Norman E. Breslow

Surgery-related factors and local recurrence of Wilms tumor in National Wilms Tumor Study 4.

OBJECTIVE To assess the prognostic factors for local recurrence in Wilms tumor. SUMMARY BACKGROUND DATA Current therapy for Wilms tumor has evolved through four studies of the National Wilms Tumor Study Group. As adverse prognostic factors were identified, treatment of children with Wilms tumor has been tailored based on these factors. Two-year relapse-free survival of children in the fourth study (NWTS-4) exceeded 91%. Factors once of prognostic import for local recurrence may lose their significance as more effective therapeutic regimens are devised. METHODS Children evaluated were drawn from the records of NWTS-4. A total of 2482 randomized or followed patients were identified. Local recurrence, defined as recurrence in the original tumor bed, retroperitoneum, or within the abdominal cavity or pelvis, occurred in 100 children. Using a nested case-control study design, 182 matched controls were selected. Factors were analyzed for their association with local failure. Relative risks and 95% confidence intervals were calculated, taking into account the matching. RESULTS The largest relative risks for local recurrence were observed in patients with stage III disease, those with unfavorable histology (especially diffuse anaplasia), and those reported to have tumor spillage during surgery. Multiple regression analysis adjusting for the combined effects of histology, lymph node involvement, and age revealed that tumor spillage remained significant. The relative risk of local recurrence from spill was largest in children with stage II disease. The absence of lymph node biopsy was also associated with an increased relative risk of recurrence, which was largest in children with stage I disease. The survival of children after local recurrence is poor, with an average survival rate at 2 years after relapse of 43%. Survival was dependent on initial stage: those who received more therapy before relapse had a worse prognosis. CONCLUSIONS This study has demonstrated that surgical rupture of the tumor must be prevented by the surgeon, because spills produce an increased risk of local relapse. Both local and diffuse spills produce this risk. Stage II children with local spill appear to require more aggressive therapy than that used in NWTS-4. The continued critical importance of lymph node sampling in conjunction with nephrectomy for Wilms tumor is also established. Absence of lymph node biopsy may result in understaging and inadequate treatment of the child and may produce an increased risk of local recurrence.

Treatment of Wilms tumor relapsing after initial treatment with vincristine, actinomycin D, and doxorubicin. A report from the national Wilms tumor study group

We evaluated the use of alternating cycles of cyclophosphamide/etoposide and carboplatin/etoposide in children entered on National Wilms Tumor Study (NWTS)‐5 who were diagnosed between August 1, 1995 and May 31, 2002 and who relapsed after chemotherapy with vincristine, actinomycin D, and doxorubicin (VAD) and radiation therapy (DD‐4A).

Clinical Significance of Pulmonary Nodules Detected by CT and Not CXR in Patients Treated for Favorable Histology Wilms Tumor on National Wilms Tumor Studies-4 and -5: A Report from the Children's Oncology Group

Metastatic lung disease in Wilms tumor (WT) patients was traditionally identified by chest radiograph (CXR). It is unclear whether patients with small lesions, detectable only by computed tomography (“CT‐only” lesions), require the more intensive therapy, including doxorubicin and lung irradiation, given to patients with metastases detectable by CXR.

Reply to Wilms tumor and breast cancer

We appreciate this opportunity to respond to the question raised by Drs Lehrer and Rosenzweig and by others regarding Wilms tumor and male breast cancer. Males account for under 1% of breast cancers in the United States and the disease is especially rare in younger men.(1) Using data from the 9th (1973-1991), 13th (1992-1999) and 18th (2000-2010) SEER registries, we calculated incidence rates of invasive + in-situ breast cancer for men and women under age 40 of 0.0433 and 13.99 per 100,000 person-years, respectively. This yielded an M:F ratio of 0.0031. Assuming that standardized incidence ratio (SIR) for male survivors of Wilms tumor was the same as we found for females, namely 9.2, we made a rough calculation of the number of male breast cancer cases we might have expected had we included men in our study. This calculation also assumed that the number of person-years of observation among males equaled that among females. The latter assumption was conservative since fewer males than females were enrolled on the National Wilms Tumor Studies, whereas death rates for teenage and young adult males are generally slightly higher. We multiplied the number of female cases observed, namely 29 invasive + 6 in-situ = 35, by the M:F ratio to arrive at an expected number of male breast cancer cases of 0.1. Using Poisson statistics, the probability of observing one or more cases of male breast cancer was also only 0.1. In fact, none were observed. Thus the answer is no to the question whether men as well as women had an increased risk of breast cancer after Wilms tumor and radiation in our study. Had we restricted the calculation above to patients receiving chest radiotherapy, assuming that the 30 fold increase we observed for females also held for males, we would have expected only 0.0031×22 = 0.07 cases. More accurately, however, the study was simply uninformative about male breast cancer. We think it likely that chest irradiation for Wilms tumor increases the risk of subsequent breast cancer in men, just as it does in women. However, a much larger population of Wilms tumor survivors, and/or follow-up through the advanced ages at which male breast cancer is more frequent, would be needed to prove the point.

Secondary malignant neoplasms after Wilms tumor

A combined cohort of 8,884 North American, 2,893 British and 1,574 Nordic subjects with Wilms tumor (WT) diagnosed before 15 years of age during 1960–2004 was established to determine the risk of secondary malignant neoplasms (SMN). After 169,641 person‐years (PY) of observation through 2005, 174 solid tumors (exclusive of basal cell carcinomas) and 28 leukemias were ascertained in 195 subjects. Median survival time after a solid SMN diagnosis 5 years or more from WT was 11 years; it was 10 months for all leukemia. Age‐specific incidence of secondary solid tumors increased from approximately 1 case per 1,000 PY at age 15 to 5 cases per 1,000 PY at age 40. The cumulative incidence of solid tumors at age 40 for subjects who survived free of SMNs to age 15 was 6.7%. Leukemia risk, by contrast, was highest during the first 5 years after WT diagnosis. Standardized incidence ratios (SIRs) for solid tumors and leukemias were 5.1 and 5.0, respectively. Results for solid tumors for the 3 geographic areas were remarkably consistent; statistical tests for differences in incidence rates and SIRs were all negative. Age‐specific incidence rates and SIRs for solid tumors were lower for patients whose WT was diagnosed after 1980, although the trends with decade of diagnosis were not statistically significant. Incidence rates and SIRs for leukemia were highest among those diagnosed after 1990 (p‐trend = 0.003). These trends may reflect the decreasing use of radiation therapy and increasing intensity of chemotherapy in modern protocols for treatment of WT.

Surgery-Related Factors and Local Recurrence of Wilms Tumor in National Wilms Tumor Study 4

From the *Department of Surgery, Childrens Hospital, Boston, Massachusetts; tDepartment of Biostatistics, University of Washington, Seattle, Washington; tDivision of Pediatric Surgery, University of Texas-Houston Medical School, Houston, Texas; §Department of Pediatric Surgery, Denver Childrens Hospital, Denver, Colorado; JINational Wilms Tumor Study Group Data & Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington; ¶Department of Pathology, Loma Linda University, Loma Linda, California; #Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; and **Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, New York, and the School of Medicine and Biomedical Sciences, University at Buffalo, State University ofNew York, Buffalo, New York