Dr. Paulino has written an excellent review of our present knowledge of Wilms' tumor. Not everyone would agree, however, that ultrasound has replaced the intravenous pyelogram (IVP). The National Wilms' Tumor Study Group (NWTSG) recommends IVP together with real-time ultrasonography as the preoperative imaging studies for the abdomen. The former is used to establish the presence of a functioning opposite kidney and of any congenital abnormality. The latter identifies the presence and status of inferior vena cava thrombi.
As neither CT nor MRI can determine, with certainty, the status of the opposite kidney, the NWTSG still calls for its mobilization at laparotomy, as Dr. Paulino notes. He appropriately points out that those who advocate eliminating exploration of the opposite kidney[2,3] base their recommendation on data from a very small numbers of patients, compared with the NWTSG data. The NWTSG, therefore, continues to recommend mobilization of the opposite kidney based on the accuracy and lack of morbidity of this procedure.
National Wilms' Tumor Study 4
As the results of the third National Wilms' Tumor Study (NWTS 3) were very good (see the author's Table 2), NWTS 4 (1985 to 1994) was designed to attempt to simplify and shorten treatment for those considered at low risk, while intensifying treatment for those at high risk. Although, in NWTS 3, the addition of cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) to vincristine, dactinomycin(Drug information on dactinomycin) (actinomycin D [Cosmegan]), and doxorubicin(Drug information on doxorubicin) achieved better results in patients with stages I to IV anaplastic Wilms' tumor, the numbers were uneven due to weighing of the randomization (21 patients receiving three drugs and 12 patients receiving four drugs), and it was felt appropriate to continue the randomization into NWTS 4.
For the remainder of the patients (excluding those with rhabdoid tumor of the kidney, who are not included in NWTS 4), the trial aimed to answer two questions: (1) Is pulse-intensive therapy (ie, a single dose of dactinomycin and doxorubicin for patients with stage III or IV, favorable histology and clear cell sarcoma) more effective than standard therapy (5 days of dactinomycin and 3 days of doxorubicin)? (2) What is the optimal duration of therapy (6 vs 15 months)? This issue of therapy duration was tested in all patients except those with stage I, favorable histology and anaplastic tumors.
A simplified version of the schema of NWTS 4 is shown in Figure 1. The results, which have been partly published in abstract form, suggest that 2-year survival rates are equivalent with the pulse-intensive and standard regimens, and that toxicity (particularly hematologic) is less severe for most patients on the pulse-intensive arm.
A recent analysis of NWTS 4 has also shown no demonstrable differences between the 6- and 15-month courses of therapy.[unpublished data, NWTS 4]
Patients with anaplastic tumors (stages II-IV) derived a benefit from the addition of cyclophosphamide to dactinomycin, vincristine, and doxorubicin if the tumor histology showed a diffuse pattern. No benefit could be discerned for focal anaplasia, however.
National Wilms' Tumor Study 5
In NWTS 5, which began enrollment in 1995, there are no randomizations. The outline is shown in Table 1, and the radiotherapy regimens are detailed in Table 2. A major objective of the protocol is to determine the prognostic significance of the loss of heterozygosity of chromosomes 16q and 1p. This stems from an analysis of 232 patients from NWTS 3 and 4 showing that overall and relapse-free survival at 2 years was significantly worse for those with the 16q abnormality and was marginally so for those with the 1p abnormality.
Also, as Dr. Paulino discusses, there is evidence that stage I patients under 2 years of age with tumors weighing less than 550 g may not need further therapy. In NWTS 1, 2, and 3, there were no differences in disease-free or overall survival in these patients regardless of the therapy employed. In NWTS 5, therefore, these patients will be treated by nephrectomy only.