Risk stratification is increasingly sophisticated using tools such as molecular tests, genetic analysis and large clinical trials.1,11,15
Current prognostic factors used by the Children's Oncology Group (COG) renal tumors committee include; pathology (favorable vs. unfavorable), stage (I–IV), age less then 2 years and tumor weight less then 550 grams for children with stage I or II, and loss of heterozygosity at loci on 1p and 16q.11,16,17
Subtypes of stage IV disease such as stage IV due to liver metastasis and stage IV due to pulmonary metastasis have not been identified previously as independent prognostic factors. What has been reported is that there is no difference in survival according to metastatic site (liver +/− lung vs. lung only) if present prior to treatment. By contrast, patients who developed liver metastases during or after treatment had an especially poor chance for survival as compared with those who developed lung deposits at those times.18
We formulated three hypotheses to address liver metastasis in a child with a Wilms tumor. The first was that children with Wilms tumor metastatic to the liver had outcomes similar to those with pulmonary metastasis. In this analysis of 129 patients from NWTS-4 and -5, we did not find that liver metastasis was an independent adverse prognostic factor for children with stage IV FH Wilms tumor. Our results, which are consistent with previous NWTS reports, would not support a more aggressive initial surgical approach for a child with Wilms tumor and liver metastasis. Varan et al. reported poor outcomes of patients with liver metastases.6
This single institutional report included 542 patients treated over thirty years, 57 of whom had stage IV disease, including 18 with liver metastases. The overall survival rate was 50.2% for those with lung metastases compared to 16.6% for those with liver metastases. The overall survival was only 56.2% for those treated after 1990 compared to 75% EFS for patients with stage IV disease in the present study. This difference suggests that other factors may have contributed to the poorer outcomes of the patients reported by Varan et al., such as timing and dosing of chemotherapy and radiation. These authors acknowledged the limitations of their single institution report of a rare disease compared to that of a large randomized controlled trial.
The second hypothesis was that survival for children with Wilms tumor and hepatic metastasis was equivalent with or without primary resection of the hepatic tumors. We assessed the therapy and outcome of patients with regard to treatment of their hepatic metastases. Although EFS for the patients who had primary resection of their liver metastases was higher than for those not resected, this was not statistically significant. If the cohort of patients with a primary resection of their liver metastases had been larger, we might have been able to demonstrate that overall outcome was improved. However, these patients may be highly selected (e.g. ease with which surgery could result in complete resection of liver disease). The extent of the hepatic metastatic disease and other factors which lead the surgeon to proceed with primary resection may be additional predictors of a favorable outcome. Thus, the improved outcome may be the result of having limited hepatic disease and being a more appropriate surgical candidate. Furthermore we did not conduct central radiology review and therefore cannot provide an estimate of how many could have undergone primary resection (as is the current practice). Only a prospective study in which patients were randomized between immediate versus delayed resection of liver metastases could answer this question.
The SIOP/GPOH group reported the outcomes of 29 patients treated on SIOP93-01/GPOH and SIOP2001/GPOH that enrolled 1,365 patients between April 1994 and September 2004. The five-year OS was 62.6% for those with hepatic metastases while the OS for all stage IV patients was 76.3%. The difference was not analyzed statistically. The SIOP histology and classification of these cases included four low risk, 18 intermediate risk, four high risk (two with diffuse anaplasia). Three tumors could not be classified because death occurred before therapy was started. Within the group of 29 children with hepatic involvement at presentation, 14 did not undergo a liver resection. In 4/29 (13%) patients, the liver metastasis responded to chemotherapy (three of whom are still alive). This response to chemotherapy was similar to our data in which 14.5%(14/96) of the cases responded to treatment of the liver metastasis with chemotherapy only. Fifteen patients had liver surgery (primary liver resection – 11; complete resection - 6 and incomplete resection – 5). All six who had a complete resection survived. Four patients underwent liver resection after adjuvant therapy, three of whom had a complete resection and all three survived. The improved survival for their patients with complete resection may reflect the same selection bias as for the NWTSG group. Alternatively, it may suggest that those tumors that responded to chemotherapy and were amenable to resection had a more favorable biology.
In both our study and the SIOP study, adult patients comprised part of the study population. In our study less then 10% were over 12 years old and 3% were over 16. In some studies older age itself has been an adverse prognostic factor19–21
although other studies showed that adults treated by stage-appropriate combined modality therapy had similar outcomes to children.22,23
A subanalysis of the liver lesions comparing those who received only chemotherapy to those who received chemotherapy and radiotherapy (with and without boost) was also performed. There was no statistical difference in survival based on the use of abdominal radiation, but the cohort of patients for analysis was small (N=14). There was no difference in outcomes for those children who received abdominal boost radiation compared to those who did not. However the doses of boost radiation were not uniform, making any assessment of efficacy difficult.
The use of radiation therapy is a concern for both short term hepatic toxicity and long term development of complications. Hepatotoxicity is a problem for children being treated for Wilms tumor.24–26
Both chemotherapy (dactinomycin) and abdominal irradiation have been shown to be important factors. Previous reports have shown that the risk of developing hepatic toxicity is significantly increased in patients receiving abdominal irradiation involving the liver, with a relative risk (RR) of 2.6.24
Long term complications from abdominal radiation are musculoskeletal problems (muscular hypoplasia, limb length inequality, kyphosis, and iliac wing hypoplasia) and second malignancy.27
Two studies of long term cancer survivors have shown that radiation is the principal contributing factor for second malignancy in patients treated for Wilms tumors.28,29
We could not detect based on the sample size available, whether routine use of a radiation boost to the liver impacted outcome. The absence of a statistically significant effect does not mean that a significant effect is not present – only that we cannot detect it.
The third hypothesis was that resection of hepatic metastasis from Wilms tumor was associated with a significant risk of surgical complications. The data for surgical complications could not be accurately analyzed in this retrospective review. Surgery was not one of the primary questions addressed in the protocols thus the data were not collected prospectively.
The SIOP/GPOH report recommended an aggressive initial surgical approach to patients with liver disease.7
It is essential to note the SIOP patients receive preoperative chemotherapy before nephrectomy and or resection of metastatic lesions. This is in contrast to the patients in this report treated with immediate nephrectomy with or without resection of metastatic lesions before chemotherapy with or without radiation therapy is given.
There are limitations in both the report from SIOP and the present study. We excluded 10 patients with anaplastic histology because of the small numbers, however if included the overall outcomes would not have changed. Furthermore this is a retrospective study and assessing early versus delayed liver resection was not part of the study objectives, therefore to definitively answer this question a future study with this as an objective would need to be conducted. The SIOP study did not report OS based on site of metastasis. The 5-year survival for all SIOP stage IV patients was similar to that of similar patients in the NWTSG studies. None of the data reported suggested that an initial aggressive surgical resection of the liver lesions in these patients was warranted. However, when considering liver resection as part of the initial therapy, complete resection was beneficial as all patients who had a complete resection survived compared to only one who had an incomplete resection. Nine of the 15 (66%) who had liver resection survived compared to 50% (7/14) of those who did not undergo liver resection. We do not know if this difference was statistically significant, why the 14 patients did not undergo a liver resection, nor what role adjuvant therapy had in converting an unresectable metastasis to a resectable one. Those that did not resolve with chemotherapy may have had more unfavorable histology.
In the SIOP study, tumor burden and response to therapy were not presented. We could not reliably comment in the present study on the extent of response of liver metastases to treatment based on the subsequent radiology reports.
The current study is the largest series in which the treatment and outcomes of patients with Wilms tumor metastatic to the liver were analyzed. We found no evidence that the presence of liver metastases was an adverse prognostic factor for patients with stage IV metastatic FH Wilms tumor treated on NWTS-4 and -5. There was no evidence to support an aggressive primary resection of the hepatic tumors. The impact of boost radiation to liver metastases on survival was not resolved. In both the present and the SIOP analyses, those patients with residual liver disease after treatment with chemotherapy and/or radiation that could be completely resected did well, suggesting there is a role for complete surgical resection of residual metastases after adjuvant therapy.