Breast cancer in female survivors of Wilms tumor: a report from the national Wilms tumor late effects study.

BACKGROUND: The standard treatment of pulmonary metastases in patients with Wilms tumor (WT) includes 12-gray radiotherapy (RT) to the entire chest. To the authors' knowledge, the risk of breast cancer (BC) in a large cohort of female survivors of WT has not previously been reported. METHODS: A total of 2492 female participants in National Wilms Tumor Studies 1 through 4 (1969-1995) were followed from age 15 years through the middle of 2013 for incident BC. The median age at the time of last contact was 27.3 years. The authors calculated cumulative risk at age 40 years (CR40), hazard ratios (HR) by Cox regression, standardized incidence ratios (SIRs) relative to US population rates, and 95% confidence intervals (95% CIs). RESULTS: The numbers of survivors with invasive BC divided by the numbers at risk were 16 of 369 (CR40, 14.8% [95% CI, 8.7-24.5]) for women who received chest RT for metastatic WT, 10 of 894 (CR40, 3.1% [95% CI, 1.3-7.41]) for those who received only abdominal RT, and 2 of 1229 (CR40, 0.3% [95% CI, 0.0-2.3]) for those who received no RT. The SIRs for these 3 groups were 27.6 (95% CI, 16.1-44.2) based on 5010 person-years (PY) of follow-up, 6.0 (95% CI, 2.9-11.0) based on 13,185 PY of follow-up, and 2.2 (95% CI, 0.3-7.8) based on 13,560 PY of follow-up, respectively. The risk was high regardless of the use of chest RT among women diagnosed with WT at age ≥10 years, with 9 of 90 women developing BC (CR40, 13.5% [95% CI, 5.6-30.6]; SIR, 23.6 [95% CI, 10.8-44.8] [PY, 1463]). CONCLUSIONS: Female survivors of WT who were treated with chest RT had a high risk of developing early BC, with nearly 15% developing invasive disease by age 40 years. Current guidelines that recommend screening only those survivors who received ≥20 Gy of RT to the chest might be reevaluated.

Pulmonary disease after treatment for Wilms tumor: a report from the national wilms tumor long-term follow-up study.

PURPOSE: This study was undertaken to evaluate the incidence of pulmonary disease among patients treated with radiation therapy (RT) for pulmonary metastases (PM) from Wilms tumor (WT). PATIENTS AND METHODS: We reviewed records of 6,449 patients treated on National Wilms Tumor Studies-1, -2, -3, and -4 whose flow sheets or annual status reports documented one of several pulmonary conditions. Cases were fully evaluable if pulmonary function test (PFT) results were available, pulmonary fibrosis was identified on a chest radiograph or was listed as the primary or a contributing factor to death. Partially evaluable cases were those for whom PFT results could not be obtained. We evaluated the relationship between RT factors and the occurrence of pulmonary disease using hazard ratios (HRs) and cumulative incidence, treating death as a competing risk. RESULTS: Sixty-four fully evaluable and 16 partially evaluable cases of pulmonary disease were identified. The cumulative incidence of pulmonary disease at 15 years since WT diagnosis was 4.0% (95% confidence interval [CI] 2.6-5.4%) among fully evaluable and 4.8% (95% CI 3.3-6.4%) among fully and partially evaluable patients who received lung RT for PM at initial diagnosis. Rates of pulmonary disease were substantially higher among those who received lung RT for PM present at initial diagnosis or relapse compared to those who received no RT or only abdominal RT (HR 30.2, 95% CI 16.9-53.9). CONCLUSION: The risk of pulmonary disease must be considered in evaluating the risk:benefit ratio of lung RT for the management of PM from WT.

Treatments and outcomes for end-stage renal disease following Wilms tumor.

BACKGROUND: Little is known about treatment outcomes for children who have end-stage renal disease (ESRD) after treatment for Wilms tumor (WT). METHODS: Time-to-transplant, graft failure, and survival outcomes were examined for 173 children enrolled on the National Wilms Tumor Study who developed ESRD. RESULTS: Fifty-five patients whose ESRD resulted from progressive bilateral WT (PBWT) experienced high early mortality from WT that limited their opportunity for transplant (47% at 5 years) and survival (44% at 10 years) in comparison to population controls. The 118 patients whose ESRD was due to other causes (termed "chronic kidney disease"), many of whom had WT-associated congenital anomalies, had transplant (77% at 5 years) and survival (73% at 10 years) outcomes no worse than those for population controls. Graft failure following transplant was comparable for the two groups. Minority children had twice the median time to transplant as non-Hispanic whites and twice the mortality rates, also reflecting population trends. CONCLUSIONS: In view of the continuing high mortality in patients with ESRD, and the dramatic improvement in outlook following kidney transplantation, re-evaluation of current guidelines for a 2-year delay in transplant following WT treatment may be warranted.

Risk factors for end stage renal disease in non-WT1-syndromic Wilms tumor.

PURPOSE: We assessed risk factors for end stage renal disease in patients with Wilms tumor without known WT1 related syndromes. We hypothesized that patients with characteristics suggestive of a WT1 etiology (early onset, stromal predominant histology, intralobar nephrogenic rests) would have a higher risk of end stage renal disease due to chronic renal failure. We predicted a high risk of end stage renal disease due to progressive bilateral Wilms tumor in patients with metachronous bilateral disease. MATERIALS AND METHODS: End stage renal disease was ascertained in 100 of 7,950 nonsyndromic patients enrolled in a National Wilms Tumor Study during 1969 to 2002. Risk factors were evaluated with cumulative incidence curves and proportional hazard regressions. RESULTS: The cumulative incidence of end stage renal disease due to chronic renal failure 20 years after Wilms tumor diagnosis was 0.7%. For end stage renal disease due to progressive bilateral Wilms tumor the incidence was 4.0% at 3 years after diagnosis in patients with synchronous bilateral Wilms tumor and 19.3% in those with metachronous bilateral Wilms tumor. For end stage renal disease due to chronic renal failure stromal predominant histology had a HR of 6.4 relative to mixed (95% CI 3.4, 11.9; p<0.001), intralobar rests had a HR of 5.9 relative to no rests (95% CI 2.0, 17.3; p=0.001), and Wilms tumor diagnosis at less than 24 months had a HR of 1.7 relative to 24 to 48 months and 2.8 relative to greater than 48 months (p=0.003 for trend). CONCLUSIONS: Metachronous bilateral Wilms tumor is associated with high rates of end stage renal disease due to surgery for progressive Wilms tumor. Characteristics associated with a WT1 etiology markedly increased the risk of end stage renal disease due to chronic renal failure despite the low risk in non-WT1 syndromic cases overall.

Early and late mortality after diagnosis of wilms tumor.

PURPOSE: To assess rates and causes of mortality in patients with Wilms tumor (WT). METHODS: Through 2002, 6,185 patients enrolled onto the National Wilms Tumor Study between 1969 and 1995 were actively observed. Deaths were classified on the basis of medical records as the result of original disease, late effects (including second malignant neoplasms [SMNs], cardiac causes, pulmonary disease, and renal failure), or other causes. Standardized mortality ratios (SMRs) and Cox regression were used to assess the effects of sex, age, and calendar period of diagnosis on mortality. RESULTS: Within 5 years of WT diagnosis, 819 deaths occurred, and 159 deaths occurred among 4,972 known 5-year survivors. The SMR was 24.3 (95% CI, 22.6 to 26.0) for the first 5 years, was 12.6 (95% CI, 10.0 to 15.7) for the next 5 years, and remained greater than 3.0 thereafter. For deaths in the first 5 years, the mortality risk decreased by 5-year calendar period of diagnosis (rate ratio [RR] = 0.78 per period). No such trend occurred for later deaths. Among 5-year survivors, 62 deaths were attributed to late effects of treatment or disease, including 27 to SMNs. A trend of decreased risk with calendar period of diagnosis was observed for late-effects mortality (RR = 0.86; 95% CI, 0.67 to 1.10) and for SMN mortality (RR = 0.82; 95% CI, 0.55 to 1.21). CONCLUSION: Although the survival outlook for WT patients has improved greatly over time, survivors remain at elevated risk for death many years after their original diagnosis.

Renal failure does not preclude cure in children receiving chemotherapy for Wilms tumor: a report from the National Wilms Tumor Study Group.

BACKGROUND: Children with Wilms tumor can develop renal failure during treatment. Since there are few published data concerning the appropriate chemotherapy for this situation, we reviewed the experience of children who developed renal failure while being treated on National Wilms Tumor Study Group (NWTSG) studies 1-4 (1969-1994). PATIENTS AND METHODS: Data files in the NWTSG Data Center for all patients with Wilms tumor were screened. Patient demographics and tumor and treatment data were abstracted from those who developed renal failure. RESULTS: Twenty-eight of 5,910 (0.47%) children with Wilms tumor registered on NWTSG studies I through IV (1971-1994) were treated with chemotherapy after developing renal failure. Among these patients vincristine at full dose (0.05 mg/kg dose) did not increase the risk of severe toxicity. Dactinomycin (full dose: 15 mcg/kg day x 5) increased the risk for severe neutropenia when given at 75-100% of full dose. There was no compelling evidence for increased toxicity of doxorubicin when given at 100% versus 50% dosing (full dose: 20 mg/m(2) day x 3), but the number of patients analyzed was small. The overall survival percentage was 39%, but 64% for those patients who were in their initial treatment phase at the time of renal failure. CONCLUSION: The data suggest that, in the setting of renal failure, reduction of dosing is not necessary for the three main agents used for treatment of newly diagnosed Wilms tumor, and cure is not precluded. Accurate pharmacologic and pharmacokinetic studies are needed for any patient being treated while in renal failure.

Bilateral Wilms' tumors with progressive or nonresponsive disease.

BACKGROUND: To provide guidelines for future cooperative group trials, we reviewed the outcomes of children with bilateral Wilms' tumors (BWTs) treated on National Wilms Tumor Study-4 (NWTS-4) who had progressive or nonresponsive disease (PNRD). METHODS: NWTS-4 enrolled 3335 patients from August 1986 to September 1994 including 188 patients with BWT (5.6%). Treatment and outcome data were collected on patients with BWT. Treatment guidelines were outlined in the protocol, but patients were not on study. RESULTS: Thirty-eight children with BWT had PNRD. Preoperative chemotherapy was given for a median of 7 months (range, 2-29 months) before definitive resection. After the initial chemotherapy regimen, 36 children went on to a second regimen, and of these, 21 children received a third regimen before resection. Eleven patients received irradiation to one or both kidneys. Pathology at resection revealed previously undiagnosed anaplasia in 3 patients (2 diffuse and 1 focal) treated for 14, 15, and 15 months before resection. A fourth patient developed a diffusely anaplastic tumor 13 months after therapy. Other pathological findings included rhabdomyomatous (4 patients) or differentiated stromal elements (10 patients) and complete necrosis (1 patient). Ten kidneys from 7 patients lacked biopsy at presentation or pathology review of those specimens. CONCLUSIONS: BWT patients with PNRD received prolonged courses of chemotherapy. Early and sequential biopsies to establish the reason for failure to respond should be obtained. This will identify anaplastic tumors managed best by early nephrectomy and intensive chemotherapy and will also distinguish differentiated tumors that are best managed with early resection, but less intensive therapy after nephrectomy.