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Treatment With Nephrectomy Only for Small, Stage I/Favorable Histology Wilms’ Tumor: A Report From the National Wilms’ Tumor Study Group

From the Department of Pediatrics, Roswell Park Cancer Institute; School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY; Department of Biostatistics, University of Washington; the Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Pathology, Loma Linda University, Loma Linda; Department of Pediatrics, Los Angeles Children’s Hospital; Department of Pediatrics, School of Medicine, University of Southern California, Los Angeles; Department of Pathology, University of California at San Diego, San Diego, CA; Department of Pediatric Surgery, University of Texas at Houston Health Science Center; Department of Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX; Department of Surgery, Children’s Hospital; Department of Surgery, Harvard Medical School, Boston, MA; Department of Pediatric Surgery, Denver Children’s Hospital, Denver, CO; Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA; Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD; Department of Pediatrics, Cooper Hospital; Departments of Pediatrics and Oncology, Cross Cancer Institute; the University of Alberta, Edmonton; Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada; Department of Pediatrics, James Riley Whitcomb Hospital for Children; Department of Pediatrics, School of Medicine, University of Indiana, Indianapolis, IN; Department of Hematology, St Jude Children’s Research Hospital, Memphis, TN; Department of Pediatrics, School of Medicine, University of Nebraska, Omaha, NE; Department of Pediatrics, Children’s Memorial Hospital, Chicago; Department of Pediatrics, School of Medicine, Northwestern University, Evanston, IL; Department of Radiation Medicine, St Joseph’s Hospital, Tampa, FL; Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH; and Department of Pathology, Portland, Oregon.

Address reprint requests to Daniel M. Green, MD, Department of Pediatrics, Roswell Park Cancer Institute, Elm and Carlton Sts, Buffalo, NY 14263; email: daniel.green{at}roswellpark.org© 2001 by American Society of Clinical Oncology. 0732-183X/01/1917-3719/$20.00

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Children younger than 24 months with small (< 550 g), favorable histology (FH) Wilms tumors (WTs) were shown in a pilot study to have an excellent prognosis when treated with nephrectomy only.

PATIENTS AND METHODS: A study of nephrectomy only for the tratment of selected children with FH WT was undertaken. Stringent stopping rules were designed to insure closure of the study if the true 2-year relapse-free survival rate was 90% or lower.

RESULTS: Seventy-five previously untreated children younger than 24 months with stage I/FH WTs for which the surgical specimen weighed less than 550 g were treated with nephrectomy only. Three patients developed metachronous, contralateral WT 1.1, 1.4, and 2.3 years after nephrectomy, and eight patients relapsed 0.3 to 1.05 years after diagnosis (median, 0.4 years; mean, 0.51 years). The sites of relapse were lung (n = 5) and operative bed (n = 3). The 2-year disease-free (relapse and metachronous contralateral WT) survival rate was 86.5%. The 2-year survival rate is 100% with a median follow-up of 2.84 years. The 2-year disease-free survival rate (excluding metachronous contralateral WT) was 89.2%, and the 2-year cumulative risk of metachronous contralateral WT was 3.1%.

CONCLUSION: Children younger than 24 months treated with nephrectomy only for a stage I/FH WT that weighed less than 550 g had a risk of relapse, including the development of metachronous contralateral WT, of 13.5% 2 years after diagnosis. All patients who experienced relapse on this trial are alive at this time. This approach will be re-evaluated in a clinical trial using a less conservative stopping rule.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE MODERN TREATMENT of children with favorable histology (FH) Wilms’ tumor (WT) includes nephrectomy and combination chemotherapy, with some patients receiving radiation therapy to the abdomen and/or lungs.¹ However Green and Jaffe² suggested that nephrectomy only might be adequate therapy for patients less than 24 months of age with tumors weighing less than 550 grams. This hypothesis was supported by the results of a small, prospective study of eight such children treated with only nephrectomy. One patient with hypospadias developed recurrence in the opposite kidney.³ A review of children treated on National Wilms’ Tumor Studies (NWTS) -1, -2, and -3 supported the hypothesis that changes in the NWTS regimens had not improved on the excellent prognosis of this group of children, suggesting that nephrectomy alone was sufficient therapy.⁴ Weeks and Beckwith⁵ identified microsubstaging variables that were associated with a higher risk of recurrence in patients with stage I/FH WT. These included invasion of the tumor capsule, presence of an inflammatory pseudocapsule, renal sinus soft tissue invasion, and the presence of tumor within intrarenal vessels.⁵ Age at diagnosis less than 24 months, and tumor weight less than 550 grams correlated highly with the absence of these features.⁶

For all medical therapy, the benefits of the treatment must be weighed against all the costs, including medical and financial factors. Life-threatening hepatic toxicity occurs during the first 10 weeks of treatment in approximately 3.5% of unirradiated WT patients.^7,8 Furthermore, the direct and indirect costs of chemotherapy administration and monitoring⁹ and the poorly quantitated impact of treatment on the child and his/her family must be considered. The available data for children who are less than 24 months of age at diagnosis who have FH WT that weigh less than 550 grams suggest that the costs of the therapy may outweigh the benefits. Thus an evaluation of nephrectomy as the only treatment for a selected group of children with WT was initiated in the fifth study of the National Wilms’ Tumor Study Group (NWTSG).

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
NWTS-5 was a multi-institutional clinical trial for patients less than 16 years of age at diagnosis with specific renal neoplasms who were diagnosed after August 1, 1995. All patients underwent an initial nephrectomy after completing a preoperative assessment, which was to include radiographic imaging of the kidneys, inferior vena cava, and lungs. The surgical procedure was to be performed through a transabdominal incision. The contralateral kidney was to be mobilized, all surfaces inspected, and any lesion suspicious for WT biopsied. Retroperitoneal lymph nodes were to be biopsied, but the protocol did not mandate routine retroperitoneal lymph node dissection. Institutional operative notes and NWTSG Surgical Forms were reviewed to confirm the surgical findings that related to the assigned stage. Rapid review of surgical forms and operative notes (R.C.S., M.L.R., and G.M.H.) and pathology forms and pathology slides (J.B.B.) was undertaken to verify the assignment of stage and histology of patients less than 24 months of age who were registered by their institution as having a stage I/FH tumor.

Microscopic slides, institutional pathology reports, and NWTSG Pathology Forms were reviewed by the NWTSG pathologist. The histology was categorized as favorable, with various subtypes of FH recorded.¹⁰ Written reports of the central review were sent to the institutional pathologist. Discrepancies between the institutional and central review were discussed. Only FH WTs were eligible for this study. A stage was assigned using the NWTSG surgical-pathologic staging system,¹¹ which was modified before the start of NWTS-5. Tumors that had evidence of invasion of vessels in the renal sinus by tumor were classified as stage II, rather than as stage I.¹² The NWTS-5 protocol and an informed consent document were approved by the institutional review board of each institution registering patients, and informed consent was obtained from the parents of all patients before participation in this study of nephrectomy-only treatment.

Statistical Design and Analysis
The quantitative measure of therapeutic outcome used for the study design was the percentage of patients who were alive and disease-free 2 years after nephrectomy. Patients who relapsed, necessitating a change in therapy, or who died of toxicity or other causes without prior relapse, were to be counted as failures. Previous NWTSG studies demonstrated that, for FH WT patients, the 2-year relapse-free survival (RFS) percentage was nearly equal to the percentage of children who were long-term, relapse-free survivors. Later events included the very occasional appearance of new disease in the contralateral kidney or death from unrelated causes.^10,13,14

Interim analyses were planned after 2, 3, and 4 years of patient accrual. If the trial was not stopped early, accrual was planned to continue for 5 years. The stopping rule was calculated so that, if the true long-term, relapse-free percentage was no better than 90%, the probability of stopping early and/or concluding that no treatment (ie, treatment with nephrectomy only) had failed was 95%. On the other hand, if the true 2-year, relapse-free percentage was 95% or better, the probability of continuing patient accrual and ultimately concluding that no treatment had succeeded was 80%.¹⁵ The Data Monitoring Committee of the NWTSG recommended to the NWTSG Study Committee on June 14, 1998, that the study be closed to further accrual, based on the results of the 3-year interim analysis.

Interim and final analyses were performed using actuarial methods to estimate the RFS and survival curves. The data were analyzed using standard statistical methods, including product-limit estimates of survival curves and the log-rank test.^16,17 Standard errors were computed using Greenwood’s formula.¹⁸ Point and interval estimates of log relative risk were based on the Cox proportional hazards model.¹⁹ These methods all account for the fact that not all patients had complete follow-up.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Seventy-five previously untreated children less than 24 months of age with stage I/FH WTs for which the surgical specimen weighed less than 550 grams were treated with nephrectomy only. Thirty-seven were female, and 38 were male. These children were 1 to 23 months of age at diagnosis (median, 11 months; mean, 10.71 months). The combined weight of the tumor and involved kidney was 18 to 549 grams (median, 260 g; mean, 288 g).

Ten patients had perilobar nephrogenic rests (PLNR), and 18 had intralobar nephrogenic rests (ILNR). Seven patients had both types of rests, 26 had no rests, and 14 had uncertain rest status in the nephrectomy specimen (Table 1).

Eleven patients relapsed or developed metachronous disease in the contralateral kidney 0.3 to 2.3 years after diagnosis (median, 4 months; mean, 0.64 years). The sites of relapse were lung (n = 5) (bilateral [n = 3] and unilateral [n = 2]) and operative bed (n = 3). Three patients developed disease in the contralateral kidney. The 2-year disease-free survival rate was 86.5%. The 2-year survival rate was 100%, with a median follow-up of 2.84 years.

Relapse or metachronous WT occurred in seven females and four males. The 2-year disease-free survival percentage was 81% for females and 89% for males (P = .29, log-rank).

Relapse or metachronous WT occurred in five of 19 patients with ILNR and three of 26 patients with no rests. Metachronous contralateral WT developed in two of 10 patients with PLNR and one of seven with ILNR + PLNR. None of 13 patients with uncertain rest status relapsed. The 2-year disease-free survival percentages were 77% for patients with PLNR, 86% for those with PLNR and ILNR, and 73% for those with ILNR only (P = .29, log-rank).

Relapse or metachronous WT occurred in seven of 35 patients with mixed WT; zero of 23 with epithelial, tubular differentiation; two of six with epithelial, undifferentiated; two of five with mixed WT, blastemal predominant; and in none of the remaining patients. The 2-year disease-free survival percentage was 100% for those with epithelial, tubular differentiation, 80% for those with mixed WT, 63% for those with epithelial, undifferentiated, and 53% for those with mixed WT, blastemal predominant (P = .28, log-rank). Relapse or metachronous WT occurred in four of 10 patients with diffuse blastema present, in seven of 63 patients with diffuse blastema absent, and in zero of two patients with diffuse blastema unable to be analyzed (P = .01).

Relapse or metachronous WT occurred in zero of seven patients whose tumors weighed less than 100 grams, three of 16 whose tumors weighed 100 to 199 grams, two of 19 whose tumors weighed 200 to 299 grams, one of 13 whose tumors weighed 300 to 399 grams, two of 10 whose tumors weighed 400 to 499 grams, and three of 10 whose tumors weighed 500 grams (P = .168, test for trend).

Relapse or metachronous WT was not significantly more frequent among those with an inflammatory pseudocapsule (P = .74, log-rank) or intrarenal vessel invasion (P = .38, log-rank). However relapse or metachronous WT was more frequent among those whose renal sinus could not be adequately evaluated for renal sinus soft tissue extension (P = .01). Relapse or metachronous WT was not more frequent among those with no lymph nodes removed at the time of nephrectomy (P = .35).

Three patients developed metachronous contralateral WT. This occurred 1.1 and 1.4 years after nephrectomy in two patients treated with nephrectomy only and 1.4 years after initiation of treatment with vincristine and dactinomycin in the third patient, after the protocol amendment in June 1998. The actuarial percentage of children 0 to 11 months of age at diagnosis who developed metachronous, contralateral WT before treatment with vincristine and dactinomycin was 3% and was 4.3% for those 12 to 23 months of age at diagnosis (P = .59). Metachronous WT was not more common in females (P = .46). All three metachronous tumors developed in patients whose initial tumor weighed 100 to 199 grams, whereas no such events occurred in the patients whose tumors were in the other weight groups (P = .087). Metachronous WT developed only in patients whose initial tumor contained PLNR with or without ILNR, whereas no patient with ILNR only or no rests developed metachronous WT (P = .067). Metachronous WT developed in two of six patients with epithelial, undifferentiated histology, and in one of five with mixed WT, blastemal predominant, but in no patient in the remaining histologic groups (P = .004). Metachronous WT was not related to the presence of an inflammatory pseudocapsule (P = .91), intrarenal vessel invasion (P = .81), or renal sinus soft tissue invasion (P = .70).

Eight patients developed local recurrence of or pulmonary metastases from WT. All eight patients had primary tumors that weighted 200 or more grams. However, there was no statistically significant relationship between local relapse or development of metastases and the six weight categories analyzed (P = .19). Local recurrence or pulmonary metastases developed only in patients whose initial tumor contained either no rests or only ILNR (P = .07). Local recurrence or pulmonary metastases developed in seven of 35 patients with mixed WT and in one of five with mixed WT, blastemal predominant, but in no patient in the remaining histologic groups (P = .45). Local recurrence or pulmonary metastases occurred in four of 10 patients with diffuse blastema present, in four of 63 patients with diffuse blastema absent, and in zero of two patients with diffuse blastema unable to be analyzed (P = .002). Local recurrence or pulmonary metastases were not related to the presence of an inflammatory pseudocapsule (P = .56) or intrarenal vessel invasion (P = .28). However local recurrence or pulmonary metastases were more frequent among patients whose renal sinus could not be adequately evaluated for renal sinus soft tissue extension (P = .006).

Five patients were treated for pulmonary metastases, four using the recommendations of the NWTSG protocol for patients with relapsed WT (Pediatric Oncology Group 9444 and Children’s Cancer Group (CCG) 4942) and one following a local institutional protocol (Children’s Hospital of Los Angeles 91LA-2). Four are in second complete remission, and the fifth is in fourth relapse.

Three patients were treated for operative bed recurrence using the recommendations of the NWTSG protocol for patients with relapsed WT (Pediatric Oncology Group 9444 and CCG 4942). Two had only microscopic residual disease after exploratory laparotomy and surgical resection of the recurrence, and one had gross residual disease after subtotal excision of the recurrence. All three are in second complete remission.

Three patients were treated for metachronous contralateral WT using the recommendations of the NWTSG protocol for patients with relapsed WT (Pediatric Oncology Group 9444 and CCG 4942). Two were treated with vincristine and dactinomycin after undergoing microscopically compete resection of the tumor, and the third was treated with vincristine, dactinomycin, doxorubicin, and local radiation therapy for gross residual disease. All three are in second complete remission.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The present trial was undertaken to determine if nephrectomy only was sufficient therapy for children less than 24 months of age with a stage I/FH WT that weighed less than 550 grams. This weight and age grouping was based on the work of Garcia et al,²⁰ as confirmed in the review of patients treated at Children’s Hospital Medical Center, Boston, MA, by Cassady et al.²¹ A subsequent review of patients treated at the Dana-Farber Cancer Institute and Children’s Hospital Medical Center, Boston, MA, documented the excellent prognosis for this group of children, whether treated with nephrectomy only, nephrectomy and abdominal radiation therapy, or nephrectomy, abdominal radiation therapy, and chemotherapy.² An analysis of the outcome of this group of patients treated on NWTS-1, -2, and -3 revealed that the relapse-free survival percentages, which were 89.1%, 96.0%, and 93.2%, respectively, did not differ statistically (P = .99).⁴

Weeks et al⁵ developed a microsubstaging system, which considered the presence of an inflammatory pseudocapsule, tumor capsule invasion, renal sinus soft tissue invasion, and tumor in intrarenal vessels to be adverse prognostic factors in stage I/FH WT. The presence of these factors was shown to be significantly more frequent among patients who were 24 or more months of age at diagnosis or whose tumor weighed more than 550 grams. At least one adverse factor was present, however, in 48.1% of patients who were less than 24 months of age and whose tumor weighed less than 550 grams.⁶ This high frequency of adverse microsubstaging variables was inconsistent with the excellent prognosis for this group of patients. As a result, treatment with nephrectomy only was studied in the entire population of young children with small tumors.

Tumor recurrence was diagnosed in eleven patients, eight of whom had local relapse of tumor or developed pulmonary metastases, and three of whom developed metachronous, contralateral WT. The estimated 2-year, disease-free survival percentage was 86.5%, which is consistent with the 87.5% figure reported earlier from the Dana-Farber Cancer Institute.³ The sequential sampling rule used in the NWTSG trial was designed conservatively to curtail patient entry and, with 95% confidence, reach a decision against the use of nephrectomy alone should the true 2-year disease-free survival percentage be 90% or lower. It was designed to continue accrual and reach a decision in favor of surgery alone with 80% confidence should the true disease-free survival percentage be 95% or better.¹⁵ The early evidence suggested a recurrence rate higher than 10%, and the study was closed. The conservative design was based in part on the assumption that only one half of the patients with recurrence could be treated successfully with the salvage regimen, as observed when combination chemotherapy was administered.²² If this salvage rate pertained also to the outcome after nephrectomy only, then salvage of one half of relapsed patients, when the 2-year, disease-free survival percentage was 90%, would result in a 2-year survival rate of 95%, consistent with the earlier NWTSG trials. In fact, the salvage rate has been more than one half, a finding that would support a less conservative lower limit for the 2-year disease-free survival percentage in future trials with this group of patients.

This study provides information previously unavailable regarding the biologic potential of tumors possessing or lacking several pathologic features. No child with an epithelial, tubular differentiation WT developed disease recurrence or metachronous contralateral WT. Bodian and Rigby²³ proposed a classification of renal tumors in childhood that included a group of tumors (type B) composed predominantly of tubular structures. These children had a survival rate of 75%.²³ Lawler et al²⁴ classified tumors on the basis of tubular content, with the +++ tumors containing "very large numbers of tubules, and almost all the tumor cells present were involved in the formation of tubules." Although these tumors represented only 8% (six of 75) of their series, the survival rate of these children was 83%.²⁴ Chambers used a modification of Lawler’s system to classify WTs, and reported that all six children with Lawler +++ histology were surviving.²⁵ Chatten²⁶ summarized this work and analyzed her own series of 95 renal tumors, nine of which (9.5%) had monomorphous epithelial tubular histology. All nine children survived.²⁶ Beckwith et al²⁷ reported that such tumors present at a lower stage, with 81% being stage I, and that these tumors represented 13.4% (100 of 745) of the unilateral, stage I WTs on NWTS-4. In the current study of children less than 24 months of age with tumors weighing less than 550 grams, this histologic pattern represented 30.7% of the total, supporting earlier suggestions that this type was more frequent among young patients. A larger series of such patients would be necessary to confirm the statistical significance of the relationship between epithelial, tubular differentiation WT and favorable outcome after treatment with nephrectomy only.

A second pathologic subtype that has been associated with high invasiveness and aggressiveness, yet with excellent and often dramatic response to chemotherapy, is the subset of WTs that have diffuse blastema histology as a component of the histologic picture. In the present study, four of 10 patients showing greater than or equal to 10% of this histologic pattern relapsed compared with seven of 63 without this histologic pattern (P = .01). All were surviving.

Four of the eight tumors that subsequently relapsed were either incompletely documented pathologically (two cases lacking sections of the renal sinus) or showed features suspicious for stage II (two cases). These features include small clusters of tumor floating in either a sinus vessel or lymph node sinus. Conversely, on retrospective analysis, two of eight patients who relapsed demonstrated none of the adverse microsubstaging features.

This study provided important information regarding the impact, if any, of chemotherapy on the conversion of nephrogenic rests to WT. Chemotherapy may act to suppress the development or progression of a WT within an existing rest or may produce a genetic event that could result in promotion of Wilms’ tumorigenesis. Although the percentage of patients who developed metachronous contralateral WTs was too small to adequately analyze statistically, it seemed similar to that reported in previous studies 2 years after diagnosis in patients of similar ages who received chemotherapy for their initial tumor.²⁸ Additional follow-up is necessary to adequately evaluate this outcome.

We conclude that the RFS rate of children with stage I/FH WT treated with nephrectomy only is marginally inferior to that of children treated on previous NWTS studies with nephrectomy, vincristine, and dactinomycin. However, the increase in relapse rate did not result in inferior survival because of the very high success rate of treatment of these children for recurrent disease. The presence of diffuse blastema and the lack of adequate sampling of the renal sinus were associated with an increased risk of operative bed recurrence and pulmonary metastases. The risks of combination chemotherapy in this group of young children include hepatic veno-occlusive disease, central venous catheter complications, such as infection and thrombosis,²⁹ and the direct and indirect costs of chemotherapy administration and monitoring.

We plan to re-evaluate treatment with nephrectomy only in a new prospective clinical trial in selected infants and children with meticulously resected, adequately examined FH WTs to define more accurately the population of patients for whom this might be the most appropriate treatment. At the present time, treatment of infants with small, stage I/FH WT with nephrectomy only should not be considered standard therapy. It should be undertaken only in the context of a prospective clinical trial by multidisciplinary pediatric oncology teams experienced in the diagnosis and management of patients with WT, including those with recurrent disease.

	ACKNOWLEDGMENTS

 
Supported in part by United States Public Health Service grant no. CA-42326.

We thank the investigators of the Pediatric Oncology Group and the Children’s Cancer Group; the many pathologists, surgeons, pediatricians, radiation oncologists, and other health professionals who managed the children entered onto the National Wilms’ Tumor Studies; Audrey Evans, MD, for assisting with the review of the flow sheets; and Mrs Diane Piacente for typing the manuscript.

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Submitted February 23, 2001; accepted May 24, 2001.

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				D. M. Green Use of Chest Computed Tomography for Staging and Treatment of Wilms' Tumor in Children J. Clin. Oncol., June 15, 2002; 20(12): 2763 - 2764. [Full Text] [PDF]

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