Pre- or Postoperative Therapy for Wilms’ Tumor?

The Wilms’ tumor debate discussed in this journal 25 years ago continues. There are those, mostly in North America and participants in the National Wilms Tumor Study (NWTS) and its successor group, who have advocated early surgery for children with suspected Wilms’ tumor. They maintain that the most accurate information needed for truly individualized therapy is obtained by operating first. There are others, following the lead of the International Society of Pediatric Oncology (SIOP), who believe that preoperative treatment is better because it makes surgery easier and is more widely applicable. However, the debate has become more muted. Some of the objections to preoperative therapy have been mitigated in the intervening two and a half decades. Major advances in imaging techniques have lessened the error frequency in preoperative diagnosis. The diagnostic error rate in the ninth SIOP study was approximately 5% (28 of 511 patients). Only eight of the 28 patients who were misdiagnosed had a benign lesion; the other 20 patients had malignant renal neoplasms of other types. The United Kingdom Children’s Cancer Study Group has adopted the preoperative strategy and is attempting to improve the diagnostic accuracy through the use of percutaneous needle biopsies before therapy starts. Vujanic et al have reported encouraging results. Diagnostic material was obtained in 232 of 241 patients; Wilms’ tumor was confirmed in 204 patients, and 28 patients had renal tumors of other types. Only in nine patients was the biopsy specimen inadequate for diagnosis. Few complications were reported by the United Kingdom Children’s Cancer Study Group investigators after needle biopsy, but a caution needs to be mentioned. One child required emergency surgery because of a subsequent, massive, postbiopsy hemorrhage. A touted advantage of the preoperative approach is a reduction in the frequency of intraoperative tumor rupture and spillage of malignant cells into the abdominal cavity. The rupture frequency in SIOP-5 was 6% among SIOP stage II and III patients (ie, patients with some degree of local extension, with residual disease or lymph node involvement but free of distant metastases). This compares favorably with a rate of approximately 20% in comparable stage patients in the fourth NWTS study (NWTS-4). However, the survival rate for patients suffering tumor spillage has not been statistically significantly worse than the rate of nonspill patients. This has held true since the early days of both trials, albeit the relapse rate is higher. Clearly, it is better to avoid the attendant medical and psychological difficulties that occur after recurrence. Another advantage claimed by the proponents of preoperative therapy is the downstaging of patients. There are more stage I patients in the SIOP trials than in the NWTS series. However, the stages are not comparable. The NWTS assesses extent of disease as the child presents; SIOP assesses extent of disease after cytolytic therapy. Preoperative treatment can be so effective as to lead to total necrosis of all the tumor cells in the operative specimen. The histologic diagnosis of Wilms’ tumor can only be surmised, but this result can be turned to clinical advantage. It presages a better prognosis after treatment appropriate for Wilms’ tumor. A less happy consequence in other patients is that the preoperative therapy can mask pre-existing or residual tumor deposits, for example, in lymph nodes. The results reported for SIOP-6 demonstrated that this is a real problem in staging. In SIOP-6, children with SIOP stage II disease who were administered preoperative chemotherapy were randomly assigned to a postoperative noradiation therapy (RT) arm. They suffered more local relapses than their flank-irradiated counterparts. These data demonstrate that preexisting local disease, probably in lymph nodes, was still present but had been reduced to invisibility. This has led SIOP investigators to cover unirradiated SIOP stage II children by adding an anthracycline to the basic two agents, dactinomycin (D) and vincristine (V). This is done even though many of the children are true stage II patients and, therefore, receive the cardiotoxic agent unnecessarily. The SIOP overtreatment of a segment of children with early-stage disease is balanced by a protocol designed by the successor to the NWTS (ie, the Renal Tumor Committee of the Children’s Oncology Group [COG]). The protocol pertains to stage II children who suffer intraoperative tumor spillage (COG Protocol No. AREN0533). In an attempt to improve the relapse-free survival rate, the children with tumor spillage are to receive 10 Gy of flank RT plus doxorubicin (DOX) added to D and V. The implantation rate for spilled cells has been estimated to be less than 20% (J. Kalapurakal, unpublished observations). This means that 40 of 50 such patients will be receiving these potentially toxic therapies in the hope of protecting the remaining 10. This is not the first time a protection approach has been adopted in pediatric oncology. The survival for early-stage Wilms’ tumor patients before the advent of chemotherapy was approximately 50%. Now most, if not all, children with early-stage tumors, half of whom would be cured by surgery alone, are administered chemotherapy to protect the other half. D and V, the two agents used most often, are not associated with any long-term disabilities. It gives one pause when an appreciable portion of the patient population not at risk receives agents such as DOX and RT, which have known late consequences, in the hope that this will cover the other vulnerable patients. It is especially troubling when the survival probability of the latter group is not appreciably worse, if at all worse, than that of their counterparts who are not at risk. Contrary to the impression perhaps left by the previous discussion, a major aim since the inception of both SIOP and NWTS research has been to reduce therapy according to well-studied and JOURNAL OF CLINICAL ONCOLOGY C E L E B R A T I N G 2 5 Y E A R S O F J C O VOLUME 26 NUMBER 25 SEPTEMBER 1 2008