Survival outcomes of different Histopathological Subtypes and stages of Wilms Tumor treated following SIOP 2001 Protocol, Children Hospital Lahore, Pakistan experience

doi:10.21203/rs.3.rs-2218914/v1

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Survival outcomes of different Histopathological Subtypes and stages of Wilms Tumor treated following SIOP 2001 Protocol, Children Hospital Lahore, Pakistan experience

https://doi.org/10.21203/rs.3.rs-2218914/v1

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Background:

Wilms tumor is the most common pediatric renal neoplasm. Following preoperative therapy, various histological subtypes, risks and clinical stages are determined. A survival outcome of different subtypes is excellent depending upon the stage of patient. In developed countries, overall survival and disease free survival is excellent due to early presentation and closer follow up.

Methods:

A retrospective study conducted at the Pediatric Hematology/Oncology department, Children Hospital, Lahore. All diagnosed WT cases from 1st January 2014 who completed their treatment before 31st December 2018 were included. Entire management was based on SIOP 2001. Patients presenting before nephrectomy received four cycles of pre-operative chemotherapy depending upon the clinical stage. After nephrectomy, postoperative chemotherapy regimen was based on stage, risk stratification and metastatic status of the patient. Survival outcome of different histopathological subtypes and stages was determined via Kaplan-Meier survival analysis and p-value was calculated via log rank test.

Results

The mean age of 93 children was 44.4 months with predominance of males (55.9%) and more commonly found in right sided kidney (55.9%). Majority patients completed the entire course of treatment (77.4%). The overall survival of all histological subtypes and stages was 77.4% and 77.1% and disease free survival was 88.2% and 89.4% respectively, at 48 months follow up. Our study showed that febrile neutropenia is major culprit affecting treatment outcome.

Conclusions

The advanced stage presentation is quite typical in developing nations and contributes towards decreased OS and DFS seen in different histological subtypes and stages. In our study OS significantly dropped from 45.3% in stage III to 12.9% in stage IV disease (P < 0.001). Despite belonging to low middle income class country and uneducated background, majority patients completed the entire course of treatment and relapse was fairly less. The perks of current study are that our hospital is the only pediatric tertiary care centre in Lahore, which have investigated a variety of parameters influencing the course of WT treatment over four-year time period.

Wilms tumor (WT)

(SIOP staging) Internal Society of Pediatric Oncology) National Wilm’s tumor Study Group (NWTS)

Post chemotherapy

Pediatric renal tumors constitute 7–8% of solid malignancies out of which wilms tumor (WT) is reported as 90% of malignant renal neoplasm. Mostly, WT affects children of age 0–4 years. Median reported incidence is 15.1 Annual Statistical Report (ASR)/million and inter quartile range (IQR) is 11.8–18.7 by World Health Organization (WHO). The median incidence of WT in Asia is 7.6 ASR/million, whereas in Pakistan and India is 3.6 and 4.8 ASR/million respectively with a slight male predominance ^1,2.

WT commonly presenting as asymptomatic abdominal mass. Grossly, up front tumors show solid homogenous cut surface whereas post treatment tumors exhibit variegated appearance as shown in Fig. 5. WT shows triphasic morphology undifferentiated blastema, epithelial component and stromal component. The nephrogenic rests in normal renal parenchyma are considered precursors ^{3,4, 5, 6}.

WT is currently managed by two treatment protocols, National Wilms Tumor study group (NWTS) which comes under Children Oncology Group (COG) and International Society of Pediatric Oncology (SIOP). The use of pre-operative chemotherapy is the main difference between NWTS and SIOP, however no difference in Overall survival (OS) and Disease free Survival (DFS) was found. ^{7, 8} Preoperative chemotherapy following SIOP-RTSG Umbrella protocol categorize WT as low risk (LR) tumors, completely necrotic (CN), intermediate risk (IR) tumors, Epithelial type (ET) (Fig. 3), Stromal Type (ST), Mixed type (MT), Regressive type (RT), Focal Anaplasia (FA) and high risk (HR) tumors, Blastemal predominant (BP) (Fig. 2) and diffuse anaplasia subtypes (DA). Stage V is bilateral tumors .^{9, 10, 11, 12}.

There are few published data on WT from Pakistan regarding treatment outcomes and it is first comprehensive research article regarding Overall Survival (OS) and Event Free Survival (EFS) from Lahore regional centre. In our centre we are following SIOP 2001 protocol. The present study is carried out to determine the survival outcomes of histopathological subtypes and stages of WT treated as per SIOP 2001 protocol.

Study Population

This retrospective descriptive study was conducted at the pediatric Hematology/Oncology department of Children’s Hospital and Institute of Child Health, Lahore, Pakistan. The hospital ethical committee approved the study vide letter number approved by Ethical Review Board vide its letter No. 02/173/17 dated 01/02/2017 and informed consent was obtained from the parents of the patients. All diagnosed cases of localized and metastatic WT registered from 1st January 2014 onwards, who completed their treatment before 31st December 2018 were included. Patients still on treatment at the time of data analysis and cases who did not receive neoadjuvant chemotherapy were excluded. Four weeks of pre-operative therapy consisting of vincristine and actinomycin (dose 1.5–50 mg/m²) in localized WT is administered. Doxorubicin (1.5mg/m²) was added in metastatic cases with extended time period of six weeks. At 5-6th week, nephrectomies done by surgical team were sent to the Histopathology Department. Histopathological subtypes of WT, risks and pathological staging were noted. Patients with localized WT completed 27 weeks of post-operative therapy combination of vincristine (1.5mg/m²), actinomycin (0.5mg/m²) and doxorubicin (1.5mg/m²). Patients with metastasis received 34 weeks of alternative blocks of chemotherapy in (cyclophosphamide and doxorubicin 50-250mg/m²), (etoposide and carboplatin 150-200mg/m²) and radiotherapy. After completion of treatment patients were scheduled every two month for the first year, quarterly for the next two years, and biannually thereafter till five years post-treatment

Data analysis:

For categorical and qualitative data, frequencies and percentages were determined. Event-free survival (EFS) was defined as the period of time following the end of treatment before the disease progressed or relapsed. Overall survival (OS) was defined as the amount of time between the diagnosis date and the day of the last follow-up or death. The Kaplan-Meier survival analysis was performed to analyze survival of various histological subtypes and stages. Survival differences were compared using Log-Rank test, and P-value < 0.05 was considered statistically significant. Multivariate analysis by logistic regression was performed with prognostic factors having P value < 0.05.

Patient demographics and clinical presentation

From January 2014 to December 2018, a total of 93 patients were included in our study. More than half of patients presented in first 36 months of age with a male predominance 52(55.9%). Majority cases were seen in right kidney (n = 52, 55.9%). (Table 1)

Table 1 Main clinicopathological features of WT

Predictors Of Treatment Outcome

OS and EFS and of the cohorts were 77.4% and 88.2% respectively. In univariate analysis, the advanced stage of the tumor and metastatic disease adversely affected the treatment outcome. Stage II had the best treatment outcome. OS was 88.9%, 80.0% and 33.3% in stage II, III and IV disease, respectively (P < 0.001) (Fig. 1). EFS was 94.4%, 88.9% and 66.7% in stage II, III and IV disease, respectively (P < 0.001) and number of events was more commonly recorded in 37–72 months age group (n = 5, 5.3%). (Table 2)

Table: 2 Comparison of OS and EFS of Clinical stage, Histological subtypes, Tumor site and different age groups in both genders of WT at 4 years follow up

Total Twenty one (4.4%) patients expired, including patients who abandon treatment (n = 8, 8.6%). Thirteen (13.9%) patients who completed entire course of treatment died due to progression of disease (n = 4, 4.3%) and febrile neutropenia (n = 9, 9.6%). Majority female patients died (n = 14, 31.8%) and relapsed (n = 9, 20.4%). As more than half of our patients were in 36 months age group, majority patients died in this age group (n = 10,10.7%). Sex, age at presentation, histological subtypes and laterality did not show any association with treatment outcome, p > 0.05. Multivariate analysis was performed for the following variable: stage of the disease and site of the tumor (Table 2). Clinically, one case of Denys-Drash syndrome and three (3.2%) cases showed presence of inferior vena cava thrombus. Largest tumor size after chemotherapy was 16 cm, seen in MT subtype (Fig. 5). Histologically, majority cases were IR (n = 70, 75.2%) and showed less than 65% of necrosis, MT subtype (n = 22, 23.4%) and least observed subtype was of DA (n = 1, 1.1%). Additional pathological findings like hilum involvement (n = 12, 12.9%), two cases (2.1%) of perinephric fat infiltration and lymph node involvement found. Apart from these only one case (1.0%) of capsular infiltration, intraoperative tumor rupture and nephrogenic rests were also noted.

Pakistan is a low-middle income country (LMIC) have around 64 million (30.76%) children under 15 years age group. Children’s Hospital & Institute of Child Health Lahore is a Pediatric regional centre in Lahore which admits patients from all over Pakistan. There is meagre amount of exclusive Haematology/ Oncology health care facilities in the country. Apart from the in house patient burden a large number of patients also come for treatment from neighboring country like Afghanistan. There is a paucity of published data on pediatric renal tumors from Pakistan. There were 28 cases of WT in year 2018 in Pakistan by annual registry of Shaukat Khanum Memorial Cancer Hospital Lahore ^{1, 13}. This single centre study deciphers the clinicopathological features and predictors of treatment outcome of WT.

In the present study, mean age, sex and right sided kidney involvement was similar to local and international studies ^(14–20). SIOP and NWTS are used to treat WT worldwide, while comparing both treatment protocols difference between OS and DFS is trivial. Our hospital is following SIOP 2001 Protocol and we calculated OS and DFS at four year follow up of our patients. In our study OS was 77.4, comparable to Faranoush et al 76% and Ghafoor .t et al 78.6% ^15,20. Anwer et al and D.K Stones et al reported slightly less 67% and 66% respectively ^19,18. In contrast NWTS reported higher OS 85.2% and 81% ^14,17. (Table 2) In our study EFS was 88.2% comparable to other authors ^14,15,17,20.

Delayed presentation with advanced-stage metastatic disease is quite common in the developing courtiers and is the major contributor to decreased EFS and OS ^21–23. In the present study, 12 (12.9%) cases had metastatic stage IV disease. This proportion of metastatic disease is higher than reported from the developed countries and similar to reported from developing countries ^24–26. The metastatic disease had statistically significant lower EFS and OS as compared to localized disease. OS decreased from 88.9% in stage II to 33.3% in stage IV disease (P < 0.001) and EFS decreased from 98.4% in stage II to 66.7% in stage IV disease (P < 0.001). Very similar results are reported by a regional study ^19,20. In our study majority patients were clinical Stage III tumors 48.3% (Table-2) similar to Guru Prasad et al and Anwar et al ^14,19. Results in stage I and II disease are comparable to documented in the western world and low in advanced stage disease ^27–30. Lack of resources and education is the main reason for the delayed and advanced-stage disease. In our study treatment related mortality and progression of disease was comparable with other studies ^19,20,24.

The significance of the present study is that multiple factors, affecting the treatment outcomes of WT over almost four years period were thoroughly evaluated. Educating general pediatricians for expeditious referral to pediatric oncologist can reduce the proportion of advanced stage disease and improve both the OS and EFS of WT cases in our country. Furthermore, acquiring one uniform protocol in all Pediatric Oncology treatment centers throughout the country, under the umbrella of Pakistan Society of Pediatric Oncology will result in congregant treatment strategy all over the country.

Acknowledgements: Not applicable.

Author contributions

Conception and design: Alia Ahmad, Fariha Sahrish

Interpretation of data: Aysha anjum, Imran Hashim

Drafting of the manuscript: Ayesha bibi,

Critical revision of the manuscript for important intellectual content: Sahar Iqbal

All authors read and approved the final manuscript.

Funding; Not applicable.

Availability of data and materials;The datasets generated and/or analyzed during the current study are available from correspondence author Alia Ahmad and co-correspondence author Fariha Sahrish repository on reasonable request.

Declarations Ethics approval and consent to participate

This study was approved by the Institutional Review Board of Children’s Hospital & Institute of Child Health Lahore vide its letter No. 02/173/17 dated 01/02/2017 and informed consent was obtained from the parents of the patients.

Consent for publication; Not applicable.

Competing interests; Not applicable

Limitations of our study

It was beyond the scope of this article to determine volume reductions in pre and post therapy kidneys, assesing the response of chemotherapeutic drugs in volume reduction of the kidneys and compare the OS and EFS of WT treated by of NWTS and SIOP.

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No competing interests reported.

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Survival outcomes of different Histopathological Subtypes and stages of Wilms Tumor treated following SIOP 2001 Protocol, Children Hospital Lahore, Pakistan experience

Status:

Version 1

Abstract

Background:

Methods:

Results

Conclusions

Figures

Background

Methods

Study Population

Data analysis:

Results

Patient demographics and clinical presentation

Predictors Of Treatment Outcome

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1