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Wilms tumor is considered the fifth most common pediatric malignancy originating from embryonal kidney tissues.1 It accounts for 6 – 7 % of all childhood cancers. . 2 The incidence is higher in children younger than 5 years (more than 80 % of the cases). 3
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In the developed countries Wilms tumor shows a long term survival rate (nearly 90 %) in localized disease and more than 70 % for metastatic disease. 1 In contrast, the long term survival in many developing countries is still between 0% – 40%. 4 The two major groups which have tremendous contributions in the management of Wilms’ tumor are National Wilms’ Tumor Study (NWTS) and the Societe Internationale D’oncologie Pediatrique (SIOP). 5
The NWTS has always adopted the immediate nephrectomy policy, which allowed the stratification of Wilms tumor according to staging and histological findings, thus giving a chance for further tailored treatment. On the contrary, the SIOP protocol adopts the concept of pretreatment chemotherapy before nephrectomy. The SIOP studies claimed that this approach reduced the incidence of tumor spillage, and made it a more safe surgery. It also increased the percentage of low stage tumor that requires less treatment. 6
Herein, in our study we assume that upfront chemotherapy reduces incidence of intra operative rupture, spillage and consequently post operative morbidity & mortality in comparison to upfront surgery in the setting of delayed referral & presentation by large abdominal mass.
- Patients and Methods:
We performed a retrospective comparative study from October 2009 till October 2011, on children presenting with Wilms tumor. The study involved only patients that were younger than 18 years old. There were 35 children that were divided in two groups; group (A); twenty one children treated with upfront chemotherapy, group (B); fourteen children treated with upfront surgery. Charts were reviewed for history of illness, clinical findings, imaging findings including U/S, CT abdomen (Fig. 1 a, b), and chest x-ray (CXR), lab investigations, and urine catecholamine. Charts were reviewed for incidence of intraoperative rupture, tumor spillage, post operative recurrence rate, residual tumor, morbidity and mortality in both groups.
Patients were treated by upfront chemotherapy, or upfront surgery according to discretion of treating physician. The upfront chemotherapy was given according to SIOP protocol 2001. Post operative chemotherapy was given according to risk stratification. Statistical analysis was performed using SPSS package 20. Descriptive statistics were done using median and interquartile range. Inference statistics were done using Mann Whitney and Chi Square tests.
35 patients were found eligible in this study. They were divided according to the upfront management whether surgery or chemotherapy. Analysis was done for both groups regarding incidence of intra-operative rupture, rupture during chemotherapy, residual tumor post surgery in both groups and finally relapse rate
- Twenty one children received preoperative chemotherapy (SIOP protocol 2001) followed by radical nephrectomy
- Fourteen children were treated by upfront surgery
There were 15 males and 20 females with a ratio of 1: 1.3. The Median age for patients in our series was 3 years, with range from (1 -17. IQ: 3).
Three patients had bilateral Wilms tumor and 32 had unilateral pathology. In unilateral Wilms tumor, 12 had right sided tumor, and 20 had left sided tumor. Radiologically the average diameter for the tumor was 9.3 cm.
Clinical presentation varied among patients. 23 (65.7%) presented with abdominal mass, 5 (14.2%) patients presented with pain, and 7 (20%) presented with hematuria.
Tumor staging varied in the two groups as shown in table (1). In all cases there were no IVC thrombus seen in preoperative imaging studies, except in one patient.
In patients with unilateral tumor, 31 patients underwent radical nephrectomy for the affected kidney (Fig. 2 a, b) and only one patient had debulking procedure. In patients with bilateral tumor, one patient had bilateral partial nephrectomy, and 2 patients underwent radical nephrectomy on one side and partial nephrectomy on the other side.
The incidence of intraoperative rupture in both groups of treatment was analyzed using the Fisher’s exact test table (2). There was a significant difference in the incidence of intraoperative rupture of the tumor between both groups of treatment. (P value 0.000)
In the preoperative Chemo group, 16 patients (45.7%) showed response to chemotherapy. In both groups Stage III&IV received radiation therapy Radiotherapy was also given to all patients with ruptured tumor or positive LNs. In group (A) only 3 patients (23.8%) received radiation, while in group (B), 11 (92.8%) patients received radiation, table (3).
When comparing the results in both groups; there was a significant difference between both groups. Group (A) needed less radiation treatment than group (B).
All patients were followed for different periods of time. The Median follow up was 12 months (1 – 27) IQ 12.
Recurrence was compared in both treatment groups table (4); however no significant difference was noted between both groups of treatment. (P value 0.221). Comparing mortality in the two groups, no significant difference was noted between 2 groups. Table (5)
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Survival was calculated using overall survival and progression free survival. PFS for upfront surgery group was 7 months, while it was not reached for upfront chemotherapy group. The OS for the upfront surgery group was 78.5 % (11/14), while that for the upfront chemotherapy group was (90.4%).
There are lots of factors that play a role in affecting the outcome of Wilms tumor management in the developing countries. For example, the high incidence of advanced stage of disease at presentation, the co morbidities in the patients and their poor nutritional status. The awareness of the parents regarding the treatment options also plays a role. Factors involving the medical service provided include the absence of well trained paramedical staff, the lack of chemotherapy drugs and appropriate radiotherapy. 5
This work is a retrospective analysis of 35 children with Wilms tumor during the period from October 2009 to October 2011. In our study; male: female ratio is 1:1.3 showing a slight female predominance. This is similar to reports from Europe & USA, which show a female predominance with ratio of 0.92: 1 to 0.6: 1 in bilateral cases.7
The median age at diagnosis in our study is 3 years (36 months). This is lower than median ages found in NWTS and SIOP studies in which the median age is 41.5 months for boys and 46.9 months for girls. 8 This result is also comparable to other Turkish and Egyptian studies. 9
Abdominal swelling was the most common presenting symptom in our patients, accounting for 65.7 %; this is lower than that reported in UKCCS2 held in Britain, which was 74 %. 10 . Abdominal pain and hematuria were the presenting symptoms in 14.2 % and 20 % of the cases respectively , which is comparable to some Italian studies.11 The consequences of late presentation include very huge and advanced tumors which make operative intervention very difficult and consequently a poor prognosis.
In group (A) in our study, stage I was the most common (52.3 %). In group (B) stage III was the most common (85.7%). This can suggest the role of upfront chemotherapy in downstaging Wilms tumor. Surgical spillage took place in 10/14 (71.4%) patients with upfront nephrectomy, however it occurred in only 1/21 (4.76%) with preoperative chemotherapy. This was statistically significant (p value = 0.000). This reflects the influence of neoadjuvant chemotherapy in reducing spillage in SIOP patients rather than NTWSG patients.
The percentage of our patients who received radiotherapy in group (A) was 33.3 % , which is slightly higher than the 9th SIOP study 12, in which only 24 % of the patients required radiation therapy. In group (B) 78.6 % required radiation treatment. This difference can be explained by the fact higher incidence of surgical spillage requiring post-operative radiotherapy.
The recurrence rate in our study was 14.3 % in group (A) and (35.7%) in group (B). These results are similar to other Egyptian reports. 13, 14 However this was higher than those demonstrated by the 9th SIOP and the 4th NWTS which were 10 %and 11% respectively 15,16. This can be explained by the advanced stage at presentation in our patients. The recurrence rate in the upfront surgery group (35.7%) was higher than that found in upfront chemotherapy group (14.3%). This was found statistically not significant (p value = 0.221). This might be explained by the higher incidence of tumor spillage during surgery.
In our series, mortality rate in group (A) was 9.5 %, while in group (B) it was 21.4 %. Although it was not statistically significant, it reflects a clear clinical significance.
OS and PFS were calculated for both groups. The upfront chemotherapy group had an OS of 90.4 % and the PFS was not reached. While in the upfront surgery group, the OS was 78.5 % and the PFS was 7 months. Guruprasad et al. 17 reported the 5 year OS for their patients was 85.2 %.
In our study upfront chemotherapy markedly improved the short term outcome. Upfront chemotherapy resulted in a significantly reduced intraoperative tumor rupture. It must be noted that the limitations of this study include the retrospective nature of the study, non randomization, small number of patients, different surgeons, and short follow up in our setting with delayed presentation. A larger size sample would provide greater confidence with respect to conclusions of this study highlighting the message that upfront chemotherapy has better influence on Wilms tumor management in the setting of developing countries with delayed referral.
Our results showed that upfront chemotherapy significantly reduces the incidence of tumor spillage and the need for post operative radiation treatment. Although incidence of recurrence and mortality were much lower in upfront chemotherapy group, it couldn’t be proved statistically.
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