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This collection contains data from the Children’s Oncology Group (COG) Clinical Trial NCT00379340, “Combination ChemotherapyNCT00352534, “Vincristine, Dactinomycin, and Doxorubicin With or Without Radiation Therapy or Observation Only in Treating Young Patients WithYounger Patients Who Are Undergoing Surgery for Newly Diagnosed Stage I, Stage IIIII, or Stage IVIII Wilms' Tumor ," Study Chair: David Dix. Principal Investigator: Conrad Fernandez, MD in Halifax, NS. It was sponsored by NCI and performed by the Children's Oncology Group under study number AREN0533AREN0532. This phase III trial is studying how well combination chemotherapyvincristine, dactinomycin, and doxorubicin with or without radiation therapy worksor observation only to see how well they work in treating youngpatients withundergoing surgery for newly diagnosed stage I, stage IIIII, or stage IV Favorable HistologyIII Wilms' tumor. Select patient-level clinical data from this trial is available via the following link: https://nctn-data-archive.nci.nih.gov/node/ 737.
Trial DescriptionPatients with stage IV favorable histology Wilms tumor (FHWT), the majority of whom have pulmonary metastases, have inferior outcomes compared with those with localized disease. Their treatment is also complicated by a risk of late effects, including cardiac dysfunction, lung toxicity, musculoskeletal and soft tissue defects, and second malignancies. The AREN0533 study applied two separate strategies for risk stratification for patients with Stage III and IV Favorable Histology Wilms Tumor. The first is the identification of patients with pulmonary nodules who can be spared bilateral pulmonary irradiation. Patients with Stage IV favorable histology Wilms tumor have a 4-year event-free survival (EFS) of 75% with chemotherapy and irradiation to sites of metastatic disease (most frequently in the lungs). European investigators are able to spare 75% of their patients with pulmonary nodules from irradiation based on the initial response to chemotherapy. The response of the lung metastases to 6 weeks of chemotherapy consisting of vincristine, dactinomycin, and doxorubicin (Regimen DD-4A) was used to determine if radiation of lung nodules is needed. Patients who had complete disappearance of their lung metastases (or who had tissue confirmation that the nodules do not contain viable tumor) at the Week 6 evaluation were considered rapid responders and continued with DD-4A. Patients who did not have complete resolution of pulmonary nodules by Chest CT underwent pulmonary irradiation and were switched to Regimen M (DD-4A variation with dactinomycin and doxorubicin given on the same day plus cyclophosphamide and etoposide). Central radiology review of the chest CTs were performed on all Stage IV patients with lung metastases at study enrollment and at Week 6. The second risk stratification variable was the allelic loss of 1p and 16q. Patients with Stage III and IV favorable histology Wilms tumor with loss of heterozygosity (LOH) of both 1p and 16q have a 4-yr EFS of 65%. Patients with LOH of 1p and 16q were assigned to Regimen M in an attempt to improve the 4-year EFS of this group of patients to 84%689. Trial Description COG AREN0532 is a treatment study of kidney tumors which have not spread to other parts of the body. 544 very low and standard risk favorable histology Wilms Tumor patients entered the trial. At accrual all patients were Stage I-III and had not received any prior therapy. Dates of therapy were from 2006 to 2013. 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 desired to improve outcomes and reduce late effects. In a 2018 JCO paper, the trial evaluated clinical and biologic variables for patients with stage III FHWT without combined loss of heterozygosity (LOH) at chromosomes 1p and 16q. This paper included 535 patients with stage III disease. Relapse after stage III treatment is associated with an overall survival (OS) of only 50% despite intensive salvage chemotherapy and/or autologous bone marrow transplantation. It is thus highly desirable to identify patients who need augmentation of initial therapy with the hope of preventing relapse. A novel finding in this study was the remarkably strong predictive value of combining LOH and lymph node status. The relapse rate was exceptionally low among patients with tumors that were LOH - and lymph node – negative. However, this trial demonstrated that those with combined lymph node involvement and LOH 1p or 16q had a significantly worse 4-year EFS outcome of 74%. There is a trend toward a poorer 4-year OS in this comparison; however, it is not statistically different. Approximately two thirds of patients had delayed-nephrectomy tissue submitted for central pathology review. Most patients with blastemal-type Wilms tumor but none of seven patients with low-risk/ completely necrotic Wilms tumor experienced relapse, consistent with the findings of the International Society of Pediatric Oncology (SIOP) that histologic response to preoperative chemotherapy plays an important role in predicting outcome. The results of this trial described the overall good outcome of patients with stage III FHWT using DD4A with radiation therapy and identified an association of combined lymph node and LOH status, as well as postchemotherapy, delayed nephrectomy histology, with EFS. Data from the 2018 J Clin Oncol. paper, cited below: 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 less than .01) and absence of LOH 1p or 16q (P less than .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). Trial Outcomes Results of the trial have been reported in the following publications: Dix DB, Seibel NL
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