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ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 27
| Issue : 1 | Page : 42-52 |
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A 10-year study of the outcome of wilms' tumor in central India and identifying practice gaps
Vikesh Agrawal1, Arpan Mishra2, Sanjay Kumar Yadav2, Dhananjaya Sharma2, Himanshu Acharya1, Aradhna Mishra3, Rekha Agrawal4, Roshan Chanchlani1
1 Department of Surgery, Pediatric Surgery Unit, Netaji Subhash Chandra Bose Government Medical College, Jabalpur , Madhya Pradesh, India
2 Department of Surgery, Netaji Subhash Chandra Bose Government Medical College, Jabalpur, Madhya Pradesh, India
3 Department of Consultant Pediatric Oncologist, Omega Children Hospital, Jabalpur, Madhya Pradesh, India
4 Department of Radiodiagnosis, Netaji Subhash Chandra Bose Government Medical College, Jabalpur , Madhya Pradesh, India
| Date of Submission | 15-Sep-2020 |
| Date of Decision | 26-Nov-2020 |
| Date of Acceptance | 29-Jun-2021 |
| Date of Web Publication | 11-Jan-2022 |
Correspondence Address:
Prof. Vikesh Agrawal
Department of Surgery, Pediatric Surgery Unit, Netaji Subhash Chandra Bose Government Medical College, Jabalpur - 482 003, Madhya Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jiaps.JIAPS_314_20
 Abstract | | |
Introduction: Despite remarkable improvement in Wilms' tumor (WT) survival in Western world, sub-optimal outcome in resource-constrained settings is influenced by late presentation, larger size, and poor access to treatment. This prompted us to study the outcome at a tertiary care center and to identify the global and local practice gaps.
Materials and Methods: A retrospective, observational study of WT was conducted from October 2009 to September 2019 at a tertiary care setting. Following the National Wilms' Tumor Study Group protocol, an upfront nephrectomy (unilateral resectable tumors) and preoperative chemotherapy (large/unresectable Stage I–III) were followed. The records were reviewed for demographics, stage, preoperative chemotherapy, predictive factors, and outcome. Survival curves were plotted by the Kaplan–Meier method, and analysis was performed using the SPSS software version 16.
Results: One hundred and fifty-six children were included, median age was 4.1 years, with a male predominance. The most common stages of the presentation were II (40.4%) and III (34.6%). An upfront surgery was done in 27.6%, while remaining received preoperative chemotherapy. The median follow-up was 22 months, and the events included relapse in 46 (29.48%) and death in 54 (34.61%). The mean survival time was 45.7 (95% confidence interval [CI], 41.08–50.30). The 2-year overall survival was 65.38% (95% CI, 59–73), and the 2-year event-free survival was 36% (95% CI, 32–41). On comparison of the impact of preoperative chemotherapy, the survival estimates in Stages I–III and relapse rate were statistically similar, tumor size reduced significantly, and tumor spill was significantly lower (P < 0.05).
Conclusion: WT is associated with late presentation, sub-optimal survival, and higher relapse in our setting associated with practice gaps related to the management including practice violations.
Keywords: Outcome, practice gaps, resource-constrained settings, Wilms' tumor
How to cite this article:
Agrawal V, Mishra A, Yadav SK, Sharma D, Acharya H, Mishra A, Agrawal R, Chanchlani R. A 10-year study of the outcome of wilms' tumor in central India and identifying practice gaps. J Indian Assoc Pediatr Surg 2022;27:42-52 |
How to cite this URL:
Agrawal V, Mishra A, Yadav SK, Sharma D, Acharya H, Mishra A, Agrawal R, Chanchlani R. A 10-year study of the outcome of wilms' tumor in central India and identifying practice gaps. J Indian Assoc Pediatr Surg [serial online] 2022 [cited 2022 Aug 8];27:42-52. Available from: https://www.jiaps.com/text.asp?2022/27/1/42/335570 |
| Introduction | |  |
Wilms' tumor (WT) is the most common primary renal malignancy in children. It is one of the most common childhood cancers where persistently innovating multimodal strategies have led to the conversion of almost uniformly fatal disease to one with excellent survival. With optimized use of current treatment strategies, including chemotherapy, surgery, and radiotherapy (RT), the 5-year overall survival (OS) of 90% can be achieved.[1],[2] Surprisingly, despite such remarkable improvement in survival in the developed countries, the outcome of WT in resource-challenged settings continue to be sub-optimal.[3],[4] OS ranged from 70% to 97% in high-income countries, 61%–94% in upper-middle income countries, 0%–85% in lower-middle income countries, and 25%–53% in low-income countries.[5] This prompted us to retrospectively analyze our 10-year data at a tertiary care center in Central India and identify the “global” and “local” practice gaps which prevent uniformity in treatment protocols and hinder the achievement of “textbook outcomes.”
| Materials and Methods | | |
This retrospective observational study of WT in children was conducted at a tertiary care center of Central India from October 2009 to September 2019. The Pediatric Surgery unit's electronic records of these children were reviewed for age at diagnosis, sex, stage, preoperative chemotherapy, type of surgery, tumor characteristics, postoperative treatment, and outcome. The staging was done according to the National Wilms' Tumor Study Group (NWTSG). A modified NWTS protocol was adopted in this study. Preoperative imaging was also used in addition to surgicopathologic assessment for the purpose of staging.[6] A contrast-enhanced computed tomography (CECT) of the abdomen and pelvis was obtained to define the local extent of the tumor. Imaging of the thorax (CECT or chest radiography) was done only when it was feasible, due to cost constraints. Doppler of inferior vena cava (IVC) was performed in all patients along with CECT to identify IVC involvement. An upfront nephroureterctomy with lymph node sampling (without preoperative chemotherapy) through a transabdominal incision was followed by adjuvant chemotherapy in children with unilateral resectable tumors evident on preoperative imaging. All Stage I–III tumors displacing or crossing aorta or vena cava and unresectable (extrarenal spread, renal vein and IVC involvement, and peritoneal spread) Stage III and IV tumors on imaging were offered preoperative chemotherapy (according to NWTS) followed by a delayed nephrectomy. The decision for resectability of the tumor was based on the preoperative imaging findings. All patients undergoing preoperative chemotherapy underwent a flank tru-cut core needle biopsy. Chemotherapy was administered as per the NWTSG-V protocol and according to the weight (<30 kg)/surface area (>30 kg), as applicable. Postoperative RT to the flank was planned according to the stage and histology of the tumor as per the NWTSG protocol and was given to all patients who got preoperative chemotherapy. In children with diffuse peritoneal implants or intraoperative spillage, whole-abdomen RT was performed. After the completion of therapy, children were followed up in the pediatric surgery outpatient department for the relapse/recurrence and outcome. The follow-up visits were scheduled once a month for the first 6 months, and then every 3 monthly for the next 6 months, and thereafter every 6 months. Children who had a relapse were treated using chemotherapy with a combination of cyclophosphamide, carboplatin, and etoposide. Survival curves were plotted for OS, event-free survival ([EFS], death and relapse were counted as events) and relapse-free survival (RFS) by the Kaplan–Meier method to know the estimates. Statistical analysis was performed using the SPSS Inc. Released 2007. SPSS for Windows, Version 16.0. Chicago, SPSS Inc. and P < 0.05 was considered statistically significant.
| Results | | |
During the study period, 156 children with previously untreated unilateral WT were registered at our center were included. The demographic and other characteristics of the included patients are summarized in [Table 1]. The median age of the affected children was 4.1 years (interquartile range [IQR], 2–5 years) with a male predominance (male:Female ratio of 1.55:1). The most common stage of the presentation was Stage II (40.4%). Stage III disease (34.6%) included extrarenal local invasion (33), positive abdominal lymph nodes by histology (8), invasion + lymph node involvement (6), and intra-operative tumor spillage.[7] Along with local extension, 2 had tumor thrombus involving the IVC at the diagnosis and 7 had thrombus reaching the renal vein but no extension into the IVC. The extra-renal extension in Stage III tumor (33) was found as an invasion in Gerota's fascia (28), Psoas fascia (4), and diaphragm (1); however, they could be excised completely. While 11 patients had lymph node involvement in Stage III (one of them being preoperatively Stage II disease but finally labeled as Stage III) and three patients had lymph node involvement in Stage IV. | Table 1: Demographics and other characteristics of patients with Wilms' tumor in the present study (n=156)
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An upfront nephrectomy followed by adjuvant chemotherapy was done in 43 patients (27.6%). The remaining 113 patients received preoperative chemotherapy and later underwent a delayed nephroureterectomy. The median duration of preoperative chemotherapy was 7 ± 2.6 weeks. After preoperative chemotherapy, the tumor size (longest dimension) regressed significantly (after chemotherapy - 4.7 ± 1.3 cm vs. before chemotherapy - 10.32 ± 3.1 cm, respectively, P < 0.0001). Of the 43 children who underwent upfront nephrectomy, 7 (16.3%) had spill and so were labelled as Stage III. None of the patients in the delayed nephrectomy group had tumor spill or rupture (P = 0.02). On exploration, four patients with large Stage II disease on preoperative imaging were found to be unresectable (Stage III disease with adherence to major abdominal vessels) who later on underwent successful oncological surgery after preoperative chemotherapy.
Among children with Stage IV diseases, the site of distant metastasis included lungs in seven cases, the liver in 1 case, and peritoneum in 1 case.
Surgical complications were infrequent and minor; however, three patients developed adhesive intestinal obstruction; one of them required operative treatment and there was no operative mortality.
Planned chemotherapy was tried to be administered according to schedules, with an effort to minimize delays. However, 34 (21.8%) patients did not complete their adjuvant treatment either because they abandoned the treatment (23) or died during the first few months of chemotherapy.[8] Of 122 patients who completed treatment, 32 patients (3 in Stage I, 12 in Stage II, and 17 in Stage III) did not follow a strict chemotherapy regimen and had a delay of more than 8 weeks in schedule completion. The course of RT was irregular due to long waiting in the RT department and poor compliance by the patients. Only 12 patients (28.6%) completed RT as per schedule, whereas others had delayed patient turn-up (24, 57.1%) or delay due to long RT waitings (14.3%). None of the patient could be started on RT within 14 days of surgery as it was not fesible in our setup.
The median follow-up was 22 months (IQR, 11–60). The KM OS and EFS estimates for all analyzed patients are shown in [Figure 1]a and [Figure 1]b and [Figure 2]a and [Figure 2]b. The mean survival time (95% confidence interval [CI]) was 45.7 (41.1–50.3). The stage-wise mean survival time was 61.7 (95% CI, 54.9, 68.4), 50 (95% CI, 44.6, 55.4), 27.6 (95% CI, 21.2, 34.1), and 10.8 (95% CI, 5.9, 15.7) for Stage I–IV, respectively. The 2-year OS was 65.38% (95% CI, 59–73) and the 2-year EFS was 36% (95% CI, 32–41). | Figure 1: (a and b) The survival estimates of the Wilms' tumor for the whole group
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 | Figure 2: (a and b) The survival estimates stratified according to stages of Wilms' tumor
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Relapse was observed in 46 of 156 patients (29.5%), and the median time of relapse was 20.5 months (IQR, 12.25–22) from the initial diagnosis. None of the patients had gross local residual disease after definitive surgery in any of the stages while only 1/9 Stage IV had complete remission. Eight children had a relapse limited to the local site, 27 had relapsed at local and distant sites, and 11 children had relapse only at a distant site. The distant sites of relapse included lungs (21), liver (14), bones (2), and brain (1). All local relapse were >5 cm, mean size of 8.8 ± 3 cm. All relapses in Stage IV were distant to the lungs. The overall 2-year estimate is shown in [Figure 3]a and [Figure 3]b. The high relapse rate was further studied and was found that 17 (36.95%) and 24 (52.17%) had poor compliance with chemotherapy and RT, respectively. Out of 46 relapses, 38 died under treatment and 8 survived (I-1, II-3, III-3, and IV-1). | Figure 3: (a and b) The 2 year relapse-free survival estimates for Wilms' tumor in the present study
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However, on comparison of the impact of preoperative chemotherapy with the Log Rank (Mantel-Cox) test, the variation in survival estimates in Stages I, II, and III was statistically insignificant (P = 0.889, 0.883, and 0.843, respectively). The local relapse for Stage I, II, and III diseases on the comparison between delayed nephrectomy (underwent tru-cut biopsy) and upfront nephrectomy (no biopsy) was statistically insignificant (P = 0.639, P = 1, and P = 1, respectively). However, none of the patients in the delayed nephrectomy group had tumor spill as compared to the upfront nephrectomy group (6/43), P = 0.02.
The mortality during the treatment course was due to advanced disease (43) and sepsis occurring during chemotherapy.[8]
| Discussion | | |
Focused research and better knowledge in WT have improved the outcome in developed countries; however, despite available knowledge expected improvements are not seen in developing countries. This prompted us to retrospectively analyze our 10-year data at a tertiary care center in Central India. We could identify many local practice gaps that are unique to resource-constrained settings and also some global practice gaps which prevent uniformity in the treatment protocols and achievement of “textbook outcomes” globally.
The sub-optimal outcome in India is mainly due to late presentation, the larger size of the tumor, poor access to specialized treatment, and lack of clarity in treatment protocols that are specific to these settings.[5],[7] This is compounded by under-reporting due to a lack of cancer registries. Published Indian studies are scarce and reports a combined total of only 319 cases, reported survival was 54%–85%, and the relapse rate was 13%–20% [Table 2].[8],[9],[10],[11],[12] All these studies uniformly show a late presentation of WT with a significant number of patients in higher stages [Table 2]. A close scrutiny of these publications reveals wide variations in the staging and management protocol selection. All authors adopted an individualized protocol, suggesting a clear need for developing a resource-poor setting-specific protocol. [Table 3] shows a detailed analysis of practice gaps in the present study. | Table 3: The practice-gap analysis and its possible impact on the practice guidelines at global and low- and middle-income countries levels
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Our overall mean survival time was 45.7 (95% CI, 41.08, 50.30). The stage-wise mean survival time was 61.67 (95% CI, 54.914, 68.443), 50 (95% CI, 44.595, 55.419), 27.6 (95% CI, 21.202, 34.084), and 10.8% (95% CI, 5.852, 15.703) for Stage I–IV, respectively. These may appear sub-optimal when compared to those from developed countries and few of the Indian studies; however, these are similar to the results found in other resource-constrained settings.[1],[2],[5] The higher age (median age of presentation 4 years), large tumor size (mean size of the tumor 10.32 + 3.1 cms), late stages on presentation (only 19.23% presented in Stage I, most of Stage II and III tumors had crossed the midline; therefore, requiring preoperative chemotherapy, upfront surgery was feasible in only 27.56% of patients), higher relapse rate (poor compliance with chemotherapy and RT schedules in only 31.14% and 28.57%, respectively), and late presentation of relapse (due to irregular follow-ups relapses were quite large by the time they were noticed and often associated with distant metastases) are the major reasons for our inferior outcomes. The major local practice gaps identified in our setting are shown in [Table 3]. The OS and EFS RFS were found to be sub-optimal in this study, which are largely related to resource-challenged factors, practice violations, early abandonment of treatment, or poor compliance to adjuvant treatment.
Apart from the findings of the present study, a further practice-gap analysis showed the current state of practice gaps and their possible impact on the practice guidelines at the local and global level, as shown in [Table 3]. These predominantly include the dichotomy in staging and treatment guidelines of Société internationale d'oncologie pédiatrique (SIOP) and Children's Oncology Group (COG) classification systems (upfront surgery vs. preoperative chemotherapy); the controversy regarding preoperative/prechemotherapy Tru-cut needle biopsy; how to tackle the low sensitivity in the detection of capsular penetration (elevating Stage I to II) by computed tomography/magnetic resonance imaging scans; importance and inclusion of weight and size of the tumor and tumor histology (anaplasia) in prognosis; quandary of stage reduction after preoperative chemotherapy; and earlier diagnosis of asymptomatic relapses by more frequent follow-ups and surveillance scans.[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[30],[31],[32],[33],[34],[35],[36],[37],[38] Already winds of change are blowing with some convergence of ideology between the guidelines of SIOP and COG systems with an attempt at the identification and selection of patients who will benefit from preoperative chemotherapy.[23],[39] The overall and stage-wise survival remains similar regardless of adopting either of the two philosophies.[24],[37] Similarly, Indian authors have incorporated the weight and size of the tumor and tumor histology (anaplasia) in the planning treatment protocol.[25] However, expectations of preoperative chemotherapy in large WTs resulting in decreased tumor spillage rate or improved survival are not always met.[8],[12],[26],[27] As a result, most of the centers in India adopt individualized policy between upfront surgery and preoperative chemotherapy in large size tumors, late stages, and hope for minimizing the risk of rupture.[25],[28] In the present study, high rate of relapse, large size relapse, and higher relapse-related mortality are another area which needs special attention and were because of late stage disease, certain protocol violations/practice gaps [Table 3], late presentation of relapse not amenable to treatment, and poor treatment compliance. Another striking finding in the study was high median time of relapse (20.5 months) which is usually less than an year in WT. The explanation for this finding may be late presentation of relapse which are noticed as large-sized relapse, all local relapses being >5 cm (mean size of 8.8 ± 3 cm).
Lack of sharply defined data from low- and middle-income countries (LMICs) is a global problem; as worldwide collated data from the International Agency for Research on Cancer contains only 8%–21% data of cancer patients from the developing world.[29] Better and systemic reporting of data, creation of more cancer registries, and improved participation in the existing National Cancer Registry Program will go a long way to mitigate this deficiency.[40]
Our 10-year retrospective analysis of WTs including practice-gap analysis leads to many questions – answers to these will help in achieving uniformity in the treatment protocols and step forward to achieve “textbook outcomes” in LMICs. Society of Pediatric Urology, under the aegis of the Indian Association of Pediatric Surgeons, has already distinguished itself in the leadership role and formulated standard treatment guidelines for WTs.[41] A revision of the WT guideline, addressing these knowledge-practice gaps will be of immense help for all the pediatric surgeons working in LMICs, similar to other societies who have modified the guidelines according to the geographical variations.[17],[18]
| Conclusion | | |
WT is associated with late presentation, large size, sub-optimal survival, higher relapse, and poor compliance to postoperative treatment in our setting. This study identifies the “global” and “local” practice gaps related to late presentation, preoperative staging/biopsy, the dichotomy of existing protocols, preoperative chemotherapy, stage redistribution, and sub-optimal survival. There is a need for the revised guidelines which address and bridge the practice gaps, which are unique to resource-constrained settings to improve the outcomes of WT.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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