Second generation of AHOPCA (Asociación de Hemato-Oncología Pediátrica de Centro América) treatment guidelines for Wilms tumor: a report of outcomes

Background: The AHOPCA (Asociaci´ on de Hemato-Oncolog´ ıa Pedi´ atrica de Centro Am´ erica) Wilms tumor (WT) treatment guidelines, adapted from NWTS-4 and -5 and recommending upfront nephrectomy (UN), were modified to include 4 to 6 weeks of preoperative chemotherapy (POC) in frail patients with advanced disease. We aim to describe the outcomes of this implemented approach. Procedure: A retrospective analysis of prospectively collected data from newly diagnosed patients with unilateral WT between 2012 and 2018.Results: Of 353 eligible patients, 247 (70%) received POC. POC group had higher initial tumor volume (median 590 ml vs. 308 ml, p<0.0001) and more stage IV disease (30% vs. 3%, p<0.0001) compared to UN group. During POC, there were 4 deaths, 14 abandonments and 11 progressive diseases. After response assessment, 62% showed partial tumor response with median tumor volume reduction to 257 ml. Two-hundred eighteen (88.2%) underwent nephrectomy. Tumor rupture/spillage occurred in 17.9% of UN and 18.8% of POC group; Local stage III was found in 55% of UN and 68.3% of POC group. Anaplasia (focal and diffuse) was present in 13.6% (17% UN and 11.9% POC). The 5-year abandonment-sensitive event-free survival (asEFS) and abandonment-sensitive overall survival (asOS) rates were 69%±2.5% and 75%±2.4%, respectively. The asEFS rates were 75%±4.3% for UN and 66%±3.0% for POC (p=0.07).Conclusions: Many AHOPCA patients presented with unresectable advanced disease, necessitating the use of POC. POC effectively reduced tumor volume and facilitated safe surgery in fragile patients. Adopting the standard SIOP WT neoadjuvant approach could enhance staging and risk stratification in AHOPCA. TITLE PAGE 1 Posted on 11 Jun 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.174962171.11168885/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. Second generation of AHOPCA (Asociaci´ on de Hemato-Oncolog´ ıa Pedi´ atrica de Centro Am´ erica) treatment guidelines for Wilms tumor: a report of outcomes Authors: Thelma Velasquez-Herrera MD1, Patricia Valverde MD1, Soad Fuentes MD2, Armando Pe˜ na MD3, Roberta Ortiz MD4, Patricia Calderon MD4, Margarita Montero MD5, Giovanna Gattuso MD6, Jessica Blanco MD7, Magda Arreola1, Israel Fernandez-Pineda9 Monika Metzger MD10, Sandra Luna-Fineman MD,11, Judith Wilimas MD8, Filippo Spreafico MD6 Credentials: 1 Unidad Nacional de Oncolog´ ıa Pedi´ atrica, Guatemala. 2Hospital Benjam´ ın Bloom, El Salvador. 3Hospital Escuela Universitario, Tegucigalpa, Honduras. 4Hospital Manuel de Jesus Rivera, Nicaragua. 5Hospital de Ni˜ nos Robert Reid Cabral, Santo Domingo, Dominican Republic. 6Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy. 7 International Agency for Research on Cancer, Lyon, France. 8St. Jude Children/acute.ts1s Research Hospital, Memphis, Tennessee. 9Department of Pediatric Surgery, Children’s Health Ireland at Crumlin Hospital, Dublin, Ireland 10 M´ edecins sans Fronti` eres, Geneva, Switzerland. 11University of Colorado, United States of America. Corresponding Author: Thelma Vel´ asquez-Herrera, MD. Unidad Nacional de Oncolog´ ıa Pedi´ atrica, 8th Street 7-02 zone 11, Guatemala, City, Guatemala. Postal Code 01011. Contact: Tel: +502 23289600 ext: 330, mail: [email protected] Word Count for: a) Abstract: 250 b) Main Text: 3090 The number of: 1. Tables: 2 2. Figures: 4 3. Supporting Information files: 2 tables and 1 figure. Short running title: Treatment guidelines for Wilms tumor in AHOPCA.

Wilms tumor, low-middle income countries, SIOP-WT guidelines, NWTS 4 and 5, treatment abandonment Abbreviations key table: 2 Posted on 11 Jun 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.174962171.11168885/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. Abbreviation Full term AHOPCA Asociaci´ on de Hemato-Oncolog´ ıa Pedi´ atrica de Centro Am´ erica ac-EFS Abandonment-censored Event Free Survival as-EFS Abandonment-sensitive Event Free Survival. ac-OS Abandonment-censored Overall Survival as-OS Abandonment-sensitive Overall Survival. COG Children’s Oncology Group CT Computed Tomography scans EFS Event Free Survival LMIC Low-Middle Income Countries. NWTSG National Wilms Tumor Study Group OS Overall Survival PD Progressive disease POC Preoperative chemotherapy RT Radiotherapy SIOP International Society of Pediatric Oncology UN Upfront Nephrectomy WT Wilms tumor The findings of this manuscript were accepted as printed abstract in the International Society of Pediatric Oncology Congress at Ottawa, Canada, identified as: No. 786: Wilms Tumor in the AHOPCA Region: Identifying Opportunities to Improve Quality of Treatment in a Consortium of Low and Middle-Income Countries

Background: The AHOPCA (Asociaci´ on de Hemato-Oncolog´ ıa Pedi´ atrica de Centro Am´ erica) Wilms tumor (WT) treat- ment guidelines, adapted from NWTS-4 and -5 and recommending upfront nephrectomy (UN), were modified to include 4 to 6 weeks of preoperative chemotherapy (POC) in frail patients with advanced disease. We aim to describethe outcomes of this implemented approach. Procedure: A retrospective analysis of prospectively collected data from newly diagnosed patients with unilateral WT between 2012 and 2018.

Of 353 eligible patients, 247 (70%) received POC. POC group had higher initial tumor volume (median 590 ml vs. 308 ml, p<0.0001) and more stage IV disease (30% vs. 3%, p<0.0001) compared to UN group. During POC, there were 4 deaths, 14 abandonments and 11 progressive diseases. After response assessment, 62% showed partial tumor response with median tumor volume reduction to 257 ml. Two-hundred eighteen (88.2%) underwent nephrectomy. Tumor rupture/spillage occurred in 17.9% of UN and 18.8% of POC group; Local stage III was found in 55% of UN and 68.3% of POC group. Anaplasia (focal and diffuse) was present in 13.6% (17% UN and 11.9% POC). The 5-year abandonment-sensitive event-free survival (asEFS) and abandonment-sensitiveoverallsurvival(asOS)rateswere69% ±2.5%and75% ±2.4%,respectively.TheasEFS rates were 75%±4.3% for UN and 66%±3.0% for POC (p=0.07).

Many AHOPCA patients presented with unresectable advanced disease, necessitating the use of POC. POC effectively reduced tumor volume and facilitated safe surgery in fragile patients. Adopting the standard SIOP WT neoadjuvant approach could enhance staging and risk stratification in AHOPCA. 3 Posted on 11 Jun 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.174962171.11168885/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. MAIN TEXT:

Wilms tumor (WT) is the most common primary malignant renal tumor in children, accounting for 5% of malignancies in patients under 15 years [1]. The development of standardized treatment protocols, including those from the Children’s Oncology Group (COG) Renal Tumor Committee and the International Society of Pediatric Oncology (SIOP) Renal Tumour Study Group, has led to cure rates of approximately 90% in high-income settings [2]. However, outcomes in low- and middle-income countries (LMICs) remain poor [3], due to factors such as advanced disease at diagnosis, malnutrition, high treatment abandonment rates, lack of access to essential medications, and sociodemographic vulnerabilities [4, 5]. Studies from the WT Africa Project and other LMIC settings highlight these challenges, including abandon- ment of treatment (7-26%) and treatment-related mortality (13-21%) as major contributors to treatment failure [6-9]. In LMICs, the incidence of advanced and metastatic tumors is also higher (22-33%), but treat- ment intensity is often reduced to avoid fatal toxicity [10, 11]. The lack of a structured multidisciplinary team and a systematic approach to upfront nephrectomy (UN) or preoperative chemotherapy (POC) impacts treatment plans and risk stratification [11, 12]. The AHOPCA( Asociaci´ on de Hemato-Oncolog´ ıa Pedi´ atrica de Centro Am´ erica) consists of pediatric can- cer centers from Guatemala (n=2), El Salvador (n=1), Honduras (n=3), Nicaragua (n=1), the Dominican Republic (n=2), Haiti (n=1), and Panama (n=2), with shared treatment guidelines for WT since 2000 [5]. These countries face challenges such as inconsistent access to computed tomography scan (CT), drug shortages (notably dactinomycin and doxorubicin), and limited access to radiotherapy (RT). The oncologic multidisciplinary team typically includes pediatric oncologists, general pediatric surgeons with varying levels of expertise in pediatric oncology surgery, along with pathologists trained in the use of the College of Ameri- can Pathologist cancer protocols for renal tumors [13], and more familiar in evaluating chemotherapy-na¨ ıve tumors. The first generation of AHOPCA guidelines, adapted from the National Wilms Tumor Studies (NWTS)4 and 5, recommended UN. Between 2000 and 2011, a growing number of local physicians began adopting POC (eventually 34%) for patients who were not suitable for UN due to advanced disease or clinical deterioration. Duringthisperiod,theabandonment-sensitiveevent-freesurvival(asEFS)andabandonment-sensitiveoverall survival (asOS) rates were 56.9% and 65.3% respectively, with treatment abandonment (15.5%), progressive disease (10.6%) and relapse (10.3%) being the main factors that impacted outcomes in AHOPCA. [5, 14]. In 2005, the AHOPCA WT Working Group was formed with the collaboration of international experts from the COG and SIOP. This group promoted continuous education and guideline adherence via the Cure4Kids platform. In 2012, AHOPCA agreed to implement the treatment guidelines based on the SIOP principles emphasizing the advantages of POC. This report aims to describe the diagnostic characteristics, treatment approaches, and outcomes of patients with a newly diagnosed WT between 2012 to 2018, focusing on iden- tifying outcome improvement in LMICs.

This is a retrospective analysis of prospectively collected data from patients younger than 18 years, newly diagnosed with unilateral WT and registered in the POND database (www.POND4Kids.org) between Ja- nuary 2012 and December 2018. Patients were treated according to AHOPCA WT guidelines at centers in Guatemala, El Salvador, Honduras, Nicaragua, and the Dominican Republic. Exclusion criteria included: age under 6 months, bilateral tumors, non-Wilms tumor, or previous chemotherapy treatment. The guidelines were approved by local ethic committees, complied with hospital regulations, and patients/parents signed informed consent at their respective treatment centers. The treatment guidelines are shown in supplementary table 1. Upon diagnosis, all patients underwent chest andabdominalCT,withanysolidnodulesfoundinthelungsorliverconsideredmetastaticdisease(regardless of size or shape). Patients deemed unresectable by the local multidisciplinary team, either for medical or 4 Posted on 11 Jun 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.174962171.11168885/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. technical reasons (i.e., large tumor volume, presence of infections or other clinical comorbidities) received POC consisting of three drugs (whether localized or metastatic): vincristine (1.5 mg/m2 once weekly for week 0-5), dactinomycin (1.5 mg/m2 on week 0), and doxorubicin (45 mg/m2 on week 3). Pre-treatment biopsy was not mandatory. Patients receiving POC were automatically classified as local stage III [15]. In patients receiving POC, a response assessment was done at week 6 with abdominal CT or ultrasound, and patients with lung metastasis performed chest CT. Chemotherapy could be extended beyond 6 weeks if: there was no operating room or surgeon available, severe infection or considered necessary after online consultation with the multidisciplinary team. In all cases, tumors without anaplasia were classified as favorable histology WT (FHWT), while those with either focal or diffuse anaplasia were classified as unfavorable histology WT (UHWT). Following nephrec- tomy, patients were stratified into three risk groups: low-risk (LR), for stage I and II, FHWT, treated with vincristine and dactinomycin (VA) for 18 weeks (adapted from EE4A regimen) [16]; intermediate-risk (IR), for stage III-IV FHWT, stage I-III focal anaplasia, and stage I diffuse anaplasia, treated with VA plus doxoru- bicin (VAD) for 24 weeks (adapted from DD4A regimen) [15]; high-risk (HR), for patients with stage II-IV diffuse anaplasia, treated with an intensified regimen adding cyclophosphamide and etoposide (VDC-CyE) to the VAD regimen for 24 weeks (adapted from Regimen I) [17]. Radiation therapy (RT) was prescribed as follows: whole lung RT (1200 cGys) for all patients with lung pulmonary metastasis regardless of metastatic response after primary chemotherapy; flank RT for stage I-II UHWT (1000 cGys), and flank or total abdo- minal RT for stage III FHWT, UHWT and/or liver metastatic disease (1200 cGys). All patients who had POC received flank/abdominal RT after nephrectomy, accordingly (Supplemental table 1). During the study period, the SIOP histological risk classification [18], was not applied systematically, alt- hough numerous patients were treated with POC. AHOPCA’s pathologists underwent a transition period, training on the SIOP pathology guidelines. Nonetheless, histologic risk stratification and local staging of pre-treated cases were ultimately assigned by the treating oncologist with the support from international mentors during weekly tumor boards. Statistical analysis was performed using R studio v.4.3.1 (free license) [19], and SAS v9.4 licensed by and in collaboration with University of Milano-Bicocca, Monza, Italy [20]. The primary outcome measures were: abandonment-sensitive event-free survival (asEFS) [21], defined as the time from the start of treatment until the first event: death by any cause; treatment abandonment (if the patient was absent for four or more consecutive weeks during therapy) [22]; progressive disease (PD) during POC, defined as intensification of chemotherapy adding cyclophosphamide, carboplatin and etoposide due to increase in tumor size making the tumor unresectable or any new lesion on imaging, and PD after nephrectomy, as the detection of new lesions while still on treatment); relapse (new lesion after ending therapy in complete remission); or second malignant neoplasm (SMN). Abandonment-sensitive overall survival (asOS) was estimated as the time from the beginning of treatment until death (from any cause) or date of treatment abandonment (presuming that patients who do not complete therapy succumb to their disease). All were censored on the date of the last follow-up if no event occurred. The asEFS and asOS probabilities were estimated using the Kaplan- Meier method with Greenwood standard error (SE) [21, 23] and compared with the log-rank test; the crude cumulative incidences (CI) of relapse or progression were estimated and compared with the Gray test [24]. EFS and OS probabilities were estimated censoring treatment abandonment to assess the outcome of those who followed the treatment regimen. Comparative analysis between UN and POC groups was made using t-test for continue variables and chi-square for categorical variables regarding age, baseline tumor volume, stage, histology (SIOP histological type for patients in POC group) and risk stratification. Significance was defined with p- values 50%, PR <50% (reduction from 25-50%), stable disease (20%. The POND database was closed in 2019, therefore, data updates were continued through local databases. For the present analysis, follow-up was frozen on August 31, 2022.

Patients’ characteristics and initial treatment 5 Posted on 11 Jun 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.174962171.11168885/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. Of 424 newly diagnosed renal tumors, 353 were WT eligible for this analysis (Fig. 1). One hundred and six (30%) cases had UN; and 247 (70%) had POC. The median age at diagnosis was 3.61 years and 168 (47.6%) were male. Seventy-seven (22%) had stage IV WT, and 28 (8.6%) had inferior vena cava thrombus. Characteristics of patients are summarized in Table 1. Upfront Nephrectomy (UN) patients Of 106 patients suitable for UN, 103 (97.2%) had localized WT. The median initial tumor volume was 380 ml (with 21% volume > 500 ml, and 5.7% >1000 ml). During surgery, two patients (1.9%) reported incomplete resection and 19 (17.9%) had tumor rupture/spill. Lymph nodes were sampled in 65 cases (61.3%). Eighteen (17%) cases were UFWT (focal or diffuse anaplasia) . The distribution of systemic stage I, II, III and IV was 14 (13.2%), 33 (31.1%), 56 (55.7%) and 3 (2.8%) respectively. Twenty-nine (27.6%) were assigned LR treatment arm, 61 (58.1%) IR, and 15 (14.3%) HR (Table 2). Preoperative Chemotherapy (POC) patients: Of 247 patients in POC group, 70% were localized (considered stage III as per guidelines). The initial tumor volume was larger (median 590 ml, p500 ml (57.9%, p 1000 ml 20.2%, (p<0.0001), and higher proportion of metastatic disease (30%, p<0.001) compared to UN group (Table 1). Two hundred and twenty-three (90%) had a response assessment, POC reduced significantly the median cohort tumor volume to 257ml, (p<0.0001), 169/223 (68.3%) had primary tumor PR, 19 (7.6%) had no reduction or increase in size, and 35 (14.1%) had no data. During POC, 4 (1.6%) patients died (3 infections, 1 due to PD), 14 (5%) abandoned treatment, and 16 (6.4%) had PD (local or pulmonary) and changed the treatment approach. Of 218 (88%) patients that performed delayed nephrectomy, the median time from diagnosis to surgery was 7 weeks(range3-26weeks).Duringsurgery,4(1.8%)hadincompletetumorresection,41(18.8%)intraoperative tumor rupture/spill, and 56 (25.6%) had no lymph node sampling. Anaplasia was diagnosed in 26 cases (11.9%), 14 focal and 12 diffuse. Patients with diffuse anaplasia received HR regimen. During multidisciplinary case discussion with mentors, 12/31 cases were classified as SIOP blastemal-type WT and treated accordingly. After evaluation of surgical and histological findings during multidisciplinary meeting, SIOP staging system was applied in patients with localized disease at diagnosis, and 8 (3.2%) were downstage to Stage I, 52 (21%) to stage II, and 113 (45.7%) remained stage III. Allocation of LR, IR and HR treatment arms was 8 (3.7%), 184 (84.4%), and 26 (11.9%) respectively (Table 2). Radiation therapy RT was often delayed with median interval from nephrectomy to RT of 6 weeks (range 1-36 weeks). In the UN group, 9/33 (27%) stage II, 41/56 (73%) stage III received flank/abdominal RT and 2/3 (66%) patients with stage IV had abdominal and whole lung RT. In the POC group, AHOPCA guidelines recommended local RT in all cases regardless of post nephrectomy stage. Abdominal RT was given to 3/8 (37.5%) cases stage I, 23/52 (42.5%) stage II, 81/113 (71.6%) stage III, and abdominal± whole lung RT was given to 53/75 (70.6%) cases stage IV. RT in stage III and IV in both groups was not given due to abandonment (n=21), PD (n=20) or death (n=7), or unavailability (n=7). In 11 cases it was avoided after discussion of surgical and histological findings in multidisciplinary meeting. Events: Of the 353 patients, 9 (2.5%) had toxic death, 4 during POC, 1 postoperative bleeding, and 4 after nephrec- tomy receiving VAD chemotherapy (septic deaths). Thirty (8.4%) abandoned therapy, 22/247 (8.9%) did so in POC and 8/106 (7.5%) in UN group. Fourteen patients abandoned therapy during POC, 10 returned and 6 Posted on 11 Jun 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.174962171.11168885/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. completed treatment, 9 of whom are alive. Fifty (14%) progressed and 23 (6.5%) relapsed. One secondary malignancy (thyroid carcinoma) was observed in the POC group (Table 2). Of the PD and relapses, 53/247 (21.4%) were in POC and 17/106 (16%) in UN group. Eleven patients with PD during neoadjuvant chemo- therapy were treated with an intensified combination of ifosfamide, carboplatin and etoposide (ICE-based regimen), 9 underwent surgery and 3 are alive. Survival results With a median follow- up of 5 years (range 0.96 to 6.1), the asEFS and asOS rates were 69%±2.5% and 75%±2.4%, and abandonment-censored EFS (acEFS) and acOS rates of 75%±2.4% and 78%±2.3%, respec- tively (Figure 2). In the UN group, the 5-year as-EFS and as-OS rates were 75%± 4.3% and 81%± 4.1%, respectively. The as-EFS was 81%± 5.8% for stages I-II, 71%± 6.5% for stage III, and 33%±27% for stage IV. The POC group showed a trend towards inferior 5-year asEFS and asOS rates (66%±3% and 73%±2.9%, respectively) compared to those managed with UN (Table 2 and Figure 3). The as-EFS rates by stage in POC were 85%± 4.5% for stage I-II, 62%± 4.6% for stage III, and 55%± 5.8% for stage IV, with no statistical difference compared to the survival rates observed in UN group (Figure 4). In both groups, patients with diffuse anaplasia were treated as high-risk tumors with intensified chemothe- rapy. The 5-year ac-EFS for these patients were 40%± 22% in UN and 33%± 13% in POC, respectively. In patients with POC, cases retrospectively classified as blastemal-type had significantly lower acEFS and acOS rates compared to those with SIOP intermediate and low risk tumors (p<0.0001) (supplementary table 2). DISCUSION The 5-year as-EFS and as-OS of WT treatment in the AHOPCA region have improved compared to the first generation of our guidelines (2000-2011). The asEFS increased from 65%±2.5% to 75%±2.4% during this period. AHOPCA has made progress in reducing treatment abandonment, which decreased from 15% to 8.5%, as well as toxic deaths, which dropped from 5.4% to 2.5% [5]. Other LMIC have documented similar results addressing non-disease related factors [3, 6, 25]. We highlight the contribution of neoadjuvant chemotherapy in allowing safer surgical resections. When censoring the abandonment, the 5-year EFS and OS between 2000-2011 and 2012-2018 periods did not change significantly (Supplementary Figure 1), hinting that treatment factors in stage and pathology accuracy need to be addressed. In our cohort, 70% of cases were ineligible for UN due to large advanced-stage tumors in frail children or with clinical deterioration. As a result, POC made 88.2% of them eventually suitable for safe nephrectomy with manageable toxicity. Moreover, a significant number of cases had large tumor volume (>1000 ml) and vena cava thrombosis among UN cohort, explaining the high incidence of intraoperative rupture (17.9%) as reported by other groups [26]. The purpose of implementing POC in AHOPCA WT guidelines was to manage complex clinical conditions while minimizing treatment-related toxicity, performing safe and adequate oncologic resections, and avoiding nephrectomy-related morbidity in frail patients with large tumors. This approach justifies the adaptation of POC regimen, that differs from the standard SIOP-2001 preoperative regimens [27, 28]. AHOPCA’s regimen, adopted from DD4A COG protocols [15], added doxorubicin to localized tumors but it is less intensive in cases with metastatic disease. As seen in SIOP studies [27, 29, 30], POC effectively reducedtumor volume, although it did not result in significant tumor downstaging when compared to UN group, as reported in SIOP studies [31]. This outcome has also been described in other LMICs, possibly due to the combination of higher tumor volume and stage in situations of poverty and limited-resources [7, 8, 32], the classification of patients receiving POC as stage III (in line with COG approach) and the high number of patients with inaccurate lymph node sampling (30% had no lymph nodes sampled). AHOPCA needs the adoption of standardized oncologic surgery practices for WT [33][34], including the accurate lymph node sampling, which is feasible in LMICs, and a critical step for accurate staging and risk stratification. 7 Posted on 11 Jun 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.174962171.11168885/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. Our experience suggests that POC is feasible, with manageable toxicity -even in malnourished children-and enabling better planning of the nephrectomy with time to improve the child’s clinical condition. We also believe that, during the POC treatment phase, the treatment team can establish a stronger relationship with families, offer social support to reduce the risk of treatment abandonment. A limitation of the AHOPCA second-generation guidelines is the lack of consideration for chemotherapy- induced histopathological changes, a hallmark of SIOP prognostic stratification. However, we view this as a learning phase for our pathologists, helping them gain expertise interpreting the tumors’ neoadjuvant chemotherapy induced response, which involves a shift from a risk stratification of chemotherapy-na¨ ıve tu- mors (based on favorable/unfavorable histology), to the SIOP response-induced histological risk classification (low, intermediate and high-risk categories) [18, 35]. For LMICs, adopting the SIOP-UMBRELLA pathology guidelines offers a clear strategy to improve outcomes, reduce unnecessary toxicity (doxorubicin) in histologi- cally low and intermediate-risk localized tumors; and ensure timely treatment intensification for tumor with high-risk histology [18, 30, 35]. Moreover, the limited access to tumor molecular characterization precludes the use of loss of heterozygosity of 1p and 16q for risk stratification [36]. Therefore we continue to train pathologists on the SIOP classification criteria and implement standard operating procedures to ensure the systematic reporting of histological and staging elements, as approved by COG [13] and SIOP [37]. We also acknowledge that there is a risk of treating non-WT with preoperative chemotherapy, in our cohort 37/424 (8.7%), however, SIOP standards for selecting patients for POC or to perform biopsy can reduce this risk [38]. Multidisciplinary case discussions have become standard practice in pediatric oncology and have been shown to impact clinical decisions concerning staging and surgical approach [12]. These discussions, involving local and international experts ensured consistent patient allocation to the most appropriate treatment options. For example, they became valuable in deciding when to safely omit RT in patients whit POC who met the criteria for stage I and II with low- and intermediate-risk histopathology (even though AHOPCA guidelines recommended RT for all patients in POC group) or when to intensify treatment for patients with high-risk histology rather than anaplasia (i.e., blastemal–type after POC). The multidisciplinary team serves as an invaluableresourcefororganizationslikeAHOPCA,whichhavelimitedexpertiseandresourcesforthoughtful and impactful discussion. In conclusion, POC was implemented and is feasible within AHOPCA. The next steps to improve AHOP- CA WT outcome involve systematically approaching all newly diagnosed renal tumors with POC, following SIOP approach, and ensuring proper interpretation of chemotherapy-induced histopathological changes to implement the SIOP risk stratification. These strategies are feasible and accessible for other LMIC as well. This approach may help reduce unnecessary toxicity in low and intermediate-risk localized WT while enab- ling timely intensification of treatment for high-risk WT. Major challenges for the region include ensuring continuous family support to prevent treatment abandonment, overcoming barriers to care access, improving surgical staging procedures, continuing pathologist training to ensuring systematic reporting of findings, evaluating toxicities, and providing supportive care and patient education. CONFLICT OF INTERESTS: The authors declare that they don’t have any conflict of interest in the development of this manuscript. AKNOWLEDGEMENTS: Maria Grazia Valzechi. Fundacion Ayudame a Vivir (AYUVI), Guatemala. Fundacion Ayudame a Vivir (AYUVI), El Salvador. Fundacion Hondurena para el Nino con Cancer, Honduras. Comision Nicaraguence de Ayuda contra el Cancer (CONANCA), Nicaragua. 8 Posted on 11 Jun 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.174962171.11168885/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. Foundacion Amigos Contra el Cancer Infantil (FACCI), Dominican Republic. Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy. St Jude Children’s Research Hospital.

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Figures.docx available at https://authorea. com/users/461252/articles/1304173-second-generation-of-ahopca-asociaci%C3%B3n-de-hemato- oncolog%C3%ADa-pedi%C3%A1trica-de-centro-am%C3%A9rica-treatment-guidelines-for-wilms- tumor-a-report-of-outcomes Hosted file Treatment guidelines for Wilms tumor in AHOPCA. Tables.docx available at https://authorea. com/users/461252/articles/1304173-second-generation-of-ahopca-asociaci%C3%B3n-de-hemato- oncolog%C3%ADa-pedi%C3%A1trica-de-centro-am%C3%A9rica-treatment-guidelines-for-wilms- tumor-a-report-of-outcomes 10 Posted on 11 Jun 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.174962171.11168885/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. 11 Posted on 11 Jun 2025 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.174962171.11168885/v1 | This is a preprint and has not been peer-reviewed. Data may be preliminary. 12