tumor Study. Cancer 68(2): 385-394, 1991.

13.Ritchey ML, Pringle KC, Breslow NE, et al.: Management and outcome of inoperable Wilms tumor: a report of National Wilms Tumor Study-3. Annals of Surgery 220(5): 683-690, 1994.

14.Green DM, Breslow NE, Evans I, et al.: The effect of chemotherapy dose intensity on the hematological toxicity of the treatment for Wilms' tumor: a report from the National Wilms' Tumor Study. American Journal of Pediatric Hematology/Oncology 16(3): 207-212, 1994.

15.Morgan E, Baum E, Breslow N, et al.: Chemotherapy-related toxicity in infants treated according to the Second National Wilms' Tumor Study. Journal of Clinical Oncology 6(1): 51-55, 1988.

16.Corn BW, Goldwein JW, Evans I, et al.: Outcomes in low-risk babies treated with half-dose chemotherapy according to the Third National Wilms' Tumor Study. Journal of Clinical Oncology 10(8): 1305-1309, 1992.

17.Green DM, Norkool P, Breslow NE, et al.: Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: a report from the National Wilms' Tumor Study. Journal of Clinical Oncology 8(9): 1525-1530, 1990.

18.Raine J, Bowman A, Wallendszusk K, et al.: Hepatopathy-thrombocytopenia syndrome - a complication of dactinomycin therapy for Wilms' tumor: a report from the United Kingdom Childrens Cancer Study Group. Journal of Clinical Oncology 9(2): 268-273, 1991.

19.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. Journal of Clinical Oncology 13(8): 1851-1859, 1995.

20.Ritchey ML, Haase GM, Shochat S: Current management of Wilms' tumor. Seminars in Surgical Oncology 9(6): 502-509, 1993.

21.Breslow NE, Palmer NF, Hill LR, et al.: Wilms' tumor: prognostic factors for patients without metastases at diagnosis: results of the National Wilms' Tumor Study. Cancer 41(4): 1577-1589, 1978.

22.Green DM, Beckwith JB, Breslow NE, et al.: Treatment of children with stages II to IV anaplastic Wilms' Tumor: a report from the National Wilms' Tumor Study Group. Journal of Clinical Oncology 12(10): 2126-2131, 1994.

23.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. Journal of Clinical Oncology 12(10): 2132-2137, 1994.

24.Green DM, Finklestein JZ, Norkool P, et al.: Severe hepatic toxicity after treatment with single-dose dactinomycin and vincristine: a report of the National Wilms' Tumor Study. Cancer 62(2): 270-273, 1988.

STAGE I WILMS' TUMOR
A major focus of the National Wilms' Tumor Study 5 is the acquisition of biologic prognostic factors that may identify those groups of patients who are more likely to suffer recurrent disease and therefore benefit from more intensive therapy. Therefore, every attempt should be made to obtain the necessary tissue samples for submission, including tumor, normal kidney, and blood. The following are the treatment arms of this study.[1]

Favorable histology tumors:
Patient age younger than 24 months and tumor weight less than 550 grams:
nephrectomy only, with close follow-up, chest radiograph, and abdominal ultrasound every 3 months during the first 2 years after diagnosis.

Patient age older than 24 months or tumor weight greater than 550 grams:
nephrectomy and 18 weeks of chemotherapy with vincristine and pulse-intensive dactinomycin.

Focal or diffuse anaplasia:
Nephrectomy and 18 weeks of chemotherapy with vincristine and pulse-intensive dactinomycin.

Clear cell sarcoma of the kidney:
Nephrectomy, abdominal irradiation, and 24 weeks of chemotherapy with vincristine, doxorubicin, etoposide, cyclophosphamide, and mesna.

Rhabdoid tumor of the kidney:
Nephrectomy, radiation therapy, and 24 weeks of chemotherapy with cyclophosphamide, mesna, etoposide, and carboplatin.

References:
1.Green DM, National Wilms' Tumor Study Group: Phase III Multimodality Therapy Based on Histology, Stage, Age, and Tumor Size for Children with Wilms' Tumor, Clear Cell Sarcoma of the Kidney, and Rhabdoid Tumors of the Kidney (Summary Last Modified 01/98), NWTS-Q9401, clinical trial, active, 07/05/95.

STAGE II WILMS' TUMOR

A major focus of the National Wilms' Tumor Study 5 is the acquisition of biologic prognostic factors that may identify those groups of patients who are more likely to suffer recurrent disease and therefore benefit from more intensive therapy. Therefore, every attempt should be made to obtain the necessary tissue samples for submission, including tumor, normal kidney, and blood. The following are the treatment arms of this study.[1]

Favorable histology tumors:
Nephrectomy and 18 weeks of chemotherapy with vincristine and pulse-intensive dactinomycin.

Focal anaplasia:
Nephrectomy, abdominal irradiation, and 24 weeks of chemotherapy with vincristine, doxorubicin, and pulse-intensive dactinomycin.

Diffuse anaplasia:
Nephrectomy, abdominal irradiation, and 24 weeks of chemotherapy with vincristine, doxorubicin, etoposide, cyclophosphamide, and mesna.

Clear cell sarcoma of the kidney:
Nephrectomy, abdominal irradiation, and 24 weeks of chemotherapy with vincristine, doxorubicin, etoposide, cyclophosphamide, and mesna.

Rhabdoid tumor of the kidney:
Nephrectomy, radiation therapy, and 24 weeks of chemotherapy with cyclophosphamide, mesna, etoposide, and carboplatin.

STAGE III WILMS' TUMOR
A major focus of the National Wilms' Tumor Study 5 is the acquisition of biologic prognostic factors that may identify those groups of patients who are more likely to suffer recurrent disease and therefore benefit from more intensive therapy. Therefore, every attempt should be made to obtain the necessary tissue samples for submission, including tumor, normal kidney and blood. The following is the treatment arm of this study.[1]

Favorable histology tumors:
Nephrectomy, abdominal irradiation, and 24 weeks of chemotherapy with vincristine, doxorubicin, and pulse-intensive dactinomycin.

Focal anaplasia:
Nephrectomy, abdominal irradiation, and 24 weeks of chemotherapy with vincristine, doxorubicin, and pulse-intensive dactinomycin.

Diffuse anaplasia:
Nephrectomy, abdominal irradiation, and 24 weeks of chemotherapy with vincristine, doxorubicin, etoposide, cyclophosphamide, and mesna.

Clear cell sarcoma of the kidney:
Nephrectomy, abdominal irradiation, and 24 weeks of chemotherapy with vincristine, doxorubicin, etoposide, cyclophosphamide, and mesna.

Rhabdoid tumor of the kidney:
Nephrectomy, radiation therapy, and 24 weeks of chemotherapy with cyclophosphamide, mesna, etoposide, and carboplatin.

Treatment options for patients with massive tumors judged too risky for initial surgical removal:

Occasional patients have tumors with such significant caval/atrial extension or that are so massive that their surgeons consider the risk of initial surgical removal too great.[2] If surgery is performed in a patient with caval or atrial extension, care should be taken to ensure that appropriate resources are available for pediatric cardiopulmonary bypass.[3,4] On the NWTS-4, these patients are treated after biopsy by initial chemotherapy with vincristine and dactinomycin, followed by radiotherapy if no reduction in tumor size has occurred within 2 weeks.[5] Surgery is performed as soon as sufficient tumor shrinkage has occurred, generally within 6 weeks of diagnosis. Patients are subsequently treated as for stage III tumors, which includes postoperative radiotherapy. Because of the 5%-10% error rate in preoperative diagnosis of renal masses after roentgenographic assessment, confirmation of the diagnosis by biopsy (which may be performed percutaneously) should be obtained prior to chemotherapy. In Europe, however, preoperative chemotherapy has been more widely used.[6]

References:
1.Green DM, National Wilms' Tumor Study Group: Phase III Randomized Comparison of Short- vs Long-Term Maintenance Chemotherapy in Children with Stages III-IV Favorable Histology Wilms' Tumor and Clear Cell Sarcoma and Comparison of DACT/VCR/DOX vs DACT/VCR/DOX/CTX in Patients with Stages II-IV Anaplastic Wilms' Tumor (Summary Last Modified 11/94), NWTS-4, clinical trial, closed, 09/01/94.

2.Oberholzer HF, Falkson G, De Jager LC: Successful management of inferior vena cava and right atrial nephroblastoma tumor thrombus with preoperative chemotherapy. Medical and Pediatric Oncology 20(1): 61-63, 1992.

3.Thompson WR, Newman K, Seibel N, et al.: A strategy for resection of Wilms' tumor with vena cava or atrial extension. Journal of Pediatric Surgery 27(7): 912-915, 1992.

4.Ritchey ML, Kelalis PP, Haase GM, et al.: Preoperative therapy for intracaval and atrial extension of Wilms tumor. Cancer 71(12): 4104-4110, 1993.

5.Green DM, Breslow NE, Evans I, et al.: The effect of chemotherapy dose intensity on the hematological toxicity of the treatment for Wilms' tumor: a report from the National Wilms' Tumor Study. American Journal of Pediatric Hematology/Oncology 16(3): 207-212, 1994.

6.Tournade MF, Com-Nougue C, Voute PA, et al.: Results of the Sixth International Society of Pediatric Oncology Wilms' Tumor Trial and Study: a risk-adapted therapeutic approach in Wilms' tumor. Journal of Clinical Oncology 11(6): 1014-1023, 1993.

STAGE IV WILMS' TUMOR

Favorable histology tumors:
Nephrectomy, abdominal irradiation according to local stage of renal tumor, bilateral pulmonary irradiation for patients with chest x-ray evidence of pulmonary metastases, and 24 weeks of chemotherapy with vincristine, doxorubicin, and pulse-intensive dactinomycin.

Focal anaplasia:
Nephrectomy, abdominal irradiation according to local stage of renal tumor, bilateral pulmonary irradiation for patients with chest x-ray evidence of pulmonary metastases, and 24 weeks of chemotherapy with vincristine, doxorubicin, and pulse-intensive dactinomycin.

Diffuse anaplasia:
Nephrectomy, abdominal irradiation, whole-lung irradiation for patients with chest x-ray evidence of pulmonary metastases, and 24 weeks of chemotherapy with vincristine, doxorubicin, etoposide, cyclophosphamide, and mesna.

Clear cell sarcoma of the kidney:
Nephrectomy, abdominal irradiation, whole-lung irradiation for patients with chest x-ray evidence of pulmonary metastases, 24 weeks of chemotherapy with vincristine, doxorubicin, etoposide, cyclophosphamide, and mesna.

Rhabdoid tumor of the kidney:
Nephrectomy, radiation therapy, and 24 weeks of chemotherapy with cyclophosphamide, mesna, etoposide, and carboplatin.

References:
1.Green DM, Breslow NE, Evans I, et al.: Treatment of children with stage IV favorable histology Wilms tumor: a report from the National Wilms Tumor Study Group. Medical and Pediatric Oncology 26(3): 147-152, 1996.

STAGE V WILMS' TUMOR
Previously, the surgical approach to bilateral Wilms' tumor was nephrectomy of the side with the larger lesion. However, initial unilateral nephrectomy may predispose patients with bilateral disease to late renal failure.[1] Furthermore, studies demonstrate no difference in survival for children who undergo initial bilateral biopsy followed by chemotherapy and then surgical resection compared with patients who have initial resection followed by chemotherapy. Current surgical strategy therefore attempts to preserve renal mass to minimize the risk of late renal failure. Toward this end, the initial procedure is usually bilateral biopsy with lymph node sampling. Following chemotherapy with vincristine, dactinomycin, and doxorubicin, a second-look operation may allow complete resection of all tumor with maximal preservation of renal mass.[2] Chemotherapy and/or radiotherapy following the second-look operation is dependent on the response to initial therapy, with more aggressive therapy required for patients with inadequate response to initial therapy observed at the second procedure.[3-7]

Approximately 10% of patients with bilateral tumors have unfavorable (anaplastic) histology and may benefit from more aggressive chemotherapy and radiotherapy and an aggressive surgical approach at the second-look operation.[3]

References:
1.Ritchey ML, Green DM, Thomas PR, et al.: Renal failure in Wilms' tumor patients: a report from the National Wilms' Tumor Study Group. Medical and Pediatric Oncology 26(2): 75-80, 1996.

2.Horwitz JR, Ritchey ML, Moksness J, et al.: Renal salvage procedures in patients with synchronous bilateral Wilms' tumors: a report from the National Wilms' Tumor Study Group. Journal of Pediatric Surgery 31(8): 1020-1025, 1996.

3.National Wilms' Tumor Study Committee: Wilms' tumor: status report, 1990. Journal of Clinical Oncology 9(5): 877-887, 1991.

4.D'Angio GJ, Breslow N, Beckwith JB, et al.: Treatment of Wilms' tumor: results of the third National Wilms' Tumor Study. Cancer 64(2): 349-360, 1989.

5.Montgomery BT, Kelalis PP, Blute ML, et al.: Extended followup of bilateral Wilms tumor: results of the National Wilms Tumor Study. Journal of Urology 146(2): 514-518, 1991.

6.Shaul DB, Srikanth MM, Ortega JA, et al.: Treatment of bilateral Wilms' tumor: comparison of initial biopsy and chemotherapy to initial surgical resection in the preservation of renal mass and function. Journal of Pediatric Surgery 27(8): 1009-1015, 1992.

7.Shearer P, Parham DM, Fontanesi J, et al.: Bilateral Wilms tumor: review of outcome, associated abnormalities, and late effects in 36 pediatric patients treated at a single institution. Cancer 72(4): 1422-1426, 1993.

RECURRENT WILMS' TUMOR

The prognosis and selection of further treatment for patients with recurrent Wilms' tumor depend on many factors, including the site of recurrence, histology, length of time from nephrectomy to recurrence, and initial chemotherapy regimen (two versus three drugs).[1]

A subgroup of patients with recurrent disease may benefit from aggressive use of conventional agents (including doxorubicin) and surgical excision and radiotherapy.[1,2] This group includes patients who after two-drug therapy have disease recurrence only in the lungs, in the abdomen (not previously irradiated), or more than 12 months after diagnosis.

Another group of patients has a poor prognosis after salvage attempts with conventional therapy.[1] This group includes patients with unfavorable histology tumors, tumor recurrence in the abdomen after treatment with radiotherapy, recurrence within 6 months of nephrectomy, or recurrence after initial three-drug therapy. An immediate trial of new agents may be justified for this group of patients. Single-agent activity has been demonstrated for ifosfamide,[3] etoposide,[4] carboplatin,[5] and cisplatin; the combinations of ifosfamide, mesna, and etoposide [6,7] and of cisplatin and etoposide [8] are being evaluated. The combination of etoposide and carboplatin has demonstrated activity in this group of patients, but significant hematologic toxicity has been observed.[9] Very high-dose chemotherapy

followed by infusion of autologous bone marrow has been used to treat a limited number of patients with recurrent Wilms' tumor; some long-term survivors have been reported.[10-12] Patients in whom such salvage attempts fail should be offered treatment on available phase I or phase II studies.

References:
1.Grundy P, Breslow N, Green DM, et al.: Prognostic factors for children with recurrent Wilms' tumor: results from the second and third National Wilms' Tumor Study. Journal of Clinical Oncology 7(5): 638-647, 1989.

2.National Wilms' Tumor Study Committee: Wilms' tumor: status report, 1990. Journal of Clinical Oncology 9(5): 877-887, 1991.

3.Tournade MF, Lemerle J, Brunat-Mentigny M, et al.: Ifosfamide is an active drug in Wilms' tumor: a phase II study conducted by the French Society of Pediatric Oncology. Journal of Clinical Oncology 6(5): 793-796, 1988.

4.Pein F, Pinkerton R, Tournade MF, et al.: Etoposide in relapsed or refractory Wilms' tumor: a phase II study by the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group. Journal of Clinical Oncology 11(8): 1478-1481, 1993.

5.de Camargo B, Melaragno R, Saba e Silva N, et al.: Phase II study of carboplatin as a single drug for relapsed Wilms' tumor: experience of the Brazilian Wilms' Tumor Study Group. Medical and Pediatric Oncology 22(4): 258-260, 1994.

6.Kung FH, Pratt CB, Vega RA, et al.: Ifosfamide/etoposide combination in the treatment of recurrent malignant solid tumors of childhood: a Pediatric Oncology Group phase II study. Cancer 71(5): 1898-1903, 1993.

7.Miser J, Krailo M, Hammond GD, et al.: The combination of ifosfamide (IFOS), etoposide (VP16), and mesna (M): a very active regimen in the treatment of recurrent Wilms' tumor (WT). Proceedings of the American Society of Clinical Oncology 12: A-1432, 417, 1993.

8.Loh W, Ortega JA, Wolff J, et al.: Cis-platinum/VP 16 for the retrieval of Wilms' tumor relapsing on chemotherapy. Proceedings of the American Society of Clinical Oncology 6: A-876, 222, 1987.

9.Pein F, Tournade MF, Zucker JM, et al.: Etoposide and carboplatin: a highly effective combination in relapsed or refractory Wilms' tumor - a phase II study by the French Society of Pediatric Oncology. Journal of Clinical Oncology 12(5): 931-936, 1994.

10.Seeger RC, Reynolds CP: Treatment of high-risk solid tumors of childhood with intensive therapy and autologous bone marrow transplantation. Pediatric Clinics of North America 38(2): 393-424, 1991.

11.Garaventa A, Hartmann O, Bernard JL, et al.: Autologous bone marrow transplantation for pediatric Wilms' tumor: the experience of the European Bone Marrow Transplantation Solid Tumor Registry. Medical and Pediatric Oncology 22(1): 11-14, 1994.

12.Pinkerton R, Philip T, Bouffet E, et al.: Autologous bone marrow transplantation in paediatric solid tumours. Clinics in Haematology 15(1): 187-203, 1986.

Date Last Modified: 01/98