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Objective: The Children's Oncology Group study AREN0534 aimed to improve event-free survival (EFS) and overall survival (OS) while preserving renal tissue by intensifying preoperative chemotherapy, completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histologic response., Background: No prospective therapeutic clinic trials in children with bilateral Wilms tumors (BWT) exist. Historical outcomes for this group were poor and often involved prolonged chemotherapy; on NWTS-5, 4-year EFS for all children with BWT was 56%., Methods: Patients were enrolled and imaging studies were centrally reviewed to assess for bilateral renal lesions. They were treated with 3-drug induction chemotherapy (vincristine, dactinomycin, and doxorubicin) for 6 or 12 weeks based on radiographic response followed by surgery and further chemotherapy determined by histology. Radiation therapy was provided for postchemotherapy stage III and IV disease., Results: One hundred eighty-nine of 208 patients were evaluable. Four-year EFS and OS were 82.1% (95% CI: 73.5%-90.8%) and 94.9% (95% CI: 90.1%-99.7%. Twenty-three patients relapsed and 7 had disease progression. After induction chemotherapy 163 of 189 (84.0%) underwent definitive surgical treatment in at least 1 kidney by 12 weeks and 39% retained parts of both kidneys. Surgical approaches included: unilateral total nephrectomy with contralateral partial nephrectomy (48%), bilateral partial nephrectomy (35%), unilateral total nephrectomy (10.5%), unilateral partial nephrectomy (4%), and bilateral total nephrectomies (2.5%)., Conclusion: This treatment approach including standardized 3-drug preoperative chemotherapy, surgical resection within 12 weeks of diagnosis and response and histology-based postoperative therapy improved EFS and OS and preservation of renal parenchyma compared with historical outcomes for children with BWT.

Objective: To determine if observation alone after nephrectomy in very low-risk Wilms tumor (defined as stage I favorable histology Wilms tumors with nephrectomy weight <550g and age at diagnosis <2 years) results in satisfactory event-free survival and overall survival, and to correlate relapse with biomarkers., Patients and Methods: The AREN0532 study enrolled patients with very low-risk Wilms tumor confirmed by central review of pathology, diagnostic imaging, and surgical reports. After nephrectomy, patients were followed without adjuvant chemotherapy. Evaluable tumors were analyzed for WT1mutation, 1p and 16q copy loss, 1q copy gain, and 11p15 imprinting. The study was powered to detect a reduction in 4-year EFS from 87% to 75% and overall survival from 95% to 88%., Results: A total of 116 eligible patients enrolled with a median follow up of 80 months (range: 5-97 months). Twelve patients relapsed. Estimated 4-year event-free survival was 89.7% (95% confidence interval 84.1-95.2%) and overall survival was 100%. First sites of relapse were lung (n = 5), tumor bed (n = 4), and abdomen (n = 2), with one metachronous tumor in the contralateral kidney (n = 1) at a median time of 4.3 months for those who relapsed (range 2.3-44 months). The presence of intralobar (P = 0.46) or perilobar rests (P = 1.0) were not associated with relapse (P = 0.16). 1q gain, 1p and 16q loss, and WT1 mutation status were not associated with relapse. 11p15 methylation status was associated relapse (20% relapse with loss of heterozygosity, 25% with loss of imprinting, and 3.3% relapse with retention of the normal imprinting (P = 0.011))., Conclusions: Most patients meeting very low-risk criteria can be safely managed by nephrectomy alone with resultant reduced exposure to chemotherapy. Expansion of an observation alone strategy for low-risk Wilms tumor incorporating both clinical features and biomarkers should be considered.

Background: Intra-operative tumor spill increases the risk of local recurrence of Wilms tumor, and adversely impacts relapse-free (RFS) and overall survival (OS) rates., Methods: Surgical checklists, operative notes, institutional pathology reports, central pathology review and flow sheets of 602 patients registered between August 1986 and September 1994 on National Wilms Tumor Study-4 as randomized, followed or switched and coded as Final Stage II, favorable histology (FH) were reviewed. RFS and OS were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were estimated using the Cox model and tested for statistical significance by the log-rank test., Results: Four hundred ninety-nine patients were found after review to have Stage II, FH Wilms tumor. The 8-year RFS percentages were 85.0% (95% confidence interval (CI): 81.1%, 88.1%) for those with no spill compared to 75.7% (65.8%, 83.2%) for those with spill. The 8-year OS percentages were 95.6% (93.1%, 97.3%) for those with no spill compared to 90.3% (82.2%, 94.9%) for those with spill. The HR for relapse among those with spill was 1.55 ((95%CI: 0.97,2.51), P = 0.067) and the HR for death was 1.94 ((0.92,4.09), P = 0.077)., Conclusions: RFS and OS were lower for patients who had intra-operative tumor spill. The majority of NWTS Stage II, FH patients with intra-operative tumor spill have an overall excellent outcome when treated with two drug chemotherapy (vincristine and actinomycin D) and no abdominal irradiation., (© 2013 Wiley Periodicals, Inc.)

Purpose: Nephrectomy with lymph node sampling is the recommended treatment for children with unilateral Wilms tumor under the Children's Oncology Group protocols. Using radiological assessment, we determined the feasibility of performing partial nephrectomy in a select group of patients with very low risk unilateral Wilms tumor., Materials and Methods: We reviewed imaging studies of 60 patients with a mean age of less than 2 years with very low risk unilateral Wilms tumor (mean weight less than 550 gm) to assess the feasibility of partial nephrectomy. We evaluated percentage of salvageable parenchyma, tumor location and anatomical features preventing a nephron sparing approach., Results: A linear relationship exists between tumor weight and computerized tomography estimated tumor volume. Mean tumor weight in the study population was 315 gm. Partial nephrectomy was deemed feasible in only 5 of 60 patients (8%)., Conclusions: When considering a select population with very low risk unilateral Wilms tumor (lower volume tumor), only a small percentage of nonpretreated patients are candidates for nephron sparing surgery., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine whether performing adrenalectomy at the time of nephrectomy for unilateral Wilms tumor impacts clinical outcome., Methods: We reviewed information on all patients enrolled on National Wilms Tumor Study-4 and -5. Data were abstracted on patient demographics, tumor characteristics, surgical and pathologic status of the adrenal gland, and patient outcomes. The primary endpoints were intraoperative spill and five-year event-free survival (EFS) in patients who did or did not undergo adrenalectomy., Results: Of 3825 patients with complete evaluable data, the adrenal was left in situ in 2264 (57.9%) patients, and was removed completely in 1367 patients (36.7%) or partially in 194 patients (5.2%). Of the adrenal glands removed, 68 (4.4%) contained tumor. Adrenal involvement was more common in patients with stage 3 (9.8%) than stage 2 disease (1.9%; p < 0.0001). After controlling for stage and histopathology, five-year EFS was similar whether or not the adrenal gland was removed (p = 0.48), or involved with tumor (p = 0.81); however, intraoperative spill rates were higher in patients undergoing adrenalectomy (26.1% vs 15.5%, p < 0.0001), likely due to larger tumor size or technical factors. No patient had clinical evidence of adrenal insufficiency or tumor recurrence in the adrenal gland during follow-up (median 9.9 years)., Conclusions: Sparing the adrenal gland during nephrectomy for unilateral Wilms tumor was not associated with a higher incidence of intraoperative spill and was associated with a similar oncologic outcome, on a per-stage basis, with cases where the adrenal was removed. Thus, adrenalectomy should not be considered mandatory during radical nephrectomy for Wilms tumor., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: The aim of the study was to determine the prognostic impact of lymph node (LN) involvement and sampling in patients with Wilms tumor (WT) and the minimum number of LNs needed for accurate staging., Methods: We reviewed all patients with unilateral, nonmetastatic WT enrolled in the National Wilms Tumor Study 4 or 5. Data were abstracted on patient demographics, tumor histology, staging, number of LNs sampled, and disease-specific and overall patient outcomes., Results: A total of 3409 patients had complete information on LN sampling. Five-year event-free survival (EFS) was lower in patients with nodal disease (P < .001); the effect of LN positivity was greater for patients with anaplastic (P = .047) than with favorable histology (P = .02). The likelihood of obtaining a positive LN was higher when sampling at least 7 LNs. However, after controlling for tumor histology and stage, the number of LNs sampled did not predict EFS variations (P = .75). Among patients with stage II disease, patients with LN sampling (P = .055) had improved EFS, largely reflecting poorer EFS in patients with anaplastic tumors (P = .03)., Conclusions: Lymph node sampling is particularly important for patients with stage II anaplastic WT. Although the likelihood of finding a positive LN was greater when more than 7 LNs were sampled, EFS was not impacted by the number of LNs sampled., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Decision analysis was used to clarify differences in survival and complication rates comparing surgery alone versus surgery plus chemotherapy for Stage I, favorable histology Wilms tumor patients., Procedure: A state transition model was used to simulate treatment with nephrectomy-only, nephrectomy with adjuvant vincristine (VCR) or with vincristine plus dactinomcyin (NWTS Regimen EE4A). Rates of relapse and complications of therapy were obtained from the literature. In sensitivity analysis, the model was probed for the value(s) at which the treatment of choice changes., Results: The overall survival (OS) is essentially the same for patients treated with any of the three strategies (OS(Nephrectomy) = 98.8%; OS(EE4A) = 98.8%; OS(VCR) = 98.6%). Rates of serious long-term complications in the surviving population are also similar across treatment strategies (nephrectomy = 1.4%; VCR = 1.2%; EE4A = 0.3%). Both the progression and salvage rates after nephrectomy-only would have to be much worse than expected for nephrectomy-only to be an unacceptable strategy., Conclusions: The differences in overall survival and rates of long-term complications between the three different initial strategies were negligible in the model. Based on this analysis, it was decided by the Children's Oncology Group that it was acceptable to continue to include nephrectomy without adjuvant chemotherapy as an experimental arm of the low risk Wilms tumor protocol with stringent eligibility criteria and close follow-up. Decision analysis can have a role in clinical trial design by making the tradeoffs between strategies more explicit. The robustness of these conclusions can be tested by widely varying the underlying assumptions., (Copyright 2010 Wiley-Liss, Inc.)

Background/purpose: Surgical technique impacts both local tumor stage and risk of local recurrence in Wilms' tumor. A surgical quality assurance program was part of National Wilms' Tumor Study-5 to assess protocol compliance., Methods: Surgical checklists, operative, and pathology reports were reviewed concurrently to arrive at the final local tumor stage. If a protocol violation occurred, a letter was sent to the responsible surgeon. Tumor laterality, extent, type of resection, contralateral exploration, node involvement, spills, and local recurrence were reviewed. Relative risk and logistic regression analyses were performed., Results: There were 1305 nephrectomies. Lymph node sampling was not performed in 117 (9%) patients: stage I, 41 (11.5%), stage II, 57 (12%), and stage III, 19 (4%). Of importance, 41% (187/457) of stage III cases were designated stage III solely on the basis of positive lymph nodes. Tumor spill occurred in 19.3% (253/1305) of children. Fifty-four local spills were in stage II tumors and 97 in stage III. Diffuse spill occurred in 102 patients with stage III tumors. Seventeen preoperative and 13 intraoperative biopsies were performed. Intraoperative tumor rupture was the most common cause of tumor spill accounting for 139 (55%) spills. Nineteen (7.5%) children were upstaged, receiving more intensive therapy because of spill. Included in the group were 3 of 17 preoperative biopsies and 5 of 13 intraoperative biopsies. Spills (13/253) were determined to be avoidable. Eight were biopsies, 5 because tumor was transected in the renal vein (4) or ureter (1). In stage II patients where lymph nodes were not sampled, there is an increase in local relapse rate that did not achieve statistical significance because of the small number of events., Conclusions: Although most surgeons complied with the surgical guidelines, numerous deviations were identified including failure to sample lymph nodes (117 cases) and unnecessary biopsies leading to tumor spill (30 cases). Protocol violations have an adverse impact on tumor staging, potentially increasing the risk for local tumor recurrence or intensity and toxicity of therapy.

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 treatment 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.

Background: Surgical complications are a recognized morbidity of the treatment of patients with Wilms tumor. This study examines the incidence of surgical complications in the most recently completed study from the National Wilms' Tumor Study Group (NWTSG)., Study Design: The fourth National Wilms' Tumor Study (NWTS-4) enrolled 3,335 patients from August 1986 to August 1994. A random sample of 534 patients was selected from 2,290 eligible patients randomized to treatment regimens or enrolled in the followed category and treated according to NWXTSG protocol. The patient records received at the NWTSG Data and Statistical Center were analyzed for surgical complications (intraoperative and postoperative)., Results: Sixty-eight patients (12.7%) experienced 76 complications. Intestinal obstruction was the most common complication (5.1% of patients), followed by extensive hemorrhage (1.9%), wound infection (1.9%), and vascular injury (1.5%). The incidence of surgical complications in NWTS-4 was significantly lower than NWTS-3 (12.7% versus 19.8%, p < 0.001). There has been a marked decrease in the risk of extensive intraoperative bleeding and major intraoperative complications. Factors previously shown to be associated with an increased risk for surgical complications, together with indicators of type of hospital and surgeon specialty, were analyzed by multiple logistic regression analysis. Intravascular extension into the inferior vena cava (IVC), the atrium, or both (p = 0.02; odds ratio [OR] 3.8, 95% confidence interval [CI] 1.2, 11.8), and nephrectomy performed through a flank or paramedian incision (p = 0.02; OR 5.3, 95% CI 1.3, 22) were both associated with increased risk of complications. Tumor diameter greater than or equal to 10cm was also associated with an increased risk of surgical complications (p = 0.05; OR 2.0, 95% CI 1.0, 3.9). The risk of complications was higher if the nephrectomy was performed by a general surgeon (OR 9.0, 95% CI 1.3, 65; p = 0.03) rather than a pediatric surgeon (reference group, OR 1.0) or pediatric urologist (OR 0.7, 95% CI 0.3, 1.8)., Conclusions: The incidence of surgical complications in NWTSG patients undergoing primary nephrectomy has significantly decreased over the past decade. But surgical morbidity should not be overlooked. It is important that surgeons treating young children with solid tumors are aware of their role and the potential risks encountered in removal of the primary tumor. This study found that surgical specialists who primarily treat children can perform these operations with lower surgical morbidity.

Methods: Eight hundred sixty-eight children presenting from 1981 to 1991 were treated on five multiagent chemotherapy protocols by members of the Pediatric Oncology Group for advanced-stage neuroblastoma with large primary tumors crossing the midline or distant metastasis. Of these children, 696 had abdominal (adrenal or paravertebral) primary tumors. One hundred sixteen children underwent greater than 50% surgical resection of these abdominal primary tumors before chemotherapy, and 233 underwent similar surgery after induction chemotherapy., Results: Among the 349 who underwent surgical resection, 52 children (14.9%) had nephrectomy or renal infarction during surgery for local control. There was a 25% incidence among those with initial resection (29 patients) and a 9.9% incidence in the postchemotherapy resections (23 patients). Reasons for nephrectomy given by the surgeons included direct involvement of the kidney by adjacent tumor (17 children), clinical impression that the tumor was a Wilms' tumor (11 children), renal vessels could not be separated from the tumor (10 children), extensive tumor surrounding the kidney (8 children), postoperative renal infarction (4 children), marked decrease in unilateral renal function after chemotherapy (1 child), and position of the tumor posterior to the kidney and vena cava making resection without nephrectomy impossible (1 child). Of the patients undergoing nephrectomy, four children had an upper pole nephrectomy in conjunction with their adrenalectomy and resection of the tumor. Pathological review of the resected tumor available in 47 cases demonstrated direct involvement of the renal parenchyma in 18 cases (38% of the nephrectomies) and in 5.2% of those undergoing resection. In children undergoing initial resection, the risk for nephrectomy (as calculated by the methods described by Gart) was more than twice compared with those undergoing resection after chemotherapy (P = .012; odds ratio, 2.32; 95% confidence interval of 1.23 to 4.42)., Conclusions: This review confirms that renal parenchymal involvement does occur in a significant number of children with abdominal neuroblastoma. It also suggests that preoperative chemotherapy may decrease the number of nephrectomies required to achieve a total or subtotal resection.

Synchronous bilateral Wilms' tumor accounts for 4% to 6% of all Wilms' tumors. Renal salvage procedures (partial nephrectomy and enucleation) have been recommended to conserve renal parenchyma. The objective of this study was to review the results of renal salvage operations performed in children who had bilateral neoplasms. The authors reviewed the records of 98 children enrolled in the Fourth National Wilms' Tumor Study who had synchronous bilateral tumors and underwent renal salvage procedures. One hundred thirty-four kidneys were managed with renal salvage procedures. Complete excision of gross disease was accomplished in 118 (88%) of the 134 kidneys. Local tumor recurrence in the remnant kidney or tumor bed occurred in 11 cases (8.2%). Overall, 72% of the kidneys were preserved, and the 4-year survival rate was 81.7%. The surgical morbidity after a salvage procedure was comparable to that of a complete nephrectomy in patients with unilateral Wilms' tumor. Although the incidence of positive surgical margins is worrisome, it did not invariably lead to local recurrence in the remnant kidney or the tumor bed.