Metastatic WT has a worse prognosis than localized disease and is less frequently seen in developed countries compared to developing world [6]. This study included 24 metastatic WT patients, constituting 23.3% of all WT patients presented to NCI, Egypt, during the study period. This percentage is similar to that reported in a similar period at Children Cancer Hospital of Egypt (CCHE) which reported 26% of their patients with WT as stage IV [7]. Reports from other developing African countries indicate a higher incidence of stage IV WT among their cohorts, with a reported incidence of 30.9%, 40%, and 42% in Nigeria, Kenya, and South Africa, respectively [8, 9]. While in developed countries, the incidence is relatively lower, with a reported incidence of 12%, 14.9%, and 17% in Children Oncology Group (COG), German study, and International Society of Pediatric Oncology (SIOP), respectively [10, 11]. This high incidence of advanced stages of WT noticed in developing countries could be attributed to several factors such as lack of awareness among caregivers and healthcare professionals regarding early presentations of WT, limited resources and poor access to health care that lead to late presentations, and advanced disease stage at diagnosis.
By the end of this study follow-up period, the 3-year EFS and OS were 48.2% and 54.2%, respectively. Comparable results were reported in similar studies—following SIOP guidelines—in South Africa with 5-year EFS and OS of 54.0% and 58.5%, respectively [12], and 5-year OS of 54.2% in another study following National Wilms Tumor Study Group (NWTSG) guidelines [13]. Another study conducted in Lebanon including only 9 patients treated for metastatic WT reported 3-year EFS of 55.6% and a 3-year OS of 67% [14]. Of note, the study carried out at CCHE reports a lower 3-year EFS of 18.2%, yet with higher 3-year OS of 66%. This might reflect a better salvage rates in their cohorts compared to ours [7].
On the other hand, international studies from developed countries report high survival rates for metastatic WT patients. In an Italian study; 5-year EFS and OS were 72.1% and 82.5%, respectively [15]. Another study in Japan reported a 5-year OS of 86.7% [16]. Also, higher rates were reported by COG and SIOP for stage IV WT patients. The SIOP 2001/GPOH trial reports a 5-year EFS and OS of 73% and 83%, respectively [17]. Similarly, NWTS-5 study reports a 5-year EFS and OS of 72% and 84%, respectively [18]. In 2018, a report from the COG AREN0533 study reported a 4-year EFS and OS of 85.4% and 95.6% respectively for stage IV WT patients (17).
There is some evidence that stage IV patients with local stage III disease have lower survival rates compared to local stage I and II patients. In SIOP 93-01, metastatic WT patients with local stage III had a significantly lower OS of 68% compared with local stage I and II patients (P < .001), and 5-year EFS rates were 82%, 83%, and 57% for patients with local stage I, II, and III disease, respectively (P < .001) [19]. Of note, all of our study patients except for 2 patients had local stage III, a fact that might—in part—explain the relatively lower survival rates of those patients.
Seven out of 9 patients (77.7%) who did an upfront nephrectomy had stage III local disease. This is relatively a high percentage of local stage III among up-front nephrectomy patients when compared to other studies. In UKW-3 trial, the immediate surgery group had 30% of tumors with stage III [20]. Notably, in the CTH and delayed surgery group, only 10% of tumors were stage III [20]. Moreover, in our study, surgical complications were reported in 3/9 patients (33.3%) who had up-front nephrectomy in comparison to one patient (7%) in the CTH and delayed nephrectomy group. A study of NWTSG—on 3335 children who underwent primary nephrectomy—reported surgical complications in 12.7% of patients [21]. The risk of tumor rupture was 15% in NWTSG for primary surgery and 3% for chemotherapy-pretreated cases in SIOP [20]. This was replicated by a randomized study in UK where surgical complications were observed in 14% of the up-front nephrectomy cohort while none of the neo-adjuvant CTH pretreated cases experienced any surgical complications [22]. A review of literature for the SIOP trials—since SIOP 1 trial until SIOP 2001—that focuses on the advantages of preoperative chemotherapy reported that surgery-related complications did not exceed 8% in the pretreated patients [23].
Up-front surgery versus delayed surgery had no statistical significance on outcome, despite high rate of surgical failure upfront. This is because of the poor outcome of the whole group and high rate of progression, and actually there is no evidence that local control can affect outcome of metastatic disease.
Pulmonary and hepatic response
The COG, United Kingdom Children’s Cancer Study Group (UKCCSG), and SIOP trials evaluated different approaches to the management of children with stage IV pulmonary-only FHWT, seeking to avoid the use of whole-lung irradiation (WLI) because of its significant acute and long-term toxicity [24].
In this cohort, there were 2 cases with treatment-related mortality, specifically from severe sepsis. One case was in RCR after week 6 and was on lower doses of chemotherapy (3-drug regimen), while the other patient was on the higher doses of chemotherapy and went into severe neutropenia. Both cases had bacterial growth in their blood cultures together with pulmonary infection. This raises the importance of proper education and counselling for parents and caregivers regarding infection control measures and more importantly regarding early recognition of infectious complications in order to seek medical support when appropriate. Also, there should be close follow-up for the patient condition and their labs to give the proper supportive measures including empirical broad spectrum antibiotics and bone marrow stimulating factors if needed.
In our study, 7 patients (33%) of 21 patients with pulmonary-only FHWT achieved RCR. The SIOP 93-01 conducted a study on 234 patients with only pulmonary metastases, who received 6 weeks of neo-adjuvant 3-drug CTH, followed by nephrectomy. One hundred forty-eight (67.3%) of 220 patients who had complete data achieved RCR with combination CTH alone. An additional 37 patients required surgical resection of one or more pulmonary nodules to achieve RCR [18]. In contrast to the SIOP study, COG reported that only 133 of 292 patients (45.5%) with only pulmonary metastases were in RCR after 6 weeks of CTH [25], a finding possibly related to the administration of lower cumulative doses of doxorubicin during the pre-nephrectomy CTH period [18].
In our study, patients with RCR post 6 weeks of CTH had a better survival outcome compared to those with SIR, although without statistical significance. Of course, such results must be carefully interpreted with consideration to the very small number of studied patient and number of events. In the SIOP 93-01 study, 5-year EFS was 77% for those who achieved complete remission (CR) with CTH only, 84% for those who required surgical resection of residual nodules to achieve CR, 46% for patients with inoperable pulmonary metastases treated without WLI, and 50% for those with inoperable pulmonary metastases treated with WLI [18]. So, surgery should be encouraged for any accessible residual pulmonary nodules after neo-adjuvant CTH. In NWTSG-5, patients with stage IV FHWT with metastases limited to the lung had 5-year EFS of 85% in the setting of complete lung nodule response (CR) by day 70 versus 74% with incomplete lung nodule response, with all patients treated with 3-drug regimen [26].
A recent COG study reported that FHWT patients with week 6 lung nodule RCR treated without lung RT had 4-year EFS and OS of 79.5% and 96.1%, respectively. While for patients with SIR, 4-year EFS and OS estimates were 88.5% and 95.4%, respectively, with more intensified CTH (5-drug regimen) together with WLI [25].
As for patients with hepatic metastases, both the NWTS and the SIOP analyses show that patients with residual liver disease after treatment with CTH and/or RT that could be completely resected did well, suggesting that there is a role for complete surgical resection of residual metastases after adjuvant therapy [27].
Local radiotherapy
As per protocol, irradiation should start at day 10–14 of therapy (with surgery done at day zero). In the current study, the median time to start radiotherapy after surgery was 19 days, with only 7/21 patients (33.3%) started their RT within 14 days from surgery date. This delay—in most cases—resulted from the burden of large numbers of patients relative to the capacity of RT machines. The National Cancer Database (NCDB) reports that for non-metastatic patients, surgery to radiotherapy interval ≤ 14 days correlates with improved overall survival. However, no association was noted for patients with metastases [28].