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Treatment of Wilms Tumor: An International Perspective

For the Wilms Tumor Study Committee, International Society of Pediatric Oncology, Amsterdam, the Netherlands

To the Editor:

The Wilms Tumor Study Committee of the International Society of Pediatric Oncology (SIOP) wishes to add to the commentary by Daniel Green¹ on "The Treatment of Stage I-IV Favorable Histology Wilms Tumor," which drew mainly from valuable data from the National Wilms Tumor Study Group (NWTSG). While this commentary includes unique, long-term outcome data on children treated for Wilms tumor since 1969 under the auspices of the NWTSG, it reports incompletely on the equally pioneering SIOP studies and those of other national groups such as the United Kingdom Children's Cancer Study Group (UKCCSG). Therefore, we would like to expand on reports of our groups’ studies and add our own perspective on this important issue for children with renal tumors worldwide.

Perhaps the most fundamental question in the management of a suspected malignant renal tumor in a child is the timing of surgery. NWTSG has always recommended immediate nephrectomy to define the uncorrupted stage and histology, on which further treatment stratification is decided. By contrast, the SIOP investigators pioneered the concept of pretreatment of renal tumors before nephrectomy and showed that pretreatment made surgery safer, reduced tumor rupture rates, and increased the proportion of children with a lower tumor stage requiring less overall treatment.² The UKCCSG recently completed a randomized comparison of these two approaches in its UKW3 trial,³ which showed a more favorable tumor stage distribution and significant reduction in the overall burden of therapy together with reduced surgical complications after elective use of prenephrectomy chemotherapy. For these reasons, the UKCCSG has now joined the current SIOP Wilms tumor 2001 clinical trial and study.⁴

The reasons given by Green to recommend immediate nephrectomy cite "several risks" of preoperative chemotherapy without further discussion. In fact, the risk of administering chemotherapy to a patient ultimately found not to have cancer was low, affecting only 1.5% and 1.6% of the referred patients in the SIOP-6 and SIOP-9 trials, respectively.^5,6 The adoption of the UKCCSG approach of initial biopsy even in children with typical clinical and imaging features of Wilms tumor reduces this to virtually zero and does not appear to be associated with an increased risk of local recurrence or upstaging.^3,7 A further small percentage of children with a possible different histologic type of malignancy may receive chemotherapy different from that currently recommended for their tumor type until histology is confirmed at nephrectomy. However, there is no evidence that this affects their outcome.

The two remaining reasons cited by Green against preoperative chemotherapy, we see as positive advantages. First, modification of tumor histology allows individualized assessment of tumor response to chemotherapy and allows definition of new risk groups for treatment stratification.^4,8 Second, so-called "loss of staging information" actually means that overall burden of treatment, particularly the use of radiotherapy and anthracyclines, can be restricted to children whose tumors do not respond adequately to relatively simple first-line chemotherapy.

The long-term survival data reported by Green question the value of doxorubicin and higher-dose radiotherapy in the treatment of Wilms tumor patients.¹ Use of both of these agents was the subject of randomized comparisons in the SIOP-6 and NWTSG-3 trials for children with stage II and III tumors, whether staged after immediate or delayed nephrectomy. While early evaluation of these trials suggested that both agents were of benefit for relapse-free survival (RFS), there was no long-term benefit, particularly for overall survival (OS), even though the trend was always in the direction of superior RFS and OS for the doxorubicin arm. Interpretation of these studies is also complicated by the fact that the intensity of administration of vincristine and dactinomycin in the two-drug arm differed from that given alongside doxorubicin in the three-drug arm in the SIOP-6 study. This surely points to the need to better define risk groups early during therapy so that doxorubicin and radiotherapy can be reserved for those children with higher-stage tumors who truly need it to ensure RFS the first time around. These considerations apply equally to children with metastatic disease (stage IV) at diagnosis. The NWTSG approach recommends pulmonary irradiation for all cases with lung metastases, regardless of speed of response. In SIOP studies, only the small minority (approximately 15%) of patients whose metastases do not resolve on chest x-ray after appropriate chemotherapy are irradiated. Both groups achieve similar disease-free survival rates of approximately 70%.

How can improved risk stratification be achieved? The NWTSG-5 study chose to exploit molecular markers measured at initial diagnosis to predict outcome. While the presence of allele loss at specified loci did indeed identify a higher risk group, the test was incompletely sensitive and specific so that the majority of relapsing patients still came from the so-called "favorable histology" group with no evidence of allele loss (P. Grundy, personal communication, June 2004). The SIOP approach of prenephrectomy chemotherapy provides the opportunity to take clinical and histologic response to chemotherapy into account. It will also allow, through its parallel laboratory studies, the correlation of molecular markers with the more easily and cheaply defined histologic risk groups.⁵ These questions are being addressed in the current SIOP WT 2001 study, including a new evaluation of the role of doxorubicin in stage II/III tumors after preoperative chemotherapy, providing the tumor histology does not fall into the newly defined high-risk category.⁴ Ultimately, both the NWTSG and SIOP studies should add to the increasing knowledge of Wims tumor biology and allow better definition of the relatively small subset of children with high risk disease.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Green D: The treatment of stage I-IV favorable histology Wilms Tumor. J Clin Oncol 22:1366-1372, 2004[Free Full Text]

2. De Kraker J: Commentary on Wilms' Tumour. Eur J Cancer 33:419-420, 1997

3. Mitchell C, Shannon R, Vujanic GM, et al: The Treatment of Wilms' Tumour: Results of the United Kingdom Children's Cancer Study Group Third Wilms' Tumour Study. Med Pediatr Oncol 41:287, 2003 (abstr O119)

4. Bergeron C, Graf N, van Tinteren H, et al: From results of SIOP-Nephroblastoma-93-01 Study to SIOP Nephroblastoma 2001 Study. Med Pediatr Oncol 41:289, 2003 (abstr O131)

5. Tournade F, Com-Nougé C, Voûte P, et al: Results of the Sixth International Society of Pediatric Oncology Wilms' Tumor Trial and Study: A Risk-adapted Therapeutic Approach in Wilms' Tumor. J Clin Oncol 11:1014-1023, 1993[Abstract/Free Full Text]

6. Tournade F, Com-Nougé C, de Kraker J, et al: Optimal duration of Preoperative Therapy in Unilateral and Non-metastatic Wilms' Tumor in children Older Than 6 Months: Results of the Ninth International Society of Pediatric Oncology Wilms' Tumor Trial and study. J Clin Oncol 19:488-500, 2001[Abstract/Free Full Text]

7. Vujanic GM, Kelsey A, Mitchell C, et al: The role of biopsy in the diagnosis of renal tumors of childhood: Results of the UKCCSG Wilms tumor study 3. Med Pediatr Oncol 40:18-22, 2003[CrossRef][Medline]

8. Vujanic GM, Sandstedt B, Harms D, et al: Revised International Society of Paediatric Oncology (SIOP) Working Classification of Renal Tumors of Childhood. Med Pediatr Oncol 38:79-82, 2002[CrossRef][Medline]

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