Patient Characteristics and Results of Wilms Tumour Treatment – A Prospective Cohort Study from Pakistan

By Farrah Bashir¹, Tariq Ghafoor^{1, 2,} Shakeel Ahmed¹, Tanveer Ashraf¹

AFFLIATIONS:

1. Department of Paediatric Oncology, Combined Military Hospital, Rawalpindi, Pakistan.
2. Armed Forces Bone Marrow Transplant Centre, Combined Military Hospital (CMH) Medical Complex, Rawalpindi, Pakistan.

DOI: https://doi.org/10.36283/PJMD10-4/002

Background: Wilms tumour, also called nephroblastoma, is the most common renal malignancy in children, presenting, mostly as an abdominal mass. Chemotherapy and surgery are the mainstays of treatment depending upon the histopathology, risk group and stage of treatment. The aim of the study was to determine the treatment outcome of Wilms tumour in a tertiary care hospital in Pakistan.

Methods: A Prospective cohort study was carried out at the Department of Pediatric Oncology, CMH-Rawalpindi, Pakistan. A cohort of patients with Wilms tumour, less than 16 years was followed prospectively from January 2012-2019. Statistical data were analysed by Chi-squared test and p-value<0.05 was considered statistically significant.

Results: The study included 39(50.6%) males and 38(49.4%) females. Abdominal mass [70(90.9%)] was the most common problem, followed by abdominal pain, hematuria, and fever. In stage I, [34(44.2%)] patients were followed up for histopathology. n=64(83.1%) patients were divided into the intermediate-risk group and 13(16.9%) in the high-risk group. The patients [50(64.9%)] with the localized disease received vincristine and Actinomycin D for chemotherapy before the operative procedure, whereas, [10(13.0%)] for metastatic disease, received preoperative chemotherapy, including vincristine, actinomycin D, and doxorubicin. Furthermore, 3(3.9%) cases had treatment-related mortality, 15(19.5%) patients relapsed, and 11(14.3%) of them died later due to their advanced stage. Overall survival (OS) was 81.8% and event-free survival (EFS) was 76.6%.

Conclusion: Stage of disease considerably affects treatment outcomes and survival. We acknowledge that low-stage Wilms tumour can be treated by early referral to a paediatric oncologist and surgeon. This intervention could improve survival of children with Wilms tumour.

Keywords: Wilms Tumour; Treatment Outcome; Developing Country; Event Free Survival.

Wilms tumour (WT) is a common and curable embryonal renal cancer. WT is one of the tumours considered by the World Health Organization’s (WHO) Global Initiative for Childhood Cancer for the overall improvement in outcomes¹. It has surfaced as the most common primary renal malignancy that affects every 1 of 10,000 children². Of these, 5% of all childhood malignancies are reported as WT. Survival rates have improved to 90% in developed countries². Histologically it resembles a developing kidney and has three components, which are stromal, epithelial, and blastemal³. The mean age of children diagnosed by Wilms tumour is 30 months for girls and 28 months for boys⁴. The tumour typically surfaces in one of the kidneys, however, in almost 5-8% of patients, bilateral or multifocal tumours were also noted. A bilateral tumour is mostly hereditary and predicted to appear early⁵. There is a racial predominance of WT more in African people than the Caucasian patients⁶.

There are two largest collaborative groups of WT management, the International Society of Paediatric Oncology (SIOP) and the Children’s Oncology Group (COG). The COG endorses primary surgery before starting any other treatment, but the SIOP recommends chemotherapy before surgery. In SIOP protocol, vincristine and actinomycin D is given for localized problem, while doxorubicin is added in case of metastatic disease. A combination of chemotherapy and surgery remains the gold standard. Radiotherapy is used as an adjunct in high-risk patients. In developed countries, 70% to 90% of patients survive, with best results (90%) in the localized non-anaplastic tumours⁷. On the other hand, in underdeveloped countries, survival rates range between 0% and 52.7% ⁷. The main reasons for the poor outcomes in the resource-constrained countries are late presentation, lack of facilities for advanced genetic testing, inability to afford therapy, and unavailability of drugs⁸.

The patients were classified into three major groups after nephrectomy based on histopathology results. 1) Low-risk tumour group includes completely necrotic ones. 2) Intermediate risk group comprises epithelial, stromal, mixed, regressive, and focal anaplasia type. 3) High-risk group contains tumours with diffuse anaplasia and blastemal type^9,10. Treatment is followed according to stage and histopathology of the tumour. International collaboration is mandatory for finding successful treatment options for unfavourable WT, for example, refractory metastatic and relapsed high-risk WT¹¹. The main objective of the study is to determine the characteristics of patients in the cohort and to evaluate the treatment outcomes. We aimed to assess the overall survival and event-free survival of WT patients treated per SIOP WT 2001 protocol in Pakistan.

This was a prospective cohort study and was conducted at the Paediatric Oncology department of Combined Military Hospital (CMH). The Ethical Committee/Institutional Review Board (IRB) of CMH gave their consent for the study (Registration Serial Number 32). Informed consent was taken from the parents/guardian. SIOP WT – 2001 protocol was followed. This is a standard management regimen to treat WT.

We included all children younger than 16 years of age with a naive diagnosis of WT treated per SIOP protocol during January 2012-2019.We excluded patients with other renal tumours, relapsed WT, or those who left during treatment. Medical history and complete examination were performed on each patient. The following variables were recorded at the time of the first admission of each patient: age, date of diagnosis, sex, time to reach the oncologist, symptoms, and history of nephrectomy. The diagnostic modalities included ultrasound, CT scan, MRI, X-rays, bone scan, and lab tests (blood and urine). We also looked for all associated congenital anomalies such as aniridia, hemihypertrophy, etc. Blood Pressure was also checked to identify hypertensive cases. Biopsy was used as a confirmatory test.

International Society of Paediatric Oncology (SIOP) protocol includes percutaneous biopsy followed by preoperative chemotherapy for localized and metastatic disease. It includes nephrectomy and postoperative histopathological confirmation of the primary diagnosis and staging of the tumour. Postoperative chemotherapy and radiotherapy were administered based on the stage of WT.

Preoperative chemotherapy for the localized disease was given for four weeks. Preoperative chemotherapy for metastatic disease was administered for 6 weeks. The period between the last preoperative chemotherapy and the first postoperative chemotherapy was 3 weeks at the most. Intermediately, nephrectomy was performed, and specimens were sent to a histopathologist. The percentage of necrosis was assessed and classified as <66% (blastemal, mixed, epithelial, and stromal type), 66-99% (regressive type), and 100% (completely necrotic type). Those patients that came after upfront nephrectomy had risk assessment on the histopathology report, and postoperative chemotherapy started according to the risk stratification of SIOP, including stages and histology of the tumour tissue. Postoperative chemotherapy for stage I of the intermediate-risk group was given for 4 weeks. The duration of treatment for low and intermediate-risk stage II / III, high-risk stage I, and high-risk stage IV with absent metastasis or completely resected tumour were 27 weeks. The duration of treatment for high-risk stage II/III and high-risk stage IV with multiple inoperable metastases or incompletely resected tumour was 34 weeks. Details of chemotherapy drugs and weeks of drug administration were maintained according to the stage of the disease.

Postoperative flank radiotherapy was given to stage III of intermediate-risk, which includes nodes positive disease, tumour rupture, and residual disease left after surgery. Postoperative flank radiotherapy was also given to stage II of the high-risk group (excluding blastemal type), stage III, IV, and V of the high-risk group according to the local stage. Pulmonary radiotherapy was given to patients with residual tumour tissue through an X-ray and CT scan of the chest. Re-assessment, according to SIOP guidelines at periodical intervals, was done according to the protocol. After treatment, periodic follow-ups were done at three months for the first two years and every 6 months later on. Each visit included abdominal ultrasound and chest X-rays. The selected cohort of seventy-seven patients was followed for seven years (January 2012-2019). Data were analysed using SPSS 23.0 and Microsoft Excel. Chi Square test was used for analysis of variables. The p-value of less than the alpha value of 0.05 was considered along with a 95% confidence level.

Wilm’s Tumour presented on right side in 39 (50.62%) patients and on left side in 38 (49.4%) patients. We had 34 (44.2%) patients in stage I, 18 (23.4%), 12 (15.6%) and 13 (16.9%) in stage II, III, IV, respectively. Preoperative chemotherapy for localized disease and metastatic disease was given to 50(64.9%) and 10 (13%) patients, respectively. Preoperative chemotherapy was not given to 17 (22.1%) cases. Some of the patients’ characteristics are presented in Table 1.

Table 1: Characteristics of patients of the study.

IR: intermediate risk, HR: high risk, AVDm: actinomycin D vincristine and doxorubicin for metastatic disease, HRm: High-Risk Regimen HRm, Metastatic Disease, VOD: Veno-occlusive disease.

There were no patients in the low-risk group after histopathology. However, 64 (83.1%) had the intermediate-risk group. In addition, 13 (16.9%) patients had the high-risk group. We had 8/77 (10.4%) of the patients who suffered complications of the surgery, including intestinal obstruction in 5 (6.5%) cases, tumour rupture in 2 (2.6%) cases, and one death. The chemotherapy details of the patients were given in Table 2.

Table 2: Chemotherapy details of the patients.

*Two-third of above the doses were administered for children <12 Kg, and for children below 6 months dose was reduced to half.

The majority of the patients did not metastasize, that is 61 (79.2%). However, 12 (15.6%), 2(2.6%), and 2 (2.6%) had pulmonary, liver, and both pulmonary and liver metastasis, respectively. Radiotherapy was given to 21 (27.3%) cases, while 56 (72.7%) did not receive it. Therefore, the association between overall survival and event free survival in Wilms tumour’ patients is shown in Table 3 while patients’ outcomes have been presented in Figure 1.

Table 3: Results of difference in survival times between the groups studied at all time points.

Figure 1: Wilms tumour treatment outcome.

TRM-Treatment Related Mortality, RRM- Relapse Related Mortality RD-Relapse Disease, OS- Overall Survival, EFS- Event Free Survival.

Based on the study results, we found out the majority of the patients who presented in stage 1 had a better outcome compared to those who presented late. We noticed only a few patients were diagnosed in stage 1V. The reasons could be either a delay in referral to the paediatric oncologist or early-undiagnosed deaths. The prolonged duration of symptoms also showed a lack of access to a tertiary care facility. We followed SIOP protocol, but a few patients had initial nephrectomy. We witnessed complications related to surgery in the form of tumour rupture and intestinal obstruction and one death. This data belongs to a tertiary care facility that receives a majority of the paediatric oncology patients. The strength of our study is that we had collected authentic data in the fullest possible detail. There is an enormous development in the outcome and survival of WT patients due to multidisciplinary management over time.

The event free survival (EFS) of a study conducted in the United Kingdom by Pritchard-Jones et al. was 77.2%, which was close to our results¹². Another study from China by Yao et al. had an OS of 81%, similar to our overall survival (OS) of 81.8% ¹³. We have compared our results to some other countries as well. Li et al. from China reported EFS 92.7% and OS 94.5% ¹⁴. Cafferata et al. from Argentina followed SIOP 01 protocol and had an EFS 85% and OS 91%¹⁵. The reason for good results can be a feasible treatment plan. A study from Lebanon by Rabeh et al. showed 85.7% EFS and 88.6% OS ¹⁶. These good results can be attributable to a better multidisciplinary team, availability of supportive care, and financial coverage of health expenditures. In comparison to the studies conducted in Pakistan, our results show a better outcome. Anwar et al. and Fadoo et al. had an EFS of 67% and 56%, respectively^17,20. The reason for the improvement in the outcome can be increasing awareness and referral to the right facility.

Gender wise prevalence was almost equal, and 56 (72.7%) patients were under four years of age. The median age was 2.67±2.34 years (5.5 Months – 11 years). This was in line with other studies done in Lebanon, Kenya, and other parts of Pakistan^17-20, and lower than Egypt and Tanzania^21,22. In this study, Abdominal mass (90.9%) was the most frequent complaint followed by hematuria, abdominal pain, coinciding with the work of Abd El-Aal et al., in which abdominal mass was the most common presenting symptom (82.3%) ²¹.

The disease stage is of utmost importance in deciding further treatment. A study carried out by a Pakistani author, Anwar et al., had 5% of patients in stage I ¹⁷. We received 44.2% of WT patients having stage I disease. This may indicate improved awareness for early screening and referral to the right hospital. Regarding the surrounding countries, Guruprasad et al. from India, who conducted a similar study, noticed a high incidence of stage III (37.7%) followed by Stage I (27.8%), stage II 1(6.4%), stage IV (14.8%,) and stage V (3.3%) disease¹⁹. It can be due to the late presentation of the patient to the paediatric oncologist. Taran et al. reported that in prognostic factors presented by SIOP, histology of the tumour is of more importance than the stage of WT ^22,23. Preoperative chemotherapy leads to some degree of regression and necrosis of the original tumour tissue, which is why the regressive subtype is added in the intermediate-risk group of WT. However, the persistence of blastemal component even after preoperative chemotherapy shows the non-responsive nature of tumour tissue to the drugs and is related to adverse outcomes. Even though the two large groups, Children’s Oncology Group (COG) and SIOP, differ scientifically from each other but with or without preoperative chemotherapy, the treatment outcome of WT in developed countries is much better than the developing countries. We have compared the treatment outcomes of the current study with other studies conducted around the world.

Vincristine and actinomycin D have played their undisputed role since the 1950s in the successful treatment of WT, followed by the addition of doxorubicin in 1970s ²⁴. Cyclophosphamide, ifosfamide, carboplatin, and etoposide are the drugs used for more advanced and resistant cases. The presence of anaplasia in WT is a strong bad prognostic factor. In another study, stage 1 anaplastic WT was treated on COG AREN0321 protocol with vincristine, actinomycin D, doxorubicin, and flank radiation showed excellent survival results²⁵. Survival rates in Pakistan have improved over the past ten years from 56% as reported by Fadoo et al. using National Wilms Tumour Study Group (NWTSG) guidelines to 76.6% in our study using SIOP WT 2001 protocol²⁰.

We have highly experienced paediatric oncologists, surgeons, histopathologists, radiologists, and tertiary care hospitals. However, most of the patients cannot get the best treatment because of a lack of financial resources to pay out of pocket for their health care expenditure. A centralized tumour data collection should be devised. It is expected that with improved awareness and availability of newer therapies, the outcomes will improve further. With a multidisciplinary approach, including a paediatric oncologists, paediatric surgeons, histopathologists, and radiation oncologists, good survival outcomes can be achieved, particularly for low-stage disease.

Accurate diagnosis by evaluating all characteristics of patients and well-timed initiation of therapy improves the outcome in children with Wilms Tumour. By using the SIOP WT 2001 protocol, we have achieved results comparable to western studies. The improvement in management and timely treatment (chemotherapy, surgery, and radiation therapy) can help the patients in recovery.

We would like to acknowledge Mr. Adnan Ghafoor for his immense contribution to data management.

The authors declared no conflict of interest.

The Ethical Committee/Institutional Review Board (IRB) of CMH approved the study with the registration serial number: 32.

Informed consents were taken from the parents/guardian of the patients.

FB collected the data and wrote the manuscript. TG analysed and interpreted the patients’ data. SA helped in writing the first draft and assisted in data interpretation. TA facilitated the literature review search.

1. Chagaluka G, Paintsil V, Renner L, Weijers J, Chitsike I, Borgstein E, et al. Improvement of overall survival in Collaborative Wilms tumour Africa Project. Pediatr Blood Cancer. 2020;67(9):1-5.
2. Njuguna F, Martijn HA, Kuremu RT, Saula P, Kirtika P, Olbara G, et al. Wilms tumour treatment outcomes: Perspectives from a low-Income setting. J Glob Oncol. 2016;3(5):555-562.
3. Mahamdallie S, Yost S, Poyastro-Pearson E, Holt E, Zachariou A, Seal S, et al. Identification of new Wilms tumour predisposition genes: an exome sequencing study. Lancet child Adolesc health. 2019;3(5):322-331.
4. Bahoush G, Saeedi E. Outcome of children with Wilms tumour in developing country. J Med Life. 2020;13(4):484-489.
5. Charlton J, Irtan S, Bergeron C, Pritchard-Jones K. Bilateral Wilms tumour: a review of clinical and molecular features. Expert Rev Mol Med. 2017;19(8):1-13.
6. Visser YT, Uys R, Van Zyl A, Stefan DC. Nephroblastoma–a 25-year review of a South African unit. J Med Life. 2014;7(3):445-449.
7. Anyanwu LJ, Atanda AT, Atanda JO. Wilms’ tumour in African children: Can an institutional approach improve outcome? Afr J Paediatr Surg. 2015;12(1):7-11.
8. Dome JS, Graf N, Geller JI, Fernandez CV, Mullen EA, Spreafico F, et al. Advances in Wilms tumour treatment and biology: Progress through international collaboration. J Clin Oncol. 2015;33(27):2999-3007.
9. Chagtai T, Zill C, Dainese L, Wegert J, Savola S, Popov S, et al. Gain of 1q As a prognostic biomarker in Wilms tumours (WTs) treated with preoperative chemotherapy in the international society of paediatric oncology (SIOP) WT 2001 Trial: A SIOP renal tumours biology consortium study. J Clin Oncol. 2016;34(26):3195-3203.
10. Pietras W. Advances and changes in the treatment of children with nephroblastoma. Adv Clin Exp Med. 2012;21(6):809-820.
11. Van Den Heuvel-eibrink MM, Hol JA, Pritchard-Jones K, Van Tinteren H, Furtwängler R, Verschuur AC, et al. Rationale for the treatment of Wilms tumour in the UMBRELLA SIOP–RTSG 2016 protocol. Nat Rev Urol. 2017;14(12):743-752.
12. Pritchard-Jones K, Moroz V, Vujanić G, Powis M, Walker J, Messahel B, et al. Treatment and outcome of Wilms’ tumour patients: an analysis of all cases registered in the UKW3 trial. Ann Oncol. 2012;23(9):2457-2463.
13. Yao W, Li K, Xiao X, Gao J, Dong K, Xiao X, et al. Outcomes of Wilms’ tumour in Eastern China: 10 years of experience at a single centre. J Invest Surg. 2012;25(3):181-185.
14. Li MJ, Tang DX, Huang Y, Wu DH, Wang JH, Lai C, et al. Neoadjuvant Transcatheter arterial chemoembolization and systemic chemotherapy for the treatment of Wilms tumour. Exon Publications. 2016:95-112.
15. Cafferata C, Cacciavillano W, Galluzzo ML, Flores P, Rose A, Zubizarreta P. Outcome of nephroblastoma treatment according to the SIOP-2001 strategy at a single institution in Argentina. J Pediatr Hematol Oncol. 2017;39(1):50-55.
16. Rabeh W, Akel S, Eid T,Muwakkit S, Abboud M, El Solh H, et al. Wilms tumour: Successes and challenges in management outside of cooperative clinical trials. Hematol Oncol Stem Cell Ther. 2016;9(1):20-25.
17. Anwar S, Faizan M, Khan S, Tallat N, Saleem M, Khalid A, et al. Five year experience of Wilms tumour at a tertiary care centre, where we stand, a developing country perspective. Pak J Med Health Sci. 2017;11(4):1263-1266.
18. Axt J, Abdallah F, Axt M, Githanga J, Hansen E, Lessan J, et al. Wilms tumour survival in Kenya. J Pediatr Surg. 2013;48(6):1254-1262.
19. Guruprasad B, Rohan B, Kavitha S, Madhumathi DS, Lokanath D, Appaji L. Wilms’ tumour: single centre retrospective study from South India. Indian J Surg Oncol. 2013;4(3):301-304
20. Fadoo Z, Hussain S, Panju S, Alvi S. Kidney tumours in children: A single centre experience from a developing country. Turk J Cancer. 2009;39(1):131-135.
21. Abd El-Aal HH, Habib EE, Mishrif MM. Wilms’ tumour: the experience of the paediatric unit of Kasr El-Aini center of radiation oncology and nuclear medicine (NEMROCK). J Egypt Natl Canc Inst. 2005;17(4):308-311.
22. Woldeab WE, Nyongole OV, Frank B. Wilm’s tumour. Presentation and outcome at Ilimanjaro Christian Medical Center. J Med Res. 2016;2(4):114-117.
23. Taran K, Sitkiewicz A, Kobos J. Histoclinical study of nephroblastoma in relation to current and previous SIOP Classification of renal tumours of childhood. Pol J Pathol. 2010;61(4):234-239.
24. Metzger ML, Dome JS. Current therapy for Wilms’ tumour. Oncologist. 2005;10(10):815-826.
25. Daw NC, Chi YY, Kim Y, Mullen EA, Kalapurakal JA, Tian J, et al. Treatment of stage 1 anaplastic Wilms tumour: a report from the Children’s Oncology Group AREN0321 study. Eur J Cancer. 2019;118:58-66.

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