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Pre- or Postoperative Therapy for Wilms’ Tumor?

Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA

The Wilms’ tumor debate discussed in this journal 25 years ago continues.¹ 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).² 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 al³ 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).⁴ This compares favorably with a rate of approximately 20% in comparable stage patients in the fourth NWTS study (NWTS-4).⁵ 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.⁶ 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.⁷ 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.⁸ In SIOP-6, children with SIOP stage II disease who were administered preoperative chemotherapy were randomly assigned to a postoperative no-radiation therapy (RT) arm. They suffered more local relapses than their flank-irradiated counterparts. These data demonstrate that pre-existing 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%.⁹ 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 well-defined risk factors. More recently, the NWTS undertook a no postoperative chemotherapy trial in a group of patients considered to be at low risk. This is because there is some morbidity, inconvenience, and even hazard associated with chemotherapy, and the two drugs, D and V, are not exceptions. Therefore, the NWTS initiated a pilot trial of simple surgery for babies with favorable tumor characteristics.¹⁰ Patients under 24 months of age with stage I neoplasms of favorable histologic (FH) type and specimen weight less than 550 g were allocated to a no postoperative treatment group. The trial was interrupted because the relapse rate exceeded that anticipated in the study plan.¹⁰ Long-term follow-up of these study patients shows that they have all survived after salvage therapies, so the trial has been resumed.

SIOP has focused on FH patients at the other end of the scale, that is, patients with lung deposits (stage IV) at diagnosis. Recognizing the long-term unfavorable consequences associated with RT administered to children, the investigators have delayed pulmonary RT in patients with pulmonary metastases.¹¹ The children are administered three-drug chemotherapy using D + V + DOX. They are then observed, and any residual lung lesions are dealt with through surgical excision, spot irradiation, or both. This policy has reduced the proportion of children receiving pulmonary RT from nearly 100% in the NWTS to approximately 10% in the preliminary SIOP report of 36 collected patients by de Kraker et al.¹¹ This was achieved while maintaining the good survival rates associated with routine, bilateral lung RT. The report by de Kraker et al¹¹ states that only four of 36 children with visible pulmonary deposits seen on standard x-ray films went on to require second-phase therapy. Moreover, 83% of patients had survived after a mean of 4 years of follow-up at the time of publication. Subsequent experience with more patients is apparently similar. COG investigators find this approach attractive; it is being tried in the current protocol (COG Protocol No. AREN0533).

These examples are cited as manifestations of the fact that both groups have borrowed freely from each other. Another example, this one in the reverse direction, concerns the NWTS observations regarding the ability to reduce treatment for early-stage FH and anaplastic tumors. SIOP tested the hypothesis and found it to be valid.¹²

The preoperative versus postoperative debate must be seen in perspective. Discussion of the pros and cons of the fine points can be indulged by those in advanced societies. It should be remembered that most children alive today were born in a nation of the developing world. The number of children in the Indian subcontinent alone is two to three times that in all of the North Atlantic Treaty Organization nations combined.¹³ For physicians in emerging societies, the management of a child with any cancer more often than not presents enormous problems. This is true even for Wilms’ tumor, where the basic elements of management are relatively simple and straightforward. A recent article by Abuidris et al¹⁴ from Sudan makes the facts starkly clear. Two of their 37 patients were so ill when first seen that treatment could not be initiated. Immediate surgery on such severely depleted children would be impossible. The respite provided by preoperative chemotherapy allows the responsible physicians time to better the nutrition, hydration, and general health status of their patients. It enables the needed major surgery to proceed with an acceptable surgical risk. Thus, it is obvious that the preoperative approach will indubitably help many more children around the world than the surgery-first policy.

Many individuals and institutions on both sides of the Atlantic have devoted expertise, time, and resources in the effort to improve the welfare of these less fortunate children. A recent article reports the results of one such mentoring program between investigators in Toronto, Canada and Amman, Jordan.¹⁵ It concerns the management of medulloblastoma patients.

The SIOP investigators have done more than blaze the scientific path to success for children in less affluent societies. They have also provided the factual backgrounds for modulation of preoperative therapy and postoperative management according to defined risks.²

The debate goes on 25 years after the first of these editorials, which ended then and could end now in paraphrase: "The SIOP method is for the aggregate; the NWTS is for the individual." In truth, the two systems now run smoothly and in parallel. Physicians, institutions, and the many national and international cooperative groups can select the method that seems best suited to the individual child and the particular patient populations. Two and a half decades later, there is even more abundant information now on which to make those judgments. Grundy et al¹⁶ have reported the results of the NWTS biology study. Loss of heterozygosity in chromosomes 1p and 16q in tumor cells worsens the prognosis; it is worst when both are affected. Other national groups like those in the United Kingdom, Germany, and Brazil have also added insights.

Crossover to the other method is common. SIOP protocols have always advocated early surgery for babies.⁶ This is because neoplasms of types other than Wilms’ tumor make up approximately 20% of those found in this age group and the histologic diagnosis needs to be established before initiating treatment.¹⁷ COG protocols accommodate preoperative therapy for children with tumors so large that the responsible surgeon believes that the risks associated with early operation are prohibitive (COG Protocol No. AREN0533).

SIOP participants, their North American colleagues, and other investigators have conducted this debate in a thoroughly collegial manner. Members of any study are welcome to attend meetings of other groups, where advice and data are willingly interchanged. The children have been the beneficiaries, as they should be.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. D'Angio GJ: SIOP and the management of Wilms’ tumor. J Clin Oncol 1:595-596, 1983[Medline]

2. Tournade MF, Com-Nougue C, de Kraker J, et al: Optimal duration of preoperative therapy in unilateral and nonmetastatic 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]

3. Vujanic MM, 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]

4. Lemerle J, Voûte PA, Tournade MF, et al: Effectiveness of pre-operative chemotherapy in Wilms’ tumor: Results of an International Society of Pediatric Oncology (SIOP) clinical trial. J Clin Oncol 1:604-609, 1983[Abstract]

5. Green DM, Breslow NE, Evans I, et al: Effect of chemotherapy dose intensity on the hematological toxicity of the treatment of Wilms’ tumor: A report from the National Wilms’ Tumor Study. Am J Pediatr Hematol Oncol 16:207-212, 1994[Medline]

6. Lemerle J, Voûte PA, Tournade MF, et al: Pre-operative versus postoperative radiotherapy, single versus multiple courses of actinomycin D in the treatment of Wilms’ tumors: Preliminary results of a controlled clinical trial conducted by the International Society of Pediatric Oncology (SIOP). Cancer 38:647-654, 1976[CrossRef][Medline]

7. Boccon-Gibod I, Rey A, Sandstedt B, et al: Complete necrosis induced by preoperative chemotherapy in Wilms tumor as an indicator of low risk: Report of the International Society of Pediatric Oncology (SIOP) Nephroblastoma Trial and Study 9. Med Pediatr Oncol 34:183-190, 2000[CrossRef][Medline]

8. Tournade MF, Com-Nougue C, Voûte 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. J Clin Oncol 11:1012-1023, 1993

9. Gross RE, Neuhauser EBD: Treatment of mixed tumors of the kidney. Pediatrics 6:843-852, 1950[Abstract/Free Full Text]

10. Green DM, Breslow NE, Beckwith JB, et al: Treatment with nephrectomy only for small, stage I/favorable histology Wilms’ tumor: A report from the National Wilms’ Tumor Study Group. J Clin Oncol 19:3719-3724, 2001[Abstract/Free Full Text]

11. de Kraker J, Lemerle J, Vôute PA, et al: Wilms’ tumor with pulmonary metastases at diagnosis: The significance of primary chemotherapy. J Clin Oncol 8:1187-1190, 1990[Abstract]

12. de Kraker J, Graf N, van Tinteren H, et al: Reduction of postoperative chemotherapy in children with stage I intermediate-risk and anaplastic Wilms’ tumour (SIOP 93-01 trial): A randomized controlled trial. Lancet 364:1229-1235, 2004[CrossRef][Medline]

13. US Census Bureau: International Database, 2007. http://www.census.gov/ipc/www/idb/

14. Abuidris DO, Elimam ME, Nugud FM, et al: Wilms’ tumor in Sudan. Pediatr Blood Cancer 50:1135-1137, 2008[CrossRef][Medline]

15. Qaddoumi I, Musharbash A, Elayyan M, et al: Closing the survival gap: Implementation of medulloblastoma protocols in a low-income country through a twinning program. Int J Cancer 122:1203-1206, 2008[CrossRef][Medline]

16. Grundy PE, Telzerow PE, Breslow N, et al: Loss of heterozygosity for chromosomes 16q and 1p in Wilms’ tumors predicts an adverse outcome. Cancer Res 54:2331-2333, 1994[Abstract/Free Full Text]

17. van den Heuvel-Eibrink MM, Grundy P, Graf N, et al: Characteristics and survival of 750 children diagnosed with a renal tumor in the first seven months of life: A collaborative study by the SIOP/GPOH/SFOP, NWTSG, and UHCCSG Wilms tumor study groups. Pediatr Blood Cancer 50:1130-1134, 2008[CrossRef][Medline]

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