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Management of Wilms' tumour
SYMPOSIUM: ONCOLOGY
Management of Wilms’ tumour
The role of co-operative groups Given the rarity of paediatric tumours, much of the success in understanding the biology and improvements in outcomes for Wilms’ tumour has been through efforts of co-operative groups. Historically, the UKCCSG (UK Children’s cancer study group), now CCLG (Children’s cancer and leukaemia group), conducted several randomized clinical trials for paediatric renal tumours and is currently part of SIOP. Societe Internationale d’Oncologie Pediatrique Renal Tumour Study Group (SIOP-RTSG) leads trials in Europe and COG (Children’s Oncology Group), previously the National Wilms’ Tumour Study Group (NWTSG) has been instrumental in conducting a series of trials in America.
Kavitha Srivatsa Sucheta J Vaidya
Abstract Wilms’ tumour (WT) is the commonest renal tumour of childhood and its treatment is regarded as one of the success stories of paediatric oncology with over 90% cure rate. Most patients present with localized unilateral tumours. Histology and stage are important prognostic factors, and children with stage IV and diffuse anaplasia have poorer outcomes. Whilst there are differences in the treatment approaches around the world, outcomes are excellent for most subgroups of te Internationale d’Oncologie Wilms’ tumour. The European Socie diatrique (SIOP) recommends pre-operative chemotherapy to chilPe dren over 6 months whilst the North American Children’s Oncology Group offers primary nephrectomy and uses biomarkers for treatment stratification. Overall, 15% patients experience a relapse and their management depends on the initial treatment they had received. The focus of research is to decrease long term side effects, reduce treatment for selected subgroups, and improve our understanding of prognostic biomarkers to help tailor treatments. This article provides an overview for paediatricians giving an update on the important recent advances.
Pathophysiology Wilms’ tumour is an embryonal tumour of childhood and has histological and molecular resemblance to the embryonic kidney. The fetal kidney develops from the ureteric bud (forming collecting ducts) and the metanephric blastema (forming the stroma, glomeruli, proximal and distal tubules and loop of Henle). The blastema usually disappears by 36 weeks of gestation, however at birth approximately 1% of infants retain residual blastema within their kidney. These cells are described as nephrogenic rests (NR). Nephrogenic rests are thought to be the precursor lesions of Wilms’ tumours and in around 40% of patients, these can be identified in the resected tumour specimen. Nephrogenic rests are of two types: intralobar nephrogenic rests (ILNR), found anywhere within the renal lobe and perilobar nephrogenic rests (PLNR), confined to the periphery of the renal lobe, and thought to develop later during embryogenesis. Nephroblastomatosis is defined as the presence of diffuse or multifocal nephrogenic rests. Histologically, Wilms’ tumour mimics the triphasic development of the normal kidney consisting of blastemal, epithelial and stromal cell types in various proportions. Five to ten percent of Wilms’ tumours demonstrate anaplastic histology, which is defined by the presence of atypical, polyploid mitotic figures, large nuclear size, and hyperchromasia.
Keywords chemotherapy; management; nephroblastoma; pathophysiology; Wilms’tumour
Epidemiology Primary renal tumours account for 4e7% of all childhood cancers. Wilms’ tumour affects approximately one child per 10,000 worldwide before the age of 15 years. In the UK, around 80 children are diagnosed with renal tumours each year. Wilms’ tumour (nephroblastoma) accounts for 90% of these. More than 80% of children are diagnosed below the age of five years, the median age at diagnosis being 3.5 years. Most present with unilateral tumours. Synchronous bilateral or multifocal tumours occur in approximately 10% of patients and generally present at an earlier age. Wilms’ tumour can also rarely occur in adults where they are uncommon representing less than 1% of all renal tumours. Incidence rates vary between ethnic groups, with Asians having substantially lower incidence. There is slight female preponderance in the Caucasian population.
Genomic alterations of prognostic significance Several genetic mutations are involved in the formation of Wilms’ tumour and some are known to have prognostic significance. Chromosome 11 Chromosome 11 harbours two distinct Wilms’ tumour suppressor genes WT1 (11p13) and WT2 (11p15). WT1 mutations occur in only 10e20% of sporadic Wilms’ tumour, suggesting other key genetic mutations are involved in tumourigenesis. Loss of both copies of WT1 has been described as a hallmark of development of Wilms’ tumour in WAGR syndrome (Wilms’ tumour, aniridia, genitourinary anomalies, and mental retardation), Denys-Drash syndrome and Frasier syndrome, suggesting a loss of tumour suppressor function. WT2 is altered in a much higher frequency in sporadic Wilms’ tumour. Loss of imprinting and loss of heterozygosity (LOH) are thought to drive different pathogenetic mechanisms leading to the development and/or progression of Wilms’ tumour.
Kavitha Srivatsa MBBS DCH DNB, Specialty Doctor, Paediatric Oncology, The Royal Marsden NHS Foundation Trust, London, UK. Conflicts of interest: none declared. Sucheta J Vaidya MBBS DCH MD FRCPCH MD, Consultant Paediatric Oncologist, The Royal Marsden NHS Foundation Trust, London, UK. Conflicts of interest: none declared.
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Loss of heterozygosity 16q and 1p Early studies utilising LOH mapping identified chromosomes 1p and 16q as regions of interest with frequency of 12% and 17% respectively (combined incidence of 5%). These have shown to have adverse prognostic significance and used in risk stratifications in the NWTS trials.
Syndromes associated with risk of Wilms’ tumour Syndrome
Genes or locus
High risk of Wilms’ tumour >20% WAGR syndrome WT, Aniridia, Genitourinary abnormalities, Mental Retardation Denys Drash Nephropathy, WT, genitourinary syndrome abnormalities Familial Wilms’ tumour
Copy number gain at 1q This is observed in 30% of tumours. The CCLG, NWTS and SIOP have independently confirmed poorer event-free survival (EFS) and overall survival (OS) in pre-treated and untreated patients with 1q gain. This is being further evaluated prospectively through the SIOP-RTSG Umbrella trial.
Perlman syndrome
Renal hamartomas, nephroblastomatosis, foetal gigantism Mosaic variegated Intrauterine growth retardation, aneuploidy microcephaly Moderate risk of Wilms’ tumour 5e20% Beckwith-Weidemann Hemihypertrophy, macroglossia, syndrome macrosomia, exomphalos Frasier syndrome Pseudohermaphroditism, progressive glomerulopathy Simpson-GolabiOvergrowth, coarse facies Behmel syndrome
Alterations in 17p and MYCN amplification TP53 mutations have been identified in 50e86% of anaplastic WT and MYCN amplification associated with anaplasia are associated with poor prognosis.
Predisposition syndromes and screening Most Wilms’ tumours develop in otherwise healthy children, without any predisposition to cancer. Congenital malformations or genetic syndromes account for around 10e15% cases.1 Screening with 3 monthly abdominal ultrasound scans is recommended for children with more than 5 % risk of developing WT following review by a clinical geneticist and is offered until the age of 7e8 years. Syndromes associated with risk of Wilms’ tumour are described in Table 1.
11p13 WT1 11p13 WT1 FWT1, FWT2 DIS3L2
11p15 WT2, IGF2 11p13 WT1 GPC3, GPC4
Table 1
Diagnostic and staging evaluation It is important to diagnose tumours early. Abdominal ultrasound is the initial imaging study of choice in a patient with a suspected abdominal mass. This can be organized with ease, can be done without any sedation or anaesthesia without exposure to ionizing radiation. Ultrasound confirms the presence of mass, site of origin and presence of tumour thrombus. Cross-sectional imaging with magnetic resonance imaging (MRI) or computerized tomography (CT) of the abdomen is necessary to provide information for a precise diagnosis. MRI is particularly favoured as it is superior to CT scan in delineating small lesions in the contralateral kidney. Functional MRI techniques such as diffusion weighted images (DWI) are being tested as tools to assess response and plan for surgery, particularly in children with
Clinical presentation Most children present asymptomatically with an abdominal mass that is noted when they are bathed or dressed, or by a health professional on a routine visit. Abdominal pain is present in 40 e50% of children. Gross haematuria occurs in about 15e20% of children and microscopic haematuria is seen in around 25% of patients. About 25e45% of children have hypertension at presentation, which is attributed to abnormal activation of the reninangiotensin system. Constitutional symptoms such as fever, anorexia, and weight loss are uncommon and occur in 10% of cases. Atypical presentations include hepatomegaly, ascites and cardiac failure due to tumour extension into the renal vein and inferior vena cava. Occasionally, a child may present with features of an acute abdomen (rapidly enlarging abdominal mass, pain, anaemia and fever) due to tumour rupture. Paraneoplastic syndromes associated with Wilms’ tumour include von Willebrand disease (4e8%), hypercalcaemia, erythrocytosis and very rarely Cushing’s syndrome. Approximately 10% of patients present with metastases through haematogenous spread, most commonly to the lungs (85%), liver (10%) and only very rarely to the bones and brain. In 5e10% of children, Wilms’ tumour may be detected through screening programmes for Wilms’ tumour predisposition syndromes. Patients in the UK have larger tumours at presentation compared to Germany which results in need for more intensive treatments. This is likely to be due to differences in primary healthcare system.
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Phenotype
Differential diagnosis for childhood renal tumours Mesoblastic nephroma Renal cyst Polycystic kidney Multicystic kidney Hydronephrosis Neuroblastoma* Clear cell sarcoma of the kidney Malignant rhabdoid tumour of the kidney Renal Cell Carcinoma Renal rhabdomyosarcoma *Catecholamines and their metabolites (VMA/creatinine, HVA/creatinine) are raised in over 90% of children with neuroblastoma and can be tested with a spot urine test. Box 1
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Staging criteria
Stage I
Stage II
Stage III
Stage IV
Staging criteria in the SIOP- Umbrella protocol
Staging criteria COG
Tumour is limited to the kidney. Tumour is present in the peri-renal fat but is surrounded by a fibrous (pseudo)capsule. The (pseudo)capsule might be infiltrated by viable tumour, which does not reach the outer surface. Tumour might show protruding (botryoid) growth into the renal pelvis or the ureter but does not infiltrate their walls. The vessels or the soft tissues of the renal sinus are not involved by tumour. Intrarenal vessel involvement might be present. Viable tumour is present in the peri-renal fat and is not covered by a (pseudo)capsule, but is completely resected (resection margins are clear). Viable tumour infiltrates the soft tissues of the renal sinus. Viable tumour infiltrates blood and/or lymphatic vessels of the renal sinus or of the peri-renal tissue, but it is completely resected. Viable tumour infiltrates the wall of the renal pelvis or of the ureter. Viable tumour infiltrates the vena cava or adjacent organs (except the adrenal gland) but is completely resected. Viable tumour is present at a resection margin. Nonviable tumour or chemotherapy-induced changes present at a resection margin are not regarded as stage III. Abdominal lymph node involvement is present by either viable or nonviable tumour. Preoperative or intraoperative tumour rupture, if confirmed by microscopic examination (viable tumour at the surface of the specimen at the area of the rupture). Viable or nonviable tumour thrombus is present at resection margins of ureter, renal vein, or vena cava inferior (always discuss resection margins with the surgeon). Viable or nonviable tumour thrombus, which is attached to the inferior vena cava wall, is removed piecemeal by a surgeon. Wedge or open tumour biopsy before preoperative chemotherapy or surgery. Tumour implants (viable or nonviable) are found anywhere in the abdomen. Tumour (viable or nonviable) has penetrated through the peritoneal surface. Haematogenous metastases (for example, lung, liver, bone and brain) or lymph node metastases outside the abdominopelvic region
Tumour limited to the kidney and completely resected Renal capsule intact The tumour was not ruptured or biopsied prior to removal Renal vein contains no tumour (intrarenal vessel involvement may be present) No residual tumour apparent beyond the margins of excision.
Tumour extends beyond the kidney but is completely resected Regional extension of tumour (vascular invasion outside the renal parenchyma or within the renal sinus and/or capsular penetration with negative excision margin) Operative tumour spill confined to flank (no peritoneal contamination) Tumour biopsy (except fine-needle aspiration) prior to surgery
Non-haematogenous metastases confined to the abdomen (e.g., tumour in regional lymph nodes), including tumour implants on or penetrating the peritoneum Gross or microscopic tumour remains postoperative (tumour at the margins of resection) Tumour spill before or during surgery not confined to flank Piecemeal excision of the tumour (removal in >1 piece)
Presence of haematogenous metastases or metastases to distant lymph nodes
(continued on next page)
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Table 2 (continued )
Stage V
Staging criteria in the SIOP- Umbrella protocol
Staging criteria COG
Bilateral renal tumours at diagnosis. Each side should be sub-staged according to the above criteria.
Bilateral renal involvement at the time of initial diagnosis
Data on SIOP pathology taken from reference 3.
Table 2
surgical and for all patients, surgery is the mainstay of treatment, but the timing of surgery differs between SIOP-RTSG and COG protocols. Each strategy has its pros and cons and survival rates are similar. Differences in upfront treatment approaches mean that there are differences in staging (Table 2) and risk stratifications (Table 3). Treatment type and intensity are influenced by several clinical and biological prognostic factors for both groups. The COG advocates for up-front surgical removal, thus providing a detailed histological staging and accurate molecular studies which are necessary for planning post-operative treatment. However, preoperative chemotherapy is recommended in cases with tumour thrombus extending above the level of the hepatic veins, gross involvement of contiguous structures, bilateral Wilms’ tumour, extensive pulmonary compromise from compression by a massive tumour or widespread metastatic disease, and when, according to the surgeon’s discretion, immediate nephrectomy would result in significant morbidity, including tumour spill or incomplete resection. Based on the histology tumours are classified as having favourable (no anaplasia) or unfavourable histology (focal and diffuse anaplasia). SIOP advocates for preoperative chemotherapy for patients over 6 months of age. This approach has the benefit of personalized in vivo assessment of histological response to chemotherapy, including the identification of a ‘high-risk’ category of blastemal-type Wilms’ tumour. Reduction in tumour size and the formation of a fibrous pseudocapsule facilitates surgical removal and decreases the risks of rupture and spillage during surgery. Pre-nephrectomy chemotherapy has also been shown to decrease the risk of intra-operative haemorrhage and lower tumour stages. Primary nephrectomy is recommended for renal tumours in children younger than 6 months old, as congenital mesoblastic nephroma is more prevalent and does not require chemotherapy. SIOP subclassifies and risk stratifies Wilms’ tumour based on histologic changes after chemotherapy. Patients are divided into low-, intermediate-, and high-risk groups considering the degree of tumour necrosis and relative proportion of each of the three cellular components (epithelial, stromal, or blastemal). Patients with diffuse anaplastic or blastemal-type Wilms’ tumour are considered to have high-risk histology.
Histologic risk classification schemas for Wilms’ tumour COG
SIOP
Favourable Wilms’ tumour favourable histology (no evidence of anaplasia)
Low risk -Cystic partially differentiated nephroblastoma Completely necrotic nephroblastoma Intermediate risk Nephroblastomasubtype mixed, regressive, epithelial, stromal, focal anaplasia Unfavourable Diffuse High risk Nephroblastoma -subtype and focal anaplasia blastemal, diffuse anaplasia Table 3
bilateral lesions. Differential diagnosis of renal masses are described in Box 1. Historically, chest X-ray (CXR) was used as a staging tool for lung metastasis. Following outcomes of clinical trials and debate about definition of metastasis, contrast enhanced CT chest is now recommended for staging and the recent prospective UMBRELLA study defines metastatic disease depending on sizes of lung nodules (3 mm) detected on CT.2
Role of biopsy Children’s Oncology Group protocols advocate upfront nephrectomy to achieve an accurate tissue diagnosis before postoperative chemotherapy. Biopsy is indicated only in tumours which are not suitable for upfront nephrectomy. The SIOP Renal Tumour Study Group protocols, use pre-operative chemotherapy and biopsy is indicated only if there is diagnostic uncertainty on radiology (e.g. calcification in tumour, psoas infiltration) and in older children. In the UK, until 2018, all patients (except children <6 months and those with completely cystic tumours) were offered a biopsy. Following a review of SIOP and UK databases it was found that Wilms’ tumour was the diagnosis in over 90% of patients between the ages of 6 monthse10 years, this practice was amended and biopsy is now only recommended for older children - and those with unusual features. It is done under image guidance and using modern co-axial percutaneous cutting needle biopsy techniques.
Preoperative chemotherapy Preoperative chemotherapy for localized Wilms’ tumour consists of vincristine and actinomycin D (VA), with addition of doxorubicin (AVD) for metastatic disease. The surgery is planned following 4 weeks or 6 weeks of treatment for localized and
Staging, risk stratification and treatment Wilms’ tumour treatment consists of surgery, chemotherapy and for some patients, radiotherapy. Staging of the tumour is post-
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if resected, response of metastatic tumour to pre-operative chemotherapy, the size of metastatic lesions. The SIOP -UMBRELLA protocol recommends stratifying patients to AVD with varying cumulative doxorubicin dose (150 mg/m2, 250 mg/m2) or a four-drug regimen including etoposide, carboplatin, cyclophosphamide and doxorubicin. Children with non-high-risk disease who have cleared their metastasis by chemotherapy or surgery avoid radiotherapy to the lungs. Historically, COG groups treated all stage 4 tumours with lung radiotherapy (RT). Following results of the SIOP protocols where response to pre-operative chemotherapy is used to determine the need for RT, COG has modified their approach to follow SIOP principles. Defining lung metastases has been a challenge. Previous protocols defined metastases on basis of CXR and those not visible on CXR but only visible on CT chest (CT-only nodules) have been evaluated by both groups. Results from the COG NWTS-4 and NWTS-5 trials showed that patients with CT-only nodules who were treated with AVD had superior EFS compared to those who received VA only, but OS was similar in both groups. These findings led to the design of COGAREN0533, where all patients with lung nodules received doxorubicin but lung RT was omitted for patients with complete remission (CR). SIOP protocols also showed that children with CT-only nodules had inferior outcomes compared to true localized tumours and SIOP Umbrella prospective trial now considers all lesions 3mm, detected on CT as metastases. Patients with liver metastases are few and are similarly treated with chemotherapy, surgery and radiotherapy
metastatic disease respectively. In bilateral tumours, the role of pre-operative treatment is to enable nephron sparing surgery (NSS) and should be done by 12 weeks to avoid development of resistant anaplastic clones.
Surgery The current standard surgical procedure for a unilateral WT is a radical nephrectomy. Adequate lymph node sampling is important, and protocols define the number of nodes to be sampled (e.g. seven nodes as per SIOP-RTSG). NSS is strongly recommended for children with bilateral lesions and for children with predisposition syndromes. For unilateral tumours, it is important to ensure complete resection of the tumour (to avoid radiotherapy) and the role of NSS is presently restricted for suitable tumours of small volume. The standard surgical technique is through a laparotomy and the role of minimally invasive or laparoscopic surgery is still being defined.
Post-operative chemotherapy The current COG protocols stratify children into risk groups based on age (>2 years), tumour weight (>550 gm), stage, risk groups and LOH 1p, 16q. Based on these parameters, treatments are stratified to include observation only, a 2 drug regimen with VA, a 3 drug regimen with AVD or more intensive regimes including cyclophosphamide, etoposide or carboplatin. In the COG protocols, children who receive preoperative chemotherapy or have a tumour biopsy are deemed to be local stage 3. In the SIOP protocol, post-surgical treatment depends on postoperative stage and risk stratification. Pre-operative tumour volume (calculated on cross-sectional imaging) is considered in certain groups. The treatment regimens last from 4 weeks to 34 weeks using 2 (VA), 3 (AVD) or 4 (carboplatin, etoposide, doxorubicin, cyclophosphamide) drug combinations. The SIOP WT-2001 trial tested the role of doxorubicin through a randomisation for stage II and III intermediate risk tumours. OS was not statistically different in the two groups and hence doxorubicin is now avoided in several subgroups. More recently, post hoc analysis of data from SIOP 2001 showed that patients with large-volume non-epithelial and non-stromal type tumours had an estimated 5-year EFS of 80% versus 90% for patients with small-volume tumours. Most importantly, EFS was significantly improved when doxorubicin was added to the treatment regimen for large-volume (500 ml) tumours. Therefore, doxorubicin is now used in postoperative treatment of patients with largevolume (500 ml) stage IIeIII non-stromal, non-epithelial tumours.
Radiotherapy Wilms’ tumour is a very radiosensitive tumour and radiotherapy was widely used in earlier protocols. Radiotherapy is now indicated for those with high stage (stage 3) or high risk tumours. The sites of radiotherapy are the flank and in case of a major rupture, the whole abdomen. For metastatic disease, radiotherapy is indicated for those with residual disease following preoperative chemotherapy and those with high risk pathology. Based on data from previous studies, the dose of irradiation has been reduced in current protocols in order to minimize long term side effects.
Bilateral Wilms’ tumour (stage V) Synchronous bilateral Wilms’ tumour (stage V) accounts for z5 e8% of instances of Wilms’ tumour and long-term overall survival is currently z80%. Patients are treated with pre-operative chemotherapy with the aim of performing nephron sparing surgery. Post-operative chemotherapy is based on local stages of individual tumours and treated according to the highest stage and minimum of 6 months. End-stage renal disease (ESRD) is the most clinically significant morbidity for patients with bilateral Wilms’ tumours and can be caused by underlying germline genetic aberrations as well as treatment-related loss of functional renal tissue. Functional renal outcomes are better with NSS. Independently of the type of treatment, children with WAGR, Denys-Drash or other syndromes associated with WT1
Metastatic Wilms’ tumour In SIOP protocols, preoperative treatment for metastatic disease includes a combined vincristine, actinomycin D, and doxorubicin (AVD) regimen for 6 weeks, followed by reassessment imaging of local tumour and metastatic sites before surgery. With this preoperative regimen, 61e67% of patients achieve a complete metastatic response before surgery. Post-operative chemotherapy depends on factors such as local stage of the primary tumour, histology of the primary tumour, histology of metastatic nodules
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Therefore, it is important for survivors to be integrated into long term follow up clinics.
mutations, are at increased risk of ESRD. Thus, avoiding total nephrectomy at initial surgery is advised for bilateral tumours and for children with predisposition syndrome.
Prognosis Relapsed Wilms’ tumour
The outcomes for children depend on their stage and risk group. 90% patients present as localized disease and overall it is an extremely curable disease with over 90% of children being cured. Children with metastatic disease and non-anaplastic histology also have a high cure rate. However, of the very small group of high risk disease and metastases, only one third are long term survivors.
Around 15% of patients in the SIOP intermediate risk and 50% in the high risk group relapse. Sites of relapse are lungs and pleura (50e60%), abdomen (30e40%). For those who relapse, the aim is to offer treatment regimens not used previously. This has been the principle of previous studies and through this approach around 75% of children are now cured. In principle, standard risk children are those who have not previously received an anthracycline or radiotherapy and are treated with anthracycline based regime including carboplatin/etoposide/cyclophosphamide/doxorubicin, with expected survival rates of 70e80%. The high-risk group includes patients with non-anaplastic histology WT who relapse after therapy with three or more agents or have received previous RT. They are recommended alternating cycles of ifosfamide, carboplatin, etoposide and cyclophosphamide, carboplatin, etoposide (ICE/CyCE). Whilst there has not been any randomized study testing the role of high dose chemotherapy with stem cell rescue, single arm studies have shown its benefit. Therefore, following chemotherapy, those who respond, may proceed to receive consolidation with high-dose melphalan and autologous stem cell transplant. For these patients, survival rates are expected to be 40e50%. The very-high-risk group includes patients with recurrent anaplastic or blastemal-type WT. These patients have a dismal long-term survival of about 10%, with very poor responses to any drug or combination, which is likely due to intrinsic drug resistance. Use of camptothecins (irinotecan and topotecan) or novel agents is advised. Surgery and radiotherapy play an important role in management of patients with relapse.
Future directions Most children with Wilms’ tumour have excellent outcomes. However, those with high-risk disease who relapse or progress after first-line treatment still have a poor prognosis. Identification of novel therapies is essential for this group. Risk-stratification has improved over the decades and current trials, focussing on understanding more about biomarkers, will pave the path for the future. A REFERENCES 1 Scott RH, Stiller CA, Walker L, Rahman N. Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour. J Med Genet 2006; 43: 705e15. 2 Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol 2017; 14: 743e52. GM, Gessler M, Ooms AHAG, et al. The UMBRELLA SIOP3 Vujanic RTSG 2016 Wilms tumour pathology and molecular biology protocol. Nat Rev Urol 2018 Nov; 15: 693e701. FURTHER READING Dome JS, Graf N, Geller JI, et al. Advances in Wilms tumor treatment and biology: progress through international collaboration. J Clin Oncol 2015; 33: 2999e3007. https://www.cancer.gov/types/kidney/hp/wilms-treatment-pdq. June 13, 2019. Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQÒ). Lopes RI, Lorenzo A. Recent advances in the management of Wilms’ tumor [version 1; referees: 2 approved]. F1000Research 2017; 6: 670. https://doi.org/10.12688/f1000research.10760.1. F1000 Faculty Rev. Oostveen RM, Pritchard-Jones K. Pharmacotherapeutic management of Wilms tumour: an update. Pediatr Drugs 2019; 21: 1e13. Phelps HM, Kaviany S, Borinstein SC, Lovvorn HN. Review:Biological drivers of Wilms tumor prognosis and treatment. Children 2018; 5: 145. Pritchard-Jones K, Graf N, van Tinteren H, et al. Evidence for a delay in diagnosis of Wilms’ tumour in the UK compared with Germany: implications for primary care for children. Arch Dis Childhood 2016; 101: 417e20. Szychot E, Apps J, Pritchard-Jones K. Wilms tumour: biology, diagnosis and treatment. Transl Pediatr 2014; 3: 12e24.
Follow up for relapse Surveillance is recommended with regular CXR and ultrasound abdomen in the first 2 years as most relapses occur by then and over 2/3rd are diagnosed through surveillance. Clinical follow up is recommended till 5 years from end of treatment. Children with bilateral Wilms’, predisposition syndromes or nephrogenic rests in kidneys need to have ultrasound scans till the age of 7 years.
Follow up for late effects Survivors of Wilms’ tumours have fewer late effects compared to most other childhood malignancies. Some patients still have an increased risk of severe chronic and life-threatening health conditions in adult life when compared to the general population. This is due to use of anthracyclines and their potential cardiotoxic effects, potential ototoxicity from use of carboplatin, risk of end stage renal disease in those with bilateral disease or those with predisposition syndromes, risks of second malignancies related to chemotherapy and radiotherapy, musculoskeletal effects and effects on growth, chronic lung changes related to RT and risk of infertility, particularly if high dose therapy was used.
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Management of Wilms’ tumour
The role of co-operative groups Given the rarity of paediatric tumours, much of the success in understanding the biology and improvements in outcomes for Wilms’ tumour has been through efforts of co-operative groups. Historically, the UKCCSG (UK Children’s cancer study group), now CCLG (Children’s cancer and leukaemia group), conducted several randomized clinical trials for paediatric renal tumours and is currently part of SIOP. Societe Internationale d’Oncologie Pediatrique Renal Tumour Study Group (SIOP-RTSG) leads trials in Europe and COG (Children’s Oncology Group), previously the National Wilms’ Tumour Study Group (NWTSG) has been instrumental in conducting a series of trials in America.
Kavitha Srivatsa Sucheta J Vaidya
Abstract Wilms’ tumour (WT) is the commonest renal tumour of childhood and its treatment is regarded as one of the success stories of paediatric oncology with over 90% cure rate. Most patients present with localized unilateral tumours. Histology and stage are important prognostic factors, and children with stage IV and diffuse anaplasia have poorer outcomes. Whilst there are differences in the treatment approaches around the world, outcomes are excellent for most subgroups of te Internationale d’Oncologie Wilms’ tumour. The European Socie diatrique (SIOP) recommends pre-operative chemotherapy to chilPe dren over 6 months whilst the North American Children’s Oncology Group offers primary nephrectomy and uses biomarkers for treatment stratification. Overall, 15% patients experience a relapse and their management depends on the initial treatment they had received. The focus of research is to decrease long term side effects, reduce treatment for selected subgroups, and improve our understanding of prognostic biomarkers to help tailor treatments. This article provides an overview for paediatricians giving an update on the important recent advances.
Pathophysiology Wilms’ tumour is an embryonal tumour of childhood and has histological and molecular resemblance to the embryonic kidney. The fetal kidney develops from the ureteric bud (forming collecting ducts) and the metanephric blastema (forming the stroma, glomeruli, proximal and distal tubules and loop of Henle). The blastema usually disappears by 36 weeks of gestation, however at birth approximately 1% of infants retain residual blastema within their kidney. These cells are described as nephrogenic rests (NR). Nephrogenic rests are thought to be the precursor lesions of Wilms’ tumours and in around 40% of patients, these can be identified in the resected tumour specimen. Nephrogenic rests are of two types: intralobar nephrogenic rests (ILNR), found anywhere within the renal lobe and perilobar nephrogenic rests (PLNR), confined to the periphery of the renal lobe, and thought to develop later during embryogenesis. Nephroblastomatosis is defined as the presence of diffuse or multifocal nephrogenic rests. Histologically, Wilms’ tumour mimics the triphasic development of the normal kidney consisting of blastemal, epithelial and stromal cell types in various proportions. Five to ten percent of Wilms’ tumours demonstrate anaplastic histology, which is defined by the presence of atypical, polyploid mitotic figures, large nuclear size, and hyperchromasia.
Keywords chemotherapy; management; nephroblastoma; pathophysiology; Wilms’tumour
Epidemiology Primary renal tumours account for 4e7% of all childhood cancers. Wilms’ tumour affects approximately one child per 10,000 worldwide before the age of 15 years. In the UK, around 80 children are diagnosed with renal tumours each year. Wilms’ tumour (nephroblastoma) accounts for 90% of these. More than 80% of children are diagnosed below the age of five years, the median age at diagnosis being 3.5 years. Most present with unilateral tumours. Synchronous bilateral or multifocal tumours occur in approximately 10% of patients and generally present at an earlier age. Wilms’ tumour can also rarely occur in adults where they are uncommon representing less than 1% of all renal tumours. Incidence rates vary between ethnic groups, with Asians having substantially lower incidence. There is slight female preponderance in the Caucasian population.
Genomic alterations of prognostic significance Several genetic mutations are involved in the formation of Wilms’ tumour and some are known to have prognostic significance. Chromosome 11 Chromosome 11 harbours two distinct Wilms’ tumour suppressor genes WT1 (11p13) and WT2 (11p15). WT1 mutations occur in only 10e20% of sporadic Wilms’ tumour, suggesting other key genetic mutations are involved in tumourigenesis. Loss of both copies of WT1 has been described as a hallmark of development of Wilms’ tumour in WAGR syndrome (Wilms’ tumour, aniridia, genitourinary anomalies, and mental retardation), Denys-Drash syndrome and Frasier syndrome, suggesting a loss of tumour suppressor function. WT2 is altered in a much higher frequency in sporadic Wilms’ tumour. Loss of imprinting and loss of heterozygosity (LOH) are thought to drive different pathogenetic mechanisms leading to the development and/or progression of Wilms’ tumour.
Kavitha Srivatsa MBBS DCH DNB, Specialty Doctor, Paediatric Oncology, The Royal Marsden NHS Foundation Trust, London, UK. Conflicts of interest: none declared. Sucheta J Vaidya MBBS DCH MD FRCPCH MD, Consultant Paediatric Oncologist, The Royal Marsden NHS Foundation Trust, London, UK. Conflicts of interest: none declared.
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Loss of heterozygosity 16q and 1p Early studies utilising LOH mapping identified chromosomes 1p and 16q as regions of interest with frequency of 12% and 17% respectively (combined incidence of 5%). These have shown to have adverse prognostic significance and used in risk stratifications in the NWTS trials.
Syndromes associated with risk of Wilms’ tumour Syndrome
Genes or locus
High risk of Wilms’ tumour >20% WAGR syndrome WT, Aniridia, Genitourinary abnormalities, Mental Retardation Denys Drash Nephropathy, WT, genitourinary syndrome abnormalities Familial Wilms’ tumour
Copy number gain at 1q This is observed in 30% of tumours. The CCLG, NWTS and SIOP have independently confirmed poorer event-free survival (EFS) and overall survival (OS) in pre-treated and untreated patients with 1q gain. This is being further evaluated prospectively through the SIOP-RTSG Umbrella trial.
Perlman syndrome
Renal hamartomas, nephroblastomatosis, foetal gigantism Mosaic variegated Intrauterine growth retardation, aneuploidy microcephaly Moderate risk of Wilms’ tumour 5e20% Beckwith-Weidemann Hemihypertrophy, macroglossia, syndrome macrosomia, exomphalos Frasier syndrome Pseudohermaphroditism, progressive glomerulopathy Simpson-GolabiOvergrowth, coarse facies Behmel syndrome
Alterations in 17p and MYCN amplification TP53 mutations have been identified in 50e86% of anaplastic WT and MYCN amplification associated with anaplasia are associated with poor prognosis.
Predisposition syndromes and screening Most Wilms’ tumours develop in otherwise healthy children, without any predisposition to cancer. Congenital malformations or genetic syndromes account for around 10e15% cases.1 Screening with 3 monthly abdominal ultrasound scans is recommended for children with more than 5 % risk of developing WT following review by a clinical geneticist and is offered until the age of 7e8 years. Syndromes associated with risk of Wilms’ tumour are described in Table 1.
11p13 WT1 11p13 WT1 FWT1, FWT2 DIS3L2
11p15 WT2, IGF2 11p13 WT1 GPC3, GPC4
Table 1
Diagnostic and staging evaluation It is important to diagnose tumours early. Abdominal ultrasound is the initial imaging study of choice in a patient with a suspected abdominal mass. This can be organized with ease, can be done without any sedation or anaesthesia without exposure to ionizing radiation. Ultrasound confirms the presence of mass, site of origin and presence of tumour thrombus. Cross-sectional imaging with magnetic resonance imaging (MRI) or computerized tomography (CT) of the abdomen is necessary to provide information for a precise diagnosis. MRI is particularly favoured as it is superior to CT scan in delineating small lesions in the contralateral kidney. Functional MRI techniques such as diffusion weighted images (DWI) are being tested as tools to assess response and plan for surgery, particularly in children with
Clinical presentation Most children present asymptomatically with an abdominal mass that is noted when they are bathed or dressed, or by a health professional on a routine visit. Abdominal pain is present in 40 e50% of children. Gross haematuria occurs in about 15e20% of children and microscopic haematuria is seen in around 25% of patients. About 25e45% of children have hypertension at presentation, which is attributed to abnormal activation of the reninangiotensin system. Constitutional symptoms such as fever, anorexia, and weight loss are uncommon and occur in 10% of cases. Atypical presentations include hepatomegaly, ascites and cardiac failure due to tumour extension into the renal vein and inferior vena cava. Occasionally, a child may present with features of an acute abdomen (rapidly enlarging abdominal mass, pain, anaemia and fever) due to tumour rupture. Paraneoplastic syndromes associated with Wilms’ tumour include von Willebrand disease (4e8%), hypercalcaemia, erythrocytosis and very rarely Cushing’s syndrome. Approximately 10% of patients present with metastases through haematogenous spread, most commonly to the lungs (85%), liver (10%) and only very rarely to the bones and brain. In 5e10% of children, Wilms’ tumour may be detected through screening programmes for Wilms’ tumour predisposition syndromes. Patients in the UK have larger tumours at presentation compared to Germany which results in need for more intensive treatments. This is likely to be due to differences in primary healthcare system.
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Phenotype
Differential diagnosis for childhood renal tumours Mesoblastic nephroma Renal cyst Polycystic kidney Multicystic kidney Hydronephrosis Neuroblastoma* Clear cell sarcoma of the kidney Malignant rhabdoid tumour of the kidney Renal Cell Carcinoma Renal rhabdomyosarcoma *Catecholamines and their metabolites (VMA/creatinine, HVA/creatinine) are raised in over 90% of children with neuroblastoma and can be tested with a spot urine test. Box 1
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Staging criteria
Stage I
Stage II
Stage III
Stage IV
Staging criteria in the SIOP- Umbrella protocol
Staging criteria COG
Tumour is limited to the kidney. Tumour is present in the peri-renal fat but is surrounded by a fibrous (pseudo)capsule. The (pseudo)capsule might be infiltrated by viable tumour, which does not reach the outer surface. Tumour might show protruding (botryoid) growth into the renal pelvis or the ureter but does not infiltrate their walls. The vessels or the soft tissues of the renal sinus are not involved by tumour. Intrarenal vessel involvement might be present. Viable tumour is present in the peri-renal fat and is not covered by a (pseudo)capsule, but is completely resected (resection margins are clear). Viable tumour infiltrates the soft tissues of the renal sinus. Viable tumour infiltrates blood and/or lymphatic vessels of the renal sinus or of the peri-renal tissue, but it is completely resected. Viable tumour infiltrates the wall of the renal pelvis or of the ureter. Viable tumour infiltrates the vena cava or adjacent organs (except the adrenal gland) but is completely resected. Viable tumour is present at a resection margin. Nonviable tumour or chemotherapy-induced changes present at a resection margin are not regarded as stage III. Abdominal lymph node involvement is present by either viable or nonviable tumour. Preoperative or intraoperative tumour rupture, if confirmed by microscopic examination (viable tumour at the surface of the specimen at the area of the rupture). Viable or nonviable tumour thrombus is present at resection margins of ureter, renal vein, or vena cava inferior (always discuss resection margins with the surgeon). Viable or nonviable tumour thrombus, which is attached to the inferior vena cava wall, is removed piecemeal by a surgeon. Wedge or open tumour biopsy before preoperative chemotherapy or surgery. Tumour implants (viable or nonviable) are found anywhere in the abdomen. Tumour (viable or nonviable) has penetrated through the peritoneal surface. Haematogenous metastases (for example, lung, liver, bone and brain) or lymph node metastases outside the abdominopelvic region
Tumour limited to the kidney and completely resected Renal capsule intact The tumour was not ruptured or biopsied prior to removal Renal vein contains no tumour (intrarenal vessel involvement may be present) No residual tumour apparent beyond the margins of excision.
Tumour extends beyond the kidney but is completely resected Regional extension of tumour (vascular invasion outside the renal parenchyma or within the renal sinus and/or capsular penetration with negative excision margin) Operative tumour spill confined to flank (no peritoneal contamination) Tumour biopsy (except fine-needle aspiration) prior to surgery
Non-haematogenous metastases confined to the abdomen (e.g., tumour in regional lymph nodes), including tumour implants on or penetrating the peritoneum Gross or microscopic tumour remains postoperative (tumour at the margins of resection) Tumour spill before or during surgery not confined to flank Piecemeal excision of the tumour (removal in >1 piece)
Presence of haematogenous metastases or metastases to distant lymph nodes
(continued on next page)
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Table 2 (continued )
Stage V
Staging criteria in the SIOP- Umbrella protocol
Staging criteria COG
Bilateral renal tumours at diagnosis. Each side should be sub-staged according to the above criteria.
Bilateral renal involvement at the time of initial diagnosis
Data on SIOP pathology taken from reference 3.
Table 2
surgical and for all patients, surgery is the mainstay of treatment, but the timing of surgery differs between SIOP-RTSG and COG protocols. Each strategy has its pros and cons and survival rates are similar. Differences in upfront treatment approaches mean that there are differences in staging (Table 2) and risk stratifications (Table 3). Treatment type and intensity are influenced by several clinical and biological prognostic factors for both groups. The COG advocates for up-front surgical removal, thus providing a detailed histological staging and accurate molecular studies which are necessary for planning post-operative treatment. However, preoperative chemotherapy is recommended in cases with tumour thrombus extending above the level of the hepatic veins, gross involvement of contiguous structures, bilateral Wilms’ tumour, extensive pulmonary compromise from compression by a massive tumour or widespread metastatic disease, and when, according to the surgeon’s discretion, immediate nephrectomy would result in significant morbidity, including tumour spill or incomplete resection. Based on the histology tumours are classified as having favourable (no anaplasia) or unfavourable histology (focal and diffuse anaplasia). SIOP advocates for preoperative chemotherapy for patients over 6 months of age. This approach has the benefit of personalized in vivo assessment of histological response to chemotherapy, including the identification of a ‘high-risk’ category of blastemal-type Wilms’ tumour. Reduction in tumour size and the formation of a fibrous pseudocapsule facilitates surgical removal and decreases the risks of rupture and spillage during surgery. Pre-nephrectomy chemotherapy has also been shown to decrease the risk of intra-operative haemorrhage and lower tumour stages. Primary nephrectomy is recommended for renal tumours in children younger than 6 months old, as congenital mesoblastic nephroma is more prevalent and does not require chemotherapy. SIOP subclassifies and risk stratifies Wilms’ tumour based on histologic changes after chemotherapy. Patients are divided into low-, intermediate-, and high-risk groups considering the degree of tumour necrosis and relative proportion of each of the three cellular components (epithelial, stromal, or blastemal). Patients with diffuse anaplastic or blastemal-type Wilms’ tumour are considered to have high-risk histology.
Histologic risk classification schemas for Wilms’ tumour COG
SIOP
Favourable Wilms’ tumour favourable histology (no evidence of anaplasia)
Low risk -Cystic partially differentiated nephroblastoma Completely necrotic nephroblastoma Intermediate risk Nephroblastomasubtype mixed, regressive, epithelial, stromal, focal anaplasia Unfavourable Diffuse High risk Nephroblastoma -subtype and focal anaplasia blastemal, diffuse anaplasia Table 3
bilateral lesions. Differential diagnosis of renal masses are described in Box 1. Historically, chest X-ray (CXR) was used as a staging tool for lung metastasis. Following outcomes of clinical trials and debate about definition of metastasis, contrast enhanced CT chest is now recommended for staging and the recent prospective UMBRELLA study defines metastatic disease depending on sizes of lung nodules (3 mm) detected on CT.2
Role of biopsy Children’s Oncology Group protocols advocate upfront nephrectomy to achieve an accurate tissue diagnosis before postoperative chemotherapy. Biopsy is indicated only in tumours which are not suitable for upfront nephrectomy. The SIOP Renal Tumour Study Group protocols, use pre-operative chemotherapy and biopsy is indicated only if there is diagnostic uncertainty on radiology (e.g. calcification in tumour, psoas infiltration) and in older children. In the UK, until 2018, all patients (except children <6 months and those with completely cystic tumours) were offered a biopsy. Following a review of SIOP and UK databases it was found that Wilms’ tumour was the diagnosis in over 90% of patients between the ages of 6 monthse10 years, this practice was amended and biopsy is now only recommended for older children - and those with unusual features. It is done under image guidance and using modern co-axial percutaneous cutting needle biopsy techniques.
Preoperative chemotherapy Preoperative chemotherapy for localized Wilms’ tumour consists of vincristine and actinomycin D (VA), with addition of doxorubicin (AVD) for metastatic disease. The surgery is planned following 4 weeks or 6 weeks of treatment for localized and
Staging, risk stratification and treatment Wilms’ tumour treatment consists of surgery, chemotherapy and for some patients, radiotherapy. Staging of the tumour is post-
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if resected, response of metastatic tumour to pre-operative chemotherapy, the size of metastatic lesions. The SIOP -UMBRELLA protocol recommends stratifying patients to AVD with varying cumulative doxorubicin dose (150 mg/m2, 250 mg/m2) or a four-drug regimen including etoposide, carboplatin, cyclophosphamide and doxorubicin. Children with non-high-risk disease who have cleared their metastasis by chemotherapy or surgery avoid radiotherapy to the lungs. Historically, COG groups treated all stage 4 tumours with lung radiotherapy (RT). Following results of the SIOP protocols where response to pre-operative chemotherapy is used to determine the need for RT, COG has modified their approach to follow SIOP principles. Defining lung metastases has been a challenge. Previous protocols defined metastases on basis of CXR and those not visible on CXR but only visible on CT chest (CT-only nodules) have been evaluated by both groups. Results from the COG NWTS-4 and NWTS-5 trials showed that patients with CT-only nodules who were treated with AVD had superior EFS compared to those who received VA only, but OS was similar in both groups. These findings led to the design of COGAREN0533, where all patients with lung nodules received doxorubicin but lung RT was omitted for patients with complete remission (CR). SIOP protocols also showed that children with CT-only nodules had inferior outcomes compared to true localized tumours and SIOP Umbrella prospective trial now considers all lesions 3mm, detected on CT as metastases. Patients with liver metastases are few and are similarly treated with chemotherapy, surgery and radiotherapy
metastatic disease respectively. In bilateral tumours, the role of pre-operative treatment is to enable nephron sparing surgery (NSS) and should be done by 12 weeks to avoid development of resistant anaplastic clones.
Surgery The current standard surgical procedure for a unilateral WT is a radical nephrectomy. Adequate lymph node sampling is important, and protocols define the number of nodes to be sampled (e.g. seven nodes as per SIOP-RTSG). NSS is strongly recommended for children with bilateral lesions and for children with predisposition syndromes. For unilateral tumours, it is important to ensure complete resection of the tumour (to avoid radiotherapy) and the role of NSS is presently restricted for suitable tumours of small volume. The standard surgical technique is through a laparotomy and the role of minimally invasive or laparoscopic surgery is still being defined.
Post-operative chemotherapy The current COG protocols stratify children into risk groups based on age (>2 years), tumour weight (>550 gm), stage, risk groups and LOH 1p, 16q. Based on these parameters, treatments are stratified to include observation only, a 2 drug regimen with VA, a 3 drug regimen with AVD or more intensive regimes including cyclophosphamide, etoposide or carboplatin. In the COG protocols, children who receive preoperative chemotherapy or have a tumour biopsy are deemed to be local stage 3. In the SIOP protocol, post-surgical treatment depends on postoperative stage and risk stratification. Pre-operative tumour volume (calculated on cross-sectional imaging) is considered in certain groups. The treatment regimens last from 4 weeks to 34 weeks using 2 (VA), 3 (AVD) or 4 (carboplatin, etoposide, doxorubicin, cyclophosphamide) drug combinations. The SIOP WT-2001 trial tested the role of doxorubicin through a randomisation for stage II and III intermediate risk tumours. OS was not statistically different in the two groups and hence doxorubicin is now avoided in several subgroups. More recently, post hoc analysis of data from SIOP 2001 showed that patients with large-volume non-epithelial and non-stromal type tumours had an estimated 5-year EFS of 80% versus 90% for patients with small-volume tumours. Most importantly, EFS was significantly improved when doxorubicin was added to the treatment regimen for large-volume (500 ml) tumours. Therefore, doxorubicin is now used in postoperative treatment of patients with largevolume (500 ml) stage IIeIII non-stromal, non-epithelial tumours.
Radiotherapy Wilms’ tumour is a very radiosensitive tumour and radiotherapy was widely used in earlier protocols. Radiotherapy is now indicated for those with high stage (stage 3) or high risk tumours. The sites of radiotherapy are the flank and in case of a major rupture, the whole abdomen. For metastatic disease, radiotherapy is indicated for those with residual disease following preoperative chemotherapy and those with high risk pathology. Based on data from previous studies, the dose of irradiation has been reduced in current protocols in order to minimize long term side effects.
Bilateral Wilms’ tumour (stage V) Synchronous bilateral Wilms’ tumour (stage V) accounts for z5 e8% of instances of Wilms’ tumour and long-term overall survival is currently z80%. Patients are treated with pre-operative chemotherapy with the aim of performing nephron sparing surgery. Post-operative chemotherapy is based on local stages of individual tumours and treated according to the highest stage and minimum of 6 months. End-stage renal disease (ESRD) is the most clinically significant morbidity for patients with bilateral Wilms’ tumours and can be caused by underlying germline genetic aberrations as well as treatment-related loss of functional renal tissue. Functional renal outcomes are better with NSS. Independently of the type of treatment, children with WAGR, Denys-Drash or other syndromes associated with WT1
Metastatic Wilms’ tumour In SIOP protocols, preoperative treatment for metastatic disease includes a combined vincristine, actinomycin D, and doxorubicin (AVD) regimen for 6 weeks, followed by reassessment imaging of local tumour and metastatic sites before surgery. With this preoperative regimen, 61e67% of patients achieve a complete metastatic response before surgery. Post-operative chemotherapy depends on factors such as local stage of the primary tumour, histology of the primary tumour, histology of metastatic nodules
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Therefore, it is important for survivors to be integrated into long term follow up clinics.
mutations, are at increased risk of ESRD. Thus, avoiding total nephrectomy at initial surgery is advised for bilateral tumours and for children with predisposition syndrome.
Prognosis Relapsed Wilms’ tumour
The outcomes for children depend on their stage and risk group. 90% patients present as localized disease and overall it is an extremely curable disease with over 90% of children being cured. Children with metastatic disease and non-anaplastic histology also have a high cure rate. However, of the very small group of high risk disease and metastases, only one third are long term survivors.
Around 15% of patients in the SIOP intermediate risk and 50% in the high risk group relapse. Sites of relapse are lungs and pleura (50e60%), abdomen (30e40%). For those who relapse, the aim is to offer treatment regimens not used previously. This has been the principle of previous studies and through this approach around 75% of children are now cured. In principle, standard risk children are those who have not previously received an anthracycline or radiotherapy and are treated with anthracycline based regime including carboplatin/etoposide/cyclophosphamide/doxorubicin, with expected survival rates of 70e80%. The high-risk group includes patients with non-anaplastic histology WT who relapse after therapy with three or more agents or have received previous RT. They are recommended alternating cycles of ifosfamide, carboplatin, etoposide and cyclophosphamide, carboplatin, etoposide (ICE/CyCE). Whilst there has not been any randomized study testing the role of high dose chemotherapy with stem cell rescue, single arm studies have shown its benefit. Therefore, following chemotherapy, those who respond, may proceed to receive consolidation with high-dose melphalan and autologous stem cell transplant. For these patients, survival rates are expected to be 40e50%. The very-high-risk group includes patients with recurrent anaplastic or blastemal-type WT. These patients have a dismal long-term survival of about 10%, with very poor responses to any drug or combination, which is likely due to intrinsic drug resistance. Use of camptothecins (irinotecan and topotecan) or novel agents is advised. Surgery and radiotherapy play an important role in management of patients with relapse.
Future directions Most children with Wilms’ tumour have excellent outcomes. However, those with high-risk disease who relapse or progress after first-line treatment still have a poor prognosis. Identification of novel therapies is essential for this group. Risk-stratification has improved over the decades and current trials, focussing on understanding more about biomarkers, will pave the path for the future. A REFERENCES 1 Scott RH, Stiller CA, Walker L, Rahman N. Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour. J Med Genet 2006; 43: 705e15. 2 Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol 2017; 14: 743e52. GM, Gessler M, Ooms AHAG, et al. The UMBRELLA SIOP3 Vujanic RTSG 2016 Wilms tumour pathology and molecular biology protocol. Nat Rev Urol 2018 Nov; 15: 693e701. FURTHER READING Dome JS, Graf N, Geller JI, et al. Advances in Wilms tumor treatment and biology: progress through international collaboration. J Clin Oncol 2015; 33: 2999e3007. https://www.cancer.gov/types/kidney/hp/wilms-treatment-pdq. June 13, 2019. Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQÒ). Lopes RI, Lorenzo A. Recent advances in the management of Wilms’ tumor [version 1; referees: 2 approved]. F1000Research 2017; 6: 670. https://doi.org/10.12688/f1000research.10760.1. F1000 Faculty Rev. Oostveen RM, Pritchard-Jones K. Pharmacotherapeutic management of Wilms tumour: an update. Pediatr Drugs 2019; 21: 1e13. Phelps HM, Kaviany S, Borinstein SC, Lovvorn HN. Review:Biological drivers of Wilms tumor prognosis and treatment. Children 2018; 5: 145. Pritchard-Jones K, Graf N, van Tinteren H, et al. Evidence for a delay in diagnosis of Wilms’ tumour in the UK compared with Germany: implications for primary care for children. Arch Dis Childhood 2016; 101: 417e20. Szychot E, Apps J, Pritchard-Jones K. Wilms tumour: biology, diagnosis and treatment. Transl Pediatr 2014; 3: 12e24.
Follow up for relapse Surveillance is recommended with regular CXR and ultrasound abdomen in the first 2 years as most relapses occur by then and over 2/3rd are diagnosed through surveillance. Clinical follow up is recommended till 5 years from end of treatment. Children with bilateral Wilms’, predisposition syndromes or nephrogenic rests in kidneys need to have ultrasound scans till the age of 7 years.
Follow up for late effects Survivors of Wilms’ tumours have fewer late effects compared to most other childhood malignancies. Some patients still have an increased risk of severe chronic and life-threatening health conditions in adult life when compared to the general population. This is due to use of anthracyclines and their potential cardiotoxic effects, potential ototoxicity from use of carboplatin, risk of end stage renal disease in those with bilateral disease or those with predisposition syndromes, risks of second malignancies related to chemotherapy and radiotherapy, musculoskeletal effects and effects on growth, chronic lung changes related to RT and risk of infertility, particularly if high dose therapy was used.
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