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Clinicopathologic findings predictive of relapse in children with stage III favorable-histology Wilms tumor.

ABSTRACT: Stage III designation in NWTS-5 (National Wilms Tumor Study-5) was determined by four pathologic criteria: positive lymph nodes (LNs), peritoneal implants, residual disease, and tumor rupture. The objective of this study was to determine the prognostic significance of each of the stage III criteria.Children with stage III Wilms tumor (WT) treated in NWTS-5 were assessed for event-free (EFS) and overall survival (OS). Sites of relapse and molecular status of tumors are reported. EFS and OS are reported 8 years after diagnosis.There were 569 patients with local stage III favorable-histology (FH) WT in this analysis, of whom 109 had overall stage IV disease. LN involvement alone was the most frequent criterion for stage III designation (38%), followed by microscopic residual disease alone (20%), microscopic residual disease and LN involvement (14%), and spill or soilage alone (9%). The 8-year EFS and OS estimates for all patients with local stage III FHWT were 82% and 91%, respectively. Multivariate analysis demonstrated that both LN involvement (relative risk, 1.89; P = .005) and microscopic residual disease (relative risk, 1.87; P = .007) were predictive of EFS, and OS results were similar. There was no apparent difference in pattern of relapse according to stage III subtype. The rate of loss of heterozygosity was higher (6%) for those with positive LNs than for those without (2%; P = .05).LN involvement and microscopic residual are the stage III criteria highly predictive of EFS and OS for patients with stage III FHWT. It is possible that in future studies, patients with different stage III criteria may receive different therapies.

SUBMITTER: Ehrlich PF

PROVIDER: S-EPMC3595426 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Clinicopathologic findings predictive of relapse in children with stage III favorable-histology Wilms tumor.

Ehrlich Peter F PF Anderson James R JR Ritchey Michael L ML Dome Jeffrey S JS Green Daniel M DM Grundy Paul E PE Perlman Elizabeth J EJ Kalapurakal John A JA Breslow Norman E NE Shamberger Robert C RC

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20130204 9

<h4>Purpose</h4>Stage III designation in NWTS-5 (National Wilms Tumor Study-5) was determined by four pathologic criteria: positive lymph nodes (LNs), peritoneal implants, residual disease, and tumor rupture. The objective of this study was to determine the prognostic significance of each of the stage III criteria.<h4>Patients and methods</h4>Children with stage III Wilms tumor (WT) treated in NWTS-5 were assessed for event-free (EFS) and overall survival (OS). Sites of relapse and molecular sta ...[more]

PMID: 23382471

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Project description:Background The National Wilms Tumor Study (NWTS) approach to treating stage III favorable-histology Wilms tumor (FHWT) is Regimen DD4A (vincristine, dactinomycin, and doxorubicin) and radiation therapy. Further risk stratification is required to improve outcomes and reduce late effects. We evaluated clinical and biologic variables for patients with stage III FHWT without combined loss of heterozygosity (LOH) at chromosomes 1p and 16q treated in the Children's Oncology Group protocol AREN0532. Methods From October 2006 to August 2013, 588 prospectively treated, centrally reviewed patients with stage III FHWT were treated with Regimen DD4A and radiation therapy. Tumor LOH at 1p and 16q was determined by microsatellite analysis. Ineligible patients (n = 5) and those with combined LOH 1p/16q (n = 40) were excluded. Results A total of 535 patients with stage III disease were studied. Median follow-up was 5.2 years (range, 0.2 to 9.5). Four-year event-free survival (EFS) and overall survival estimates were 88% (95% CI, 85% to 91%) and 97% (95% CI, 95% to 99%), respectively. A total of 58 of 66 relapses occurred in the first 2 years, predominantly pulmonary (n = 36). Eighteen patients died, 14 secondary to disease. A better EFS was associated with negative lymph node status ( P < .01) and absence of LOH 1p or 16q ( P < .01), but not with gross residual disease or peritoneal implants. In contrast, the 4-year EFS was only 74% in patients with combined positive lymph node status and LOH 1p or 16q. A total of 123 patients (23%) had delayed nephrectomy. Submitted delayed nephrectomy histology showed anaplasia (n = 8; excluded from survival analysis); low risk/completely necrotic (n = 7; zero relapses), intermediate risk (n = 63; six relapses), and high-risk/blastemal type (n=7; five relapses). Conclusion Most patients with stage III FHWT had good EFS/overall survival with DD4A and radiation therapy. Combined lymph node and LOH status was highly predictive of EFS and should be considered as a potential prognostic marker for future trials.

Project description:The gene expression patterns of favorable histology Wilms tumors (FHWT) that relapsed were compared with those that did not relapse using oligonucleotide arrays; Description: 250 FHWT of all stages enriched for relapses treated on National Wilms Tumor Study 5 passed quality parameters and were suitable for analysis using oligonucleotide arrays. Relapse risk stratification utilized Support Vector Machine; two and ten fold cross-validation was applied. The number of genes associated with relapse was less than that predicted by chance alone for 106 patients (32 relapses) with stages I and II FHWT and no further analyses were performed. This number was greater than expected by chance for 76 local stage III patients. Cross validation including an additional 68 local stage III patients (total 144 patients, 53 relapses) demonstrated that classifiers for relapse composed of 50 genes were associated with a median sensitivity of 47%, specificity 70%, and total error rate of 38%. Analysis of genes differentially expressed in relapse patients revealed apoptosis, Wnt signaling, IGF pathway, and epigenetic modification to be mechanisms important in relapse. Potential therapeutic targets include FRAP/MTOR and CD40. Experiment Overall Design: 144 stage 3 FHWT, with fifty-three relapses (cases) and ninety-one non-relapses (controls) with a minimum of three years follow-up, included all relapses and a 30% random selection of non-relapses for which frozen tumor tissue was available who passed all quality control parameters. The NWTS-5 protocol was approved by the review boards of institutions that registered patients. Histological diagnosis and local stage were confirmed by central review. Experiment Overall Design: Quality control steps taken: Experiment Overall Design: 1. Samples were snap frozen immediately following surgery and were mailed on dry ice to the Tumor Bank and retained at -80C. Experiment Overall Design: 2. Frozen sections were evaluated histologically and tumors with less than 80% viable tumor cellularity were excluded. Experiment Overall Design: 3. Array images were assessed by eye to confirm scanner alignment and the absence of significant bubbles or scratches. Experiment Overall Design: 4. Samples for which the 3'/5' ratios for GAPDH were greater than 3.2 were excluded. Experiment Overall Design: 5. The BioB spike controls were confirmed as present; BioC, BioD and cre were confirmed as increasing intensity. Experiment Overall Design: 6. When scaled to a target intensity of 2500, scaling factors were between 12 and 53; background levels were 34 â 115: Q values were 1.3 â 3.7 and mean intensities were within acceptable limits. Experiment Overall Design: 7. The range of percent present calls was from 38% to 52%. Experiment Overall Design: 8. Verification of gene expression was performed utilizing quantitative RT-PCR for five genes. Â Â Experiment Overall Design: Statistical Analysis: Positional-dependent-nearest-neighbor model (PDNN) software was used to translate the scanned images into expression analysis files and to normalize the data across all arrays (http://odin.mdacc.tmc.edu/~zhangli/PerfectMatch/). Genes with maximum expression less than a log scale of 6 across all tumors and Affymetrix control genes were excluded, resulting in 20,931 probe sets for analysis. Support Vector Machine (SVM) as developed by Chang and Lin (http://www.csie.ntu.edu.tw/~cjlin/libsvm) and implemented in an R software package, e1071 was chosen for relapse risk stratification using the p-value of the t-test comparison between case and control to select the genes. Using all 144 tumors, 109 genes were identified with p-value <0.001 and are provided in the data table labelled "t-test comparison between case and control" (ie, Supplemental table 2, in related publication)." Two and ten fold cross validations were utilized to investigate the ability of classifiers established in randomly selected training set to predict relapse in an independent test set comprised of the remaining tumors. For two-fold cross validation, the dataset was randomly divided 500 times into training and corresponding test sets of equal size, each including half the patients who relapsed. A classifier for relapse was identified for each training set and used to assign tumors in the corresponding test set to low and high risk categories. The training and test sets were then swapped. The number of top K genes in each classifier evaluated ranged from 1-150. Therefore, a total of 150,000 different classifiers were developed, one for each value of K from 1-150, for each of the 1,000 (500*2) training sets. For ten-fold cross validation the dataset was randomly divided 500 times into ten groups of approximately equal size. Each group included approximately the same number of relapses. For each such group, a classifier was built with the remaining 9/10 of the samples and then used to categorize tumors in the group as low or high risk; the process was repeated until all tumor samples were categorized as low or high risk. For all the cross validation procedures, to avoid gene-selection bias, classifiers were completely rebuilt in each cross validation iteration.

Project description:Purpose The National Wilms Tumor Study (NWTS) treatment of favorable histology Wilms tumor with lung metastases was vincristine/dactinomycin/doxorubicin (DD4A) and lung radiation therapy (RT). The AREN0533 study applied a new risk stratification and treatment strategy to improve event-free survival (EFS) while reducing exposure to lung RT. Methods Patients with favorable histology Wilms tumor and isolated lung metastases showing complete lung nodule response (CR) after 6 weeks of DD4A continued receiving chemotherapy without lung RT. Patients with incomplete response (IR) or loss of heterozygosity at chromosomes 1p/16q received lung RT and four cycles of cyclophosphamide/etoposide in addition to DD4A drugs (Regimen M). AREN0533 was designed to preserve a 4-year EFS of 85% for lung nodule CR and improve 4-year EFS from 75% to 85% for lung nodule IR. Results Among 292 assessable patients, 133 had CR and 159 had IR. For patients with CR, 4-year EFS and overall survival (OS) estimates were 79.5% (95% CI, 71.2% to 87.8%) and 96.1% (95% CI, 92.1% to 100%), respectively. Expected versus observed event rates were 15% and 20.2% ( P = .052), respectively. For patients with IR, 4-year EFS and OS estimates were 88.5% (95% CI, 81.8% to 95.3%) and 95.4% (95% CI, 90.9% to 99.8%), respectively. Expected versus observed event rates were 25% and 12.2% ( P < .001), respectively. Overall, 4-year EFS and OS were 85.4% (95% CI, 80.5% to 90.2%) and 95.6% (95% CI, 92.8% to 98.4%) compared with 72.5% (95% CI, 66.9% to 78.1%; P < .001) and 84.0% (95% CI, 79.4% to 88.6%; P < .001), respectively, in the predecessor NWTS-5 study. Conclusion Excellent OS was achieved after omission of primary lung RT in patients with lung nodule CR, although there were more events than expected. EFS was significantly improved, with excellent OS, in patients with lung nodule IR using four cycles of cyclophosphamide/etoposide in addition to DD4A drugs. The overall AREN0533 treatment strategy yielded EFS and OS estimates that were superior to previous studies.

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Clinicopathologic findings predictive of relapse in children with stage III favorable-histology Wilms tumor.

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Clinicopathologic findings predictive of relapse in children with stage III favorable-histology Wilms tumor.

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