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SIOP trials
In SIOP-93-01, postoperative therapy was based on stage and pathological response to chemotherapy. From postoperative histology, tumours were classified as low, intermediate, or high risk according to the Stockholm working classification of renal tumours. It could be shown by a prospective randomized question that postoperative treatment for patients with stage I intermediate risk or anaplasia can be reduced to 4 weeks from the standard 18 weeks, while maintaining equivalent event-free survival. Because about 60 % of patients will have stage I disease after receiving preoperative chemotherapy, most of the patients with unilateral disease can be cured after only 4 weeks of preoperative chemotherapy, tumor nephrectomy and 4 weeks of postoperative chemotherapy with only 2 drugs (vincristine and dactinomycin). This approach is cost-effective by also not causing severe acute or late toxicity.
The paradigm of maximizing cure while minimizing toxicity is being further evaluated in the ongoing SIOP-2001 protocol, in which postoperative chemotherapy is tailored according to histologic features, as defined by the SIOP classification system. Another aim of the study is to decrease late cardiac toxicity in patients with stage II or III and histologically intermediate-risk disease. These patients are randomly assigned to receive a treatment with or without doxorubicin, which is known to cause late cardiac toxicity.
NWTSG and upcoming COG trials
The fourth NWTSG study investigated the efficacy, toxicity, and cost of different schedules of dactinomycin and doxorubicin administration, finding that dactinomycin could be given safely in 1 day rather than over 5 days and doxorubicin in 1 day rather than over 3 days. These so-called pulse-intensive regimens were as effective as the standard courses but were accompanied by less severe haematological toxicity and fewer health-care encounters. As a consequence pulse-intensive therapy has become the standard of care for treatment of Wilms? tumour in North America.
Having almost reached cure for most patients and knowing that better stratification parameters for treatment are only possible by finding prognostic molecular markers, the major aim of the closed non-randomised NWTS-5 trial therefore was to assess the prognostic value of loss of heterozygosity at chromosomes 1p and 16q and DNA ploidy. The results of NWTS-5 provide the framework for future Children?s Oncology Group studies of Wilms? tumor. It could be shown that LOH at 1p and 16 q is an adverse prognostic indicator. For the first time molecular markers are now used as stratification parameters in the upcoming COG trials for nephroblastoma. On the basis of the lower than expected survival rate for patients with stage I anaplasia, the upcoming study will also augment therapy for this group of patients.
Stage IV disease
About 10 % of patients are diagnosed with metastatic disease. The most common sites of metastases of Wilms' tumor are the lungs, the regional nodes, and the liver. Of patients presenting with hematogenous metastases at diagnosis (stage IV), the lungs were the only site in approximately 80% of cases. The liver, with or without lungs, was involved in 15%. Bone and brain metastases are rare in Wilms tumor. Patients with stage IV disease are particularly challenging to treat. In children with lung metastases detected on chest radiograph, whole lung irradiation continues to be administered in North America, whereas in Europe response to preoperative chemotherapy is used for stratification of lung irradiation. In NWTS-3, the 4-year relapse-free survival was 71.9%, and the 4-year survival was 78.4% in children with favourable histology Wilms? tumour and lung metastases. SIOP investigators continue to avoid radiotherapy for patients with intermediate risk histology whose lung metastases disappear completely after 6 weeks of prenephrectomy chemotherapy with vincristine, dactinomycin, and doxorubicin. Their outcome is not different to the NWTSG series with a 4 year relapse free survival of 83 % in patients achieving a complete remission after preoperative chemotherapy compared to 65 % without a CR. The corresponding overall survival is 95 % versus 75 %. Children with metastatic disease to lungs do better than those with other metastatic sides. Up to now, there is no clear statement, what is the best treatment for patients with CT-only metastasis to the lung. High malignancy and local stage III are bad prognostic features in stage IV patients (Graf N, unpublished data of SIOP 93-01/GPOH). Although there are genuine concerns about radiation toxicity, the poor outcome in children who relapse after initial treatment necessitates a critical assessment of the role of pulmonary irradiation in these patients.
Bilateral disease
Various reports record the incidence of synchronous bilateral Wilms' tumor as ranging from 4.4% to 7.0% and that of metachronous bilateral Wilms' tumor from 1.0% to 1.9% of Wilms' tumor patients. The existence of precursor lesions to Wilms' tumor has been recognized for many years. These nephrogenic rests are found in almost 1% of unselected pediatric autopsies, in 35% of kidneys with unilateral Wilms' tumor, and in nearly 100% of kidneys with bilateral Wilms' tumor. They are composed of abnormally persistent embryonal nephroblastic tissue with small clusters of blastemal cells, tubules, or stromal cells. Nephrogenic rests are classified by their position within the kidney. Intralobar nephrogenic rests (ILNR) are randomly distributed, but tend to be situated deep within the renal lobe. These lesions are commonly stroma-rich and intermingle with the adjacent renal parenchyma. Perilobar nephrogenic rests (PLNR) are located at the periphery, and are usually subcortical, sharply demarcated, and contain predominantly blastema and tubules. These presumably reflect later developmental disturbances in nephrogenesis. The term nephroblastomatosis is used to refer to the presence of multiple nephrogenic rests. Only a small number develop a clonal transformation into Wilms' tumor. When this happens, the Wilms' tumor is typically spherical and develops a pseudocapsule separating it from the nephrogenic rest.
About 6% of all children with Wilms? tumour present with simultaneous bilateral tumours (stage V) at the time of diagnosis. Although more than 70% survive, these children are at high risk of renal failure. This risk has led to the recommendation that such patients undergo preoperative chemotherapy to shrink the tumour and facilitate renal-sparing procedures. Primary excision of the tumour masses is not recommended. After 6?8-12 weeks of chemotherapy, the patient is reassessed and the feasibility of resection assessed. If there is no response to preoperative chemotherapy, further intensifying of treatment is seldom successful, most often caused by stromal predominant histology. In this situation surgical excision of the tumor should be performed. In general, definitive surgery should be done within 12?16 weeks of diagnosis to limit the risk of chemoresistant clonal expansion. Postoperative treatment is done according to the criteria for unilateral disease, always using the highest stage and worst histology of one side into consideration. The treatment for nephroblastomatosis has to be prolonged with vincristin and dactinomycin. Late occruing Wilms tumors can develop in patients with nephroblastomatosis. In such cases histology is necessary to rule out anaplasia, which is of poor prognosis. In the long follow-up much attention has to be given to the renal function. An NWTSG review found that 9.1% of patients with synchronous bilateral Wilms' tumors and 18.8% of those with metachronous bilateral tumors have developed renal failure. The most common etiology for renal failure was the need for bilateral nephrectomy for persistent or recurrent tumor in the remaining kidney after initial nephrectomy. Treatment-related injury (radiation-induced damage, surgical complications) to the remaining kidney was the second leading cause for renal insufficiency. Renal insufficiency secondary to hyperfiltration-induced injury (focal glomerulosclerosis) was rare. Kidney transplantation has to be considered in these situations.