**4. Secondary malignant neoplasms**

With the increase in survivorship in children with WT, there has been an accompanying increase in secondary malignant neoplasms (SMN). Among long-term WT survivors in the CCSS cohort, the cumulative incidence of SMN was 3.0% at 25 years. The most common SMNs were soft tissue sarcomas which occurred in six survivors. Five WT survivors had confirmed breast cancer. RT exposure of the breast in these patients ranged from 13 to 17.5 Gy. There were four bone tumors: two osteogenic sarcomas; one Ewing sarcoma; and one other bone tumor. The other SMNs were four adenocarcinomas, three melanoma, three thyroid cancers, two lymphoid leukemias, one medulloblastoma, and seven other cancers including one secondary renal cell carcinoma. SMNs were the most common cause of death in long-term WT survivors [3]. A SEER database review noted an incidence of SMN in patients treated for WT at 0.6% at 10 years, increasing to 1.6% at 20 years and 3.8% at 30 years [19]. A combined cohort study of patients from the NWTS, CCSS British and Nordic national registries provided data on 13,351 subjects diagnosed under the age of 15 in 1960 or later followed for a median of 11.6 years. After 169,641 person-years (PY) of observation

### *Long-Term Toxicities among Wilms Tumor Survivors DOI: http://dx.doi.org/10.5772/intechopen.110130*

through 2005, 174 solid tumors (exclusive of basal cell carcinomas) and 28 leukemias were ascertained in 195 subjects. Age-specific incidence of secondary solid tumors increased from approximately 1 case per 1000 PY at age 15 to 5 cases per 1000 PY at age 40. The cumulative incidence of solid tumors at age 40 was 6.7%. Leukemia risk, by contrast, was highest during the first 5 years following WT diagnosis. The Standardized incidence ratios (SIRs) for solid tumors and leukemias were 5.1 and 5.0, respectively. Among solid tumors, the most common were cancers of the digestive organs, most commonly hepatocellular carcinoma with 8 cases. There were 23 cases of breast cancer, 15 thyroid cancers and 11 osteosarcomas. There was a demonstrated difference in the observed incidence over time. At 10 years from diagnosis, the incidence was 1 SMN per 1000 survivors per year which increased to 5–6 solid tumors per 1000 survivors per year by 35 years after diagnosis. Also noted was a 49% increase in standardized incidence ratio (SIR) for SMN for patients diagnosed and treated after the age of 5 years. The occurrence of a solid SMN dramatically affected survival prospects [20]. The Mayo Clinic reported on 8295 patients treated from 1970 to 2020 for pediatric cancers. Eleven patients were identified to have developed subsequent renal neoplasms. Six of these eleven were patients previously treated for WT with clear cell sarcoma being the most common secondary renal cancer [21].

The use of RT and doxorubicin has been clearly associated with higher risk of SMNs. In the British Childhood Cancer Survivor Study, the majority of solid tumors (35 of 39, 89.7%) of the thorax, abdomen or pelvis developed within irradiated fields [22]. In the NWTS series, RT increased the risk of a SMN (SIR, 1.43/10 Gy) and doxorubicin potentiated the RT effect. Among 234 patients who received doxorubicin and > 35 Gy of abdominal RT, the SIR was 36. The changes in RT doses in NWTS protocols from 40 Gy in the 1960s to 10 Gy in the 1990s was also associated with a decrease in time-specific incidence rates of SMNs [23].

Due to the utilization of WLI in the management of WT with lung metastases, the incidence of breast cancer in WT survivors is significantly increased compared to the general population. A report from the NWTS reported the incidence and risk factors for breast cancer among 2492 female patients treated from 1969 to 1995. There were 29 cases of invasive breast cancer and 6 cases of ductal carcinoma in-situ, representing a SIR of 9.1 for invasive disease and cumulative risk at age 40 (CR40) of 4.5%. Among women who had chest RT, the SIR was 27.6 and CR40 was 14.8%. The majority of patients received 12Gy. WART was associated with a SIR of 7.2 and flank only RT had a SIR of 5.8. The CR40 was 3.1% for female patients who received abdominal RT. Patients not undergoing RT had a SIR of 2.2., The SIR for DCIS in patients undergoing chest or abdominal RT was 9.2, comparable to that for invasive disease [24]. Subsequent analysis of this data set included an assessment of male breast cancer and no excess risk was identified [25]. Among 20,276 CCSS survivors of which 6498 women were eligible for analysis, 95 women had 111 confirmed cases of breast cancer. The majority (65 patients) were treated for Hodgkin lymphoma. Only 3 patients were treated for WT with 2 of the 3 cases receiving chest RT [26].
