Treatment of recurrent Wilms tumor: a 10-year experience of a single center in Southern China

Background: This study aimed to report our 10-year experiences on the treatment of recurrent Wilms tumor (WT) to improve the therapeutic outcome of recurrent WT in China. Patients and Methods: From August 2006 to August 2017, 14 patients (7 males and 7 females) with recurrent Wilms’ tumor treated at our center were included. Their medical records were reviewed. Results: Primary WT were mainly diagnosed at the age of 1-3 years (50%). The main histology of primary WT was unclassified types (42.9%), followed by blastemal types (35.7%). Four cases did not receive standardized postoperative chemotherapy after the initial surgery. Recurrence mostly occurred within the first year after initial surgery (57.1%). The recurrent WT mainly occurred at the primary location and ipsilateral lymph nodes (35.7%), followed by extensive peritoneal metastasis (28.6%). Eleven patients underwent surgery for complete resection of the recurrent lesions. There were 9 patients achieved event-free survival for 1 year 2 months to 9 years. Three, one, one and one patients died of extensive intraperitoneal metastases, brain metastasis, peritoneal metastasis, severe intestinal obstruction vomiting, electrolyte imbalance and tumor invasion of the spinal cord, respectively. Conclusions: Individualized multimodal treatment can effectively improve long-term survival of the patients of recurrence WT.

the median age at initial diagnosis is 3.5 years [5].
The current standard therapy for WT patients is a multimodal treatment, namely a combination of surgery and chemotherapy, with the additional radiotherapy for high-risk patients, which has resulted in a significant improvement in therapeutic outcomes [6]. The 2-year event-free survival rates of WT patients in developed countries have reportedly up to 85-90% [7,8]. However, event-free survival in developing countries remains unsatisfactory due to economic factors and non-standard therapy [9].
According to the post-nephrectomy histology, WT can be classified into epithelial type, mesenchymal type, mixed type, blastemal type, and anaplastic type [10]. Patients with an anaplastic type of WT are regarded as of unfavorable histology and high-risk for a worse prognosis [2]. Yao et al. have reported that WT patients with an unfavorable histology have a significantly higher recurrence rate than those with a favorable histology [11]. On the other hand, tumor recurrence is also a crucial risk factor associated with poor outcomes for WT patients [12,13]. The second and third National Wilms Tumor Studies (NWTS) trials II and III have shown that the 3-year survival rate after WT recurrence is markedly reduced to 30± 3% [14].
The recurrence rate for WT has been reported to be around 10 to 20% [11,[15][16][17]. So far, published literature on the treatment of recurrent WT in China is still limited. The current study aimed to report our experiences with the treatment of children with recurrent WT at our center over the last ten years, with the purpose to improve the therapeutic outcome of recurrent WT in China.

Patients
A total of 14 patients with recurrence of Wilms' tumor were treated at Department of Pediatric Surgery, the First Affiliated Hospital of Sun Yat-sen University from August 2006 to May 2016. The medical records of these patients were retrospectively reviewed.
Patients' demographics, records of diagnosis, surgery, histology, chemotherapy, radiotherapy, sites of recurrence and interval from primary surgery to recurrence were collected. This study was approved by the institutional review board of the First Affiliated Hospital of Sun Yat-Sen University, and written informed consent was obtained from the patients.

Surgical management
The flow chart of treatment strategy for recurrent Wilms tumor in our center was shown in the Fig. 1. For patients who can undergo surgery, the recurrent tumor should be completely excised without rupture as much as possible. Regarding surgical incision, the abdominal transverse incision was considered for patients with abdominal recurrence. The incision must be large enough to fully expose the whole abdominal cavity. The original surgical incision in the initial surgery could be used and appropriately extended if full exposure can be achieved. For patients with pulmonary metastases, thoracotomy or thoracoscopic surgery could be considered. Thoracoabdominal incision could be considered if patients with tumor embolism. The tumor, including adjacent suspicious malignant tissue and regional lymph nodes and all the swollen lymph nodes should be removed. If the tumor was connected to an adjacent organ (such as the spleen, colon, pancreas), complete tumor resection was performed by partial resection of the adjacent organs. If complete tumor resection cannot be achieved, the patients should receive chemotherapy first, followed by the radical surgery. Within one week after surgery, the tumor staging was determined again according to the findings of surgical exploration and pathological examination.

Radiotherapy
The radiotherapy was started within 9 days after surgery. Patients with recurrent abdominal disease underwent tumor bed radiotherapy with a total dose of 10.8 Gy (1.8 Gy/time). For patients with tumor greater than 3 cm (diameter), the total dose could be increased to 21.6 Gy. The total dose of whole abdominal radiotherapy was 10.5 Gy (1.5 Gy/time). Patients with distant metastasis received radiotherapy in the metastatic region.

Chemotherapy
Chemotherapy regiments were determined according to whether or not the patients had received the standard chemotherapy before the tumor recurrence. The chemotherapy dose should be reduced to 50% and 75% for the patients aged <10 months and 10-12 months, respectively. In the preoperative chemotherapy, the patients without prior standard chemotherapy in the initial surgery received two sessions of chemotherapy containing actinomycin D (Act-D) 15 µg/kg d1-5 + vincristine (VCR) 1.5 mg/m 2 d1 + adriamycin (ADR) 50 mg/m 2 d1, and the patients were evaluated if they can receive surgery. If the tumor volume did not reduce after two sessions of above chemotherapy or for patients with prior chemotherapy in the initial surgery, the patients should receive two sessions of alternate chemotherapy (cyclophosphamide (CTX) 1.2g/m 2 d1 + VCR 1.4 mg/m 2 +ADR 50 mg/m 2 d1 and Carboplatin (CBP) 400 mg/m 2 d1+ Vepesid (VPI6) 100 mg/m 2 d1-d5). If the assessment shows that the patient still cannot undergo surgery, the chemotherapy regimen needed to be changed.
For patients with standard preoperative and postoperative chemotherapy in the initial surgery or those with no response to ACT-D+VCR+ADR, the regiments were alternate chemotherapy CAV (CTX+VCR+THP-ADM) and CE (Carboplatin + Etoposide), 3 weeks apart.

Tumor recurrence
The clinical characteristics of relapsed tumor of the 14 patients were summarized in Table   2. Tumor recurrence was mainly found via regular postoperative imaging examinations (n=12), or the examinations after the incidence of intestinal obstruction (n=2). Regarding the relapse-free interval, eight patients had a recurrence within one year 1 after the initial surgery, while six patients had recurrence more than one year after initial surgery. As for the location of recurrence, there were 5 cases with primary location and ipsilateral lymph nodes (case 2, 3, 6, 10, 11), 4 cases with extensive peritoneal metastasis (case 8,9,12,14), one with primary location and pulmonary metastases at the same time (case 1, Fig. 2), one with pulmonary metastasis (case 4), one with pulmonary ( Fig. 3), pleural and brain

Discussion
It has been shown that early recurrence at <12 months after initial diagnosis is a poor prognostic factor for recurrent WT [14]. Among the 14 recurrent WT in this study, 8 cases (57.1%) and 5 cases (35.7%) had a recurrence within the first and the second year after the initial surgery, respectively. This finding is consistent with the previous report that most recurrent WT occur within the first 2 years after the initial diagnosis [14]. In our series, a case had a recurrence at 5 years after the initial surgery, which is a late recurrence case defined as recurrence longer than 5 years after the initial diagnosis.
However, long-term regular follow-up is necessary for all WT patients since the extremely rare cases such as long-delayed late recurrences longer than 20 years after the initial diagnosis have been reported [18,19].
In the current study, there were 5 cases of blastemal WT at first histology, accounting for In this study, tumor recurrence mostly occurred in the ipsilateral peritoneum (5/14, 35.7%), followed by the extensive peritoneal metastasis (4/14, 28.6%). Intracranial metastasis was rare. Notably, all the 4 cases with extensive peritoneal metastasis had a history of preoperative/intraoperative tumor rupture or spillage at the initial surgery.
Specifically, case 8, 9, and 14 had a preoperative spontaneous tumor rupture while case 12 had an intraoperative tumor rupture. It is known that whole abdominal radiotherapy is In the current study, one patient (case 2) had a recurrent tumor on the residual ureter in the lesional side, indicating that the initial surgical resection (removal of ipsilateral kidney and ureter) was not thoroughly carried out. In the second surgery, the recurrent tumor and the residual tissue at left kidney were completely resected. After postoperative chemotherapy and radiotherapy, the patient has been achieving disease-free survival for 31 months. Meanwhile, 3 patients (case 3, 10, 11) did not receive removal of the lymph nodes at the initial surgery, which may contribute to the tumor recurrence. Case 3 received the initial surgery in the other hospital. Case 10 and case 11 were the early cases of our hospital and the importance of removing the lymph nodes was not emphasized at that time.
In our series, case 7 presented primary WT combined with tumor thrombus into the superior vena cava but thrombectomy was not performed at the initial surgery. The patient received standardized postoperative chemotherapy. At 25 months after the first surgery, tumor recurrence was found at ipsilateral lymph node and the tumor thrombus continued to enlarge, which might contribute to the tumor recurrence. The tumor thrombus was then successfully removed at the second surgery. For WT patients combined with tumor emboli, thrombectomy should be included in the preoperative assessment before the initial surgery. In addition, thoracotomy open-heart surgery could be conducted for thrombectomy if necessary.
In addition to the initial surgery for WT, standardized postoperative chemotherapy (sufficient dosage, sufficient treatment course, and regular interval) is also crucial for reducing the incidence of recurrence. In our series, three cases of recurrent WT did not At present, individualized multimodal treatment combining chemotherapy, surgery, radiotherapy remains the standard treatment for recurrence WT, and which can significantly improve long-term survival of the patients [13]. In this study, except for 3 patients which cannot be treated with surgical management, the remaining 11 patients all underwent surgery for complete resection of the recurrent lesions. There were 8 patients achieved event-free survival for 25 months to 11 years. Nevertheless, three, one, one and one patients died of extensive intraperitoneal metastases, brain metastasis, peritoneal metastasis, severe intestinal obstruction vomiting, electrolyte imbalance and tumor invasion of the spinal cord, respectively.

Conclusions
In summary, our study suggested that non-standard surgery for the primary WT and nonstandard postoperative chemotherapy after the first surgery may contribute to recurrent WT. In China, therefore, the importance of standardized treatments for primary WT should be emphasized and strictly performed to reduce the incidence of recurrent WT, especially

Consent for publication
Written informed consent was obtained from the parents/legal guardians of patients for publication of this study and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Availability of data and material
All the data and material were presented in the main paper.

Competing interests
The authors declare that they have no competing interests.     The preoperative CT images of case 5 (the first recurrence) showed a huge mass with a size of about 53 × 62 × 73 mm, uneven density and unclear border in the right lower lobe of lung. The enhanced CT showed uneven enhancement.

Figure 4
The imaging findings of Case 5 after cerebral hemorrhage (the third recurrence).