Results of the SIOP 93-01/GPOH trial and study for the treatment of patients with unilateral nonmetastatic Wilms Tumor

BACKGROUND: The treatment of Wilms Tumor is integrated into clinical trials since the 1970's. In contrast to the National Wilms Tumor Study Group (NWTSG) the SIOP trials and studies largely focus on the issue of preoperative therapy to facilitate surgery of a shrunken tumor and to treat metastasis as early as possible. PATIENTS AND METHODS: In the SIOP 93-01/GPOH trial and study 1 020 patients with a newly diagnosed renal tumor were registered. 847 of them had a histological proven Wilms Tumor, of whom 637 were unilateral localized, and 173 tumors had an other histology [40 congenital mesoblastic nephroma (CMN), 51 clear cell sarcoma (CCSK), 24 rhabdoid tumor (RTK) and 58 other tumors]. Preoperative chemotherapy in benign tumors was given to 1.3 % of the patients. The main objective of the trial was the randomized question, if the postoperative two drug chemotherapy for stage I in intermediate risk or anaplasia can be reduced from conventional 3 courses to an experimental 1 course without loss of efficacy. RESULTS: 519 patients with unilateral nonmetastatic Wilms did receive preoperative chemotherapy. The histology in this group of patients was of intermediate risk in 469 (90 %) patients, 14 (3 %) tumors were low risk and 36 (7 %) high risk. The stage distribution of the tumors was stage I in 315 (61 %), stage II N- in 126 (24 %), stage II N+ in 25 (5 %) and stage III in 36 (7 %) patients. In 17 (3 %) patients the tumor stage remained unclear. Tumor volume was measured in 487 patients before and in 402 after preoperative chemotherapy. The median tumor volume did shrink from 353 to 126 ml. The amount of volume reduction depends on the histological subtype. The event free survival (EFS) after 5 years was 91 % for all patients with unilateral Wilms tumor without distant metastasis. Randomisation was done in 43.7 % for stage I patients and there was no difference in EFS for both treatment arms (90 versus 91 %). The EFS is identical for patients with stage I and II N- (0.92), as well as for stage II N+ and III (0.82). The tumor volume after chemotherapy is a prognostic factor for intermediate risk tumors with the exception of epithelial and stromal predominant tumors. These two subtypes often present as large tumors, they do not shrink during preoperative chemotherapy but they still have an excellent prognosis. On the other hand the prognosis of patients with blastemal predominant subtype after preoperative chemotherapy is worse than in any other patient group of intermediate risk tumors. There are less blastemal predominant tumors compared to primary surgery, but they are chemotherapeutic resistant selected by the preoperative chemotherapy. CONCLUSION: Patients with unilateral Wilms tumor without metastasis have an excellent prognosis. The post-operative chemotherapy in stage I can be reduced to 4 weeks without worsening treatment outcome. The reduction of the tumor volume could be identified as a helpful marker for stratification of post-operative treatment. Post-chemotherapy blastemal predominant subtype of Wilms tumor has to be classified as high risk tumor. Focal anaplasia has a better prognosis than diffuse anaplasia and will be classified as intermediate risk tumor.     

Feasibility of using CT volume as a predictor of specimen weight in a subgroup of patients with low risk Wilms tumors registered on COG Study AREN03B2: Implications for central venous catheter placement

ObjectivePatients with stage I Wilms tumor, age ≤2 years, tumor ≤550 g may not require therapy beyond nephrectomy. This study's aims were to determine: (1) if a linear relationship exists between tumor weight and computed tomography (CT) estimated volume; (2) describe the accuracy of a slope–intercept equation in estimating weight; and (3) determine the potential impact of weight estimation on port placement decisions.Materials and methodsTumor weight and port placement information were abstracted from 105 patients, age ≤2 years, with tumors ±550 g, enrolled in COG AREN03B2. One radiologist estimated tumor size from CT scan. Prolate ellipse volume (PEV) was calculated, linear regression performed, slope–intercept equation calculated, equation estimated weight determined, and potential impact of the on port placement evaluated.ResultsA strong relationship exists between PEV and weight (R² = 0.87). The slope–intercept equation for weight was: weight = 1.04(PEV) + 58.75. Overall median relative error for the equation was 0.9%, and −3% in tumors weighing 350–750 g. Fifty-five ports were placed, 29 in patients with tumor weight ≤550 g, and six not placed in patients with tumor weight >550 g.ConclusionsThe relationship between PEV and weight produced a reliable weight prediction equation. Preoperative consideration of specimen weight may diminish the number of ports placed in this population.     

Screening for Wilms tumor in children with Beckwith-Wiedemann syndrome or idiopathic hemihypertrophy

BACKGROUND: Children with Beckwith-Wiedemann syndrome and idiopathic hemihypertrophy (BWS/HH) are at increased risk for developing Wilms tumor and screening with abdominal sonography is frequently recommended. However, there is a paucity of published data supporting this strategy. The purpose of this study was to determine whether sonographic screening at intervals of 4 months or less reduced the proportion of late-stage Wilms Tumor (WT) in children with BWS/HH. PROCEDURE: A case series analysis was employed to compare the proportion of late-stage (stage III or IV) Wilms tumor in patients with BWS/HH who were screened with sonography (n = 15) to the proportion of late-stage Wilms tumor in unscreened patients with BWS/HH (n = 59). Patients were identified from the BWS Registry and from previously published studies. Screened patients had sonograms at intervals of 4 months or less. RESULTS: None of the 12 screened children with Wilms tumor had late-stage disease, whereas 25 of 59 (42%) of unscreened children had late-stage Wilms tumor, a difference that was statistically significant (P < 0.003). Three children had false positive screening studies. They were operated on for suspected Wilms tumor but the lesions proved to be complicated renal cysts (n = 2) or nephroblastomatosis (n = 1). CONCLUSIONS: This study suggests that children with BWS/HH may benefit from screening sonograms at intervals of 4 months or less. However, false positive screening exams may result in unnecessary surgery. Given the rarity of BWS/HH, a larger, prospective international screening study is necessary to determine if the benefits of screening outweigh the risks.     

Prognostic value of quantifying apoptosis factor expression in favorable histology wilms tumors

Important in the homeostasis of normal tissues, apoptosis can be altered to favor cell survival within tumors. High expression of survivin, an inhibitor of apoptosis, and absence of caspase 8, a pro-apoptotic enzyme, independently correlate with poor outcomes in several tumor types. Favorable histology Wilms tumor has a remarkably high cure rate; as a result, the focus of therapy is now aimed at reducing treatment-related morbidity. With the goal of safely reducing therapy in select subgroups of patients, the authors investigated whether the levels of apoptotic factors in tumors could predict the risk for recurrence. Tumor apoptotic factor levels were surveyed in a case-control study from the National Wilms Tumor Study 5 (NWTS-5) and measured via quantitative real-time RT-PCR. Survivin and caspase 8 levels were surveyed in 92 primary tumor specimens and SMAC, Bid, and CD95 were surveyed in 24 specimens. All four pro-apoptotic factors studied (caspase 8, SMAC, Bid, and CD95) were analyzed individually and in relation to survivin expression. Although survivin mRNA was present at markedly greater levels than in normal kidney, none of the factors assayed independently or as a ratio was associated with stage of disease or risk for tumor recurrence in this group of tumors.     

Improved survival for patients with recurrent Wilms tumor: the experience at St. Jude Children's Research Hospital

BACKGROUND: Reported estimates of survival for patients with recurrent Wilms tumor are 24% to 43%. Because published survival data are more than a decade old and do not reflect advances in therapy, the authors reviewed their experience in treating recurrent Wilms tumor to determine whether the probability of survival has increased. PATIENTS AND METHODS: The authors reviewed the cases of 54 patients with recurrent Wilms tumor who were treated on one of six consecutive clinical trials at St. Jude Children's Research Hospital between 1969 and 2000. RESULTS: Five-year overall survival estimates after relapse were 63.6 +/- 15.7% for patients treated during or after 1984 (n = 20) and 20.6 +/- 6.5% for patients treated before 1984 (n = 34) (P = 0.002). When the analysis was restricted to patients with high-risk clinical features, 5-year overall survival estimates were 47.6 +/- 15.7% for those treated in the modern era (n = 16) and 11.1 +/- 5.2% for those treated in the earlier era (n = 25) (P = 0.005). Only three patients received high-dose chemotherapy with autologous stem cell rescue; one survived. No patients with recurrent anaplastic histology disease survived. CONCLUSIONS: Significant progress has been achieved in the treatment of recurrent favorable-histology Wilms tumor using multimodality salvage regimens with conventional doses of chemotherapy. Novel therapeutic strategies will be necessary to cure patients with recurrent anaplastic Wilms tumor.     

P-Glycoprotein Expression,Tumor Weight,Age, and Relapse in Patients with Stage I and II Favorable-Histology Wilms’ Tumor

Fifteen percent of patients with Wilms’ tumor (WT) experience relapse. It has been suggested that weight and age may affect the chances of relapse. Few studies have investigated the role, if any, between P-glycoprotein (P-gp) and relapse. The authors assessed the prognostic value of tumor weight and age at diagnosis and asked whether some other potential biological markers, specifically P-gp protein expression, had a prognostic value in favorable-histology WT. No association between age and relapse could be found. Patients with tumor weight ≥550 g were 6 times more likely to relapse, whereas P-gp expression was positive in 18/40 (45%) of the patients, of which 10/12 (83.3%) relapsed and 8/28 (28.6%) did not. Further studies are necessary to elucidate whether or not P-gp is related to relapse in patients with histologically favorable Wilms’ tumor. If confirmed, the protein may be used in the future as a target for new drugs and treatments for this group of patients.     

Imaging in unilateral Wilms tumour

Wilms tumour is one of the most common malignancies in children, with an excellent prognosis after therapy. There is a very diverse approach to treatment according to geographical location. This variation in therapeutic attitude toward Wilms tumour, particularly between the United States and Europe, has consequences for the choice of imaging modality at diagnosis. In Europe, the International Society of Paediatric Oncology (SIOP) treatment protocol is based on chemotherapy followed by surgery. Imaging (US, CT and MRI), clinical history and examination will help predict whether the findings are consistent with Wilms tumour. Furthermore, in the UK preoperative image-guided biopsy is advised to help identify the small group of patients who, despite typical imaging features of Wilms tumour, have other types of neoplasia that require alternative management. In the United States, the National Wilms Tumor Study (NWTS) advises surgery prior to chemo- and radiotherapy. Hence imaging must provide detailed anatomical information for surgical planning. This article discusses the role of imaging at diagnosis and the relative strengths and weaknesses of the available radiological techniques. We also focus on imaging the lung for metastatic disease and the consequences (to the patient’s ultimate outcome) of CT-diagnosed small pulmonary nodules and discuss the radiological diagnosis and consequences of tumour rupture present at diagnosis.     

Childhood cancer in offspring of two Wilms tumor survivors

A search was made for cancers among offspring and siblings of 149 Connecticut-born children with Wilms tumor reported to the Connecticut Tumor Registry during 1935 to 1973. Nasopharyngeal rhabdomyosarcoma developed in the daughter of a man with unilateral Wilms tumor that also affected his sister. Hodgkin disease developed in the daughter of a woman who had unilateral Wilms tumor. One other patient had a sibling with Wilms tumor and three had a sibling with other cancers (two Hodgkin disease, one testicular seminoma). The survey suggests an excess risk of other forms of cancer among the progeny and siblings of Wilms tumor patients.     

Extrarenal Wilms tumor.

The previous reports of extrarenal Wilms tumor are reviewed and two additional patients presented. The clinical and pathologic features are discussed. The diagnosis of extrarenal Wilms tumor does not imply a bad prognosis. Treatment should utilize multidrug chemotherapy similar to the guidelines set by the National Wilms Tumor Study.     

Hepatotoxicity of chemotherapy following nephrectomy and radiation therapy for right-sided Wilms tumor.

Two children developed hepatotoxicity during treatment for right-sided Wilms Tumor. Treatment consisted of nephrectomy, irradiation, and chemotherapy with actinomycin D and vincristine. Hepatic enlargement, thrombocytopenia, and abnormalities in liver function and seen on the liver scan occurred at the time of the course of chemotherapy administered 20 days after completion of irradiation. These abnormalities disappeared when treatment was temporarily suspended. Vincristine and actinomycin D were subsequently reintroduced without evidence of hepatotoxicity. Actinomycin D after irradiation for right-sided Wilms tumor may produce severe liver toxicity.     

Predictive factor for intraoperative tumor rupture of Wilms tumor

Purpose

For Wilms tumor, intraoperative tumor rupture with wide tumor spillage during surgical manipulation raises the classification to stage 3. Then, postoperative chemotherapy must be more intensive, and abdominal radiotherapy is added. Therefore, intraoperative tumor rupture should be avoided if possible. However, predictive factors for intraoperative tumor rupture have not been sufficiently described. Here we examined the risk factors for intraoperative tumor rupture.

Methods

Patients with Wilms tumor who underwent treatment according to the National Wilms Tumor Study or the Japanese Wilms Tumor Study protocol at our institution were reviewed retrospectively. Collected cases were categorized into two groups: the ruptured group and the non-ruptured group. Risk factors for intraoperative tumor rupture, including the ratio of the tumor area to the abdominal area in a preoperative single horizontal computed tomography slice (T/A ratio), were investigated in both groups.

Results

The two groups were not different in age, body weight, tumor laterality, sex, or histological distribution. The T/A ratio in the ruptured group was significantly higher than that in the non-ruptured group. Receiver operating characteristic curve analysis identified a discriminative value for a T/A ratio >0.5.

Conclusion

The T/A ratio can be a predictive factor for intraoperative tumor rupture of Wilms tumor.

     

Optimum radiation technique for retinoblastoma in conserved eyes

The study evaluated 121 consecutive unoperated cases of retinoblastoma in children. They received radiation as the primary treatment for their ocular disease. The stage grouping was done according to Reese classification. Ninety four children had their disease evaluated by CT scan. All except one had imaged lesions in both eyes. In addition, twenty six had thickened optic nerves and twenty one showed chiasmal infiltration. Radiation field selection was based on clinical and CT imaged disease. A tumor dose of 4500c Gy in 16 to 19 fractions over 18 to 24 days was delivered by cobalt teletherapy. The target volume encompassed ora serrata anteriorly and optic chiasma posteriorly in all cases. Tumor response and patient survival was correlated with the initial stage and radiation factors utilised amongst them. Encouraging results were obtained using three field radiation technique with an open anterior field and a TDF between 75 and 90.     

Wilms tumor treatment protocol compliance and the influence on outcomes for children in Tanzania

Background

Standardized Wilms tumor treatment protocols exist for low- and middle-income countries, but outcomes equivalent to high-income countries are not achieved outside of clinical trials. As Wilms tumor treatment protocols in Africa shift with increasing resource capacity, it is not known how treatment compliance to each stage of therapy affects outcomes and where the critical breakpoints are for protocol adherence in clinical practice.

Procedure

We describe both treatment outcomes and treatment protocol adherence in a retrospective single-center cohort study of pediatric Wilms tumor patients at a zonal cancer referral hospital in Tanzania from 2016 to 2019, treated per the International Society of Paediatric Oncology standard (2016–2017) or Tanzania adapted (2018–2019) therapy protocols.

Results

A total of 69 patients were evaluated. The two-year overall survival and event-free survival rates were 40% and 29%, respectively. Only 29% of patients completed recommended chemotherapy per protocol, and completion of preoperative and postoperative chemotherapy was predictive of two-year overall survival (odds ratio [OR] 14.4, p < .001). There were delays at almost every stage of treatment, especially time from preoperative chemotherapy to surgery (56 days), from surgery to pathology report (30 days), and from surgery to initiation of postoperative chemotherapy (38 days).

Conclusions

Nonadherence with recommended Wilms tumor treatment guidelines due to key health system delays correlated to reduced overall survival rates, with chemotherapy nonadherence due to abandonment, lack of surgery, and deaths on therapy as the strongest contributors. Future interventions targeting health system delays and reducing deaths during therapy are critical to improving protocol compliance and increasing overall survival for pediatric Wilms tumor patients in low-resource settings.     

Correlation between CT-estimated tumor volume,pathologic tumor volume,and final pathologic specimen weight in children with Wilms' tumor

ObjectiveTo evaluate the relationship of Wilms' tumor (WT) volume to weight, and evaluate computed tomography (CT) scan-derived final pathologic specimen weight estimation models.MethodsWe retrospectively reviewed WT patients from 2003 to 2011 who had a pre-operative CT scan, final pathologic specimen weight, and tumor dimensions. A partial nephrectomy tumor cohort (n = 12) was used derive WT density. A radical nephrectomy cohort (n = 45) was used to develop a simplified estimation equation of final pathologic specimen weight, and analysis of all known estimation models was performed.ResultsFifty-two patients were identified. WT volume and weight were not equivalent (p = 0.0410). WT density was 1.3091 g/cm³. WT volume and final pathologic specimen weight were not significant (p = 0.0007). Our model (p = 0.9983) and CT estimated ellipsoidal volume (p = 0.0741) were able to estimate final pathologic specimen weight in all tumors. However, CT-estimated ellipsoidal volume failed to estimate final pathologic specimen weight in specimens < 250 g (p = 0.0066).ConclusionPathologic WT volume is not equivalent to final pathologic specimen weight. Final pathologic specimen weight can be estimated from a pre-operative CT scan, which suggests that it may be used to improve pre-operative surgical planning and to reduce treatment morbidity.     

Screening of children with hemihypertrophy,aniridia, and Beckwith-Wiedemann syndrome in patients with wilms tumor: A report from the national Wilms tumor study

To evaluate the usefulness of regular radiographic screening to detect an asymptomatic intraabdominal tumor in patients with an increased risk of developing Wilms tumor, we reviewed the files of patients with hemihypertrophy, aniridia, or Beckwith-Wiedemann syndrome who were registered on the National Wilms Tumor Studies. Screening was employed infrequently in the management of children with hemihypertrophy, with only 25% (6/24) of those whose hemihypertrophy was identified more than 30 days prior to the diagnosis of Wilms tumor undergoing such examinations. Most patients with aniridia were evaluated regularly for the occcurrence of Wilms tumor. There were more stage 1 tumors identified in patients whose tumor was detected only through radiographic evaluation. The role of routine radiographic screening needs to be carefully evaluated in a homogeneous group of patients such as those with aniridia using a prospective study design to determine if such screening improves the survival rate of children with this rapidly growing, but readily treatable form of childhood cancer. © 1993 Wiley-Liss, Inc.     

Complete necrosis induced by preoperative chemotherapy in Wilms tumor as an indicator of low risk: report of the international society of paediatric oncology (SIOP) nephroblastoma trial and study 9

BACKGROUND: The SIOP Nephroblastoma therapeutic protocols include a period of preoperative chemotherapy followed by nephrectomy and a period of postoperative chemotherapy. From the outset, identification of low-risk groups has been an aim of the SIOP Nephroblastoma Trials and Studies. Now that 90% of children with Wilms tumor can be cured, attention is even more focused on the identification of patients who could benefit from less aggressive postoperative therapy, thus minimizing the morbidity and late effects associated with treatment. The prognostic implications of total necrosis in nephroblastoma after chemotherapy have not been investigated hitherto. PROCEDURE: Between November 1, 1987 and June 30, 1993, 599 patients referred to the SIOP-9 Nephroblastoma Trial and Study were preoperatively treated and classified as stages I-IV nonanaplastic Wilms tumor. RESULTS: Of these 599 patients, pathologic examination of the nephrectomy specimen revealed a completely necrotic Wilms tumor (CNWT) with no viable tumor remaining in 59 (10%): these comprised 37 stages I-III and 22 stage IV. Of these patients, 58 (98%) had no evidence of disease at 5 years vs. 90% for the rest of the cohort (P < 0.05). Stages I-III patients represented 63% of CNWT and had a 97% overall survival rate. The only death was related to veno-occlusive disease and occurred in a stage I patient in the month following nephrectomy. Stage IV patients represented 37% of CNWT (vs. only 10% of all other cases of unilateral nonanaplastic Wilms tumor) and had a 100% rate of survival. Children with CNWT were older (mean 59 months vs. 43 months); their tumor at diagnosis was larger and had regressed more significantly at subsequent ultrasound examination. The data also uphold the hypothesis that Wilms tumors of blastemic pattern are most aggressive, but also are extremely responsive to chemotherapy. CONCLUSIONS: Patients with unilateral nonanaplastic WT that showed total necrosis following preoperative chemotherapy had excellent outcome and should benefit from less aggressive postoperative treatment in further trials. Other very responsive tumors, such as Wilms with <10% viable tumor, should also be assessed.     

Role of preoperative 3D CT reconstruction for evaluation of patients with esophageal atresia and tracheoesophageal fistula

Objective

The role of preoperative contrast-enhanced computerized tomography (CT) of chest with three-dimensional (3D) reconstructions was evaluated in neonates with esophageal atresia and tracheoesophageal fistula.

Methods

This was a prospective study which investigated 30 cases of esophageal atresia with tracheoesophageal fistula. All patients were evaluated preoperatively with contrast-enhanced spiral CT using a low-dose CT protocol. 3D CT reconstruction images were evaluated for the type of esophageal atresia, the distance between the upper and lower esophageal pouches, origin, level and position of the fistula, and the presence or absence of any other cardiac, pulmonary or mediastinal lesions and the findings were correlated with the findings at surgery. The radiation dose for each patient was calculated using the formula—Effective dose (E)?=?DLP?×?(E/DLP)age.

Results

All the 30 cases had type-C esophageal atresia with tracheoesophageal fistula as per Gross classification. The exact site of the fistula could be identified only in 26 (80?%) cases. The mean gap between the upper pouch and lower fistula was 0.95?±?0.57?cm (range 0.2–2.8?cm) on CT scan and 1.38?±?0.61?cm (range 0.5–3.2?cm) at surgery. On statistical analysis, the correlation was found to be significant (p?Conclusion Though preoperative CT scan of chest has many advantages, it involves significant exposure to ionizing radiation and risk of radiation-induced cancer in the future. Additionally in 20?% of cases, the fistula could not be located on CT scan. The most common variety of esophageal atresia and tracheoesophageal fistula is Gross type C (86?%) that has low to intermediate gap (97?%) and can be anastomosed primarily. Thus, CT scan can provide good anatomical delineation, but may not help in surgical decision making. Hence, performing CT in these cases would unnecessarily expose the neonates to ionizing radiation. Therefore, there is no role for CT scan in the routine preoperative assessment of EA with distal TEF.     

Billateral Polycystic Kidneys in a Girl with WAGR Syndrome

The WAGR contiguous gene deletion syndrome is a combination of Wilms tumor, aniridia, genito-urinary abnormalities, and mental retardation. An 8.5-year-old girl was initially investigated at the age of 18 months for congenital bilateral aniridia, cataracts, glaucoma and epicantus. The ultrasound (US) scan showed polycystic kidney disease. FISH study revealed deletion of the WT1 and PAX6 gene in the 11p13 WAGR region. Forty days after the first kidney US, the second US revealed a 3 cm tumor in the right kidney: a Wilms tumour, treated successfully with the Wilm’s tumor protocol. The authors conclude that the identification of the deletions in the WAGR region in patients with aniridia should definitely be done. In addition, Wilms tumor can have a very rapid growth, which, per se requires frequent and careful ultrasound kidney controls. Polycystic kidneys can be part of the WAGR presentation.     

A registry-based study of gender, fetal growth, and risk of Wilms tumor

The possibility of an interaction between gender and fetal growth on the risk of Wilms tumor is poorly examined. Using nationwide population-based registries, the authors identified all children (= 126) diagnosed with Wilms tumor in Denmark, 1973-1993, and selected 10 matched population controls per case. Data on birth weight, gestational age, and ponderal index were used to examine the association between gender, fetal growth, and risk of Wilms tumor. It was found that the risk of Wilms tumor increased with fetal growth in girls, but decreased with fetal growth in boys, although the findings did not reach statistical significance.