Recurrent Wilms Tumor Research Articles

Abstract CT256: A pilot clinical study of VAL-413 (Orotecan®, oral irinotecan HCl) in patients with recurrent pediatric solid tumors

Abstract Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label for a range of adult and pediatric solid tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Recently, commercially available intravenous irinotecan has been administered orally (IRN-IVPO) in pediatric patients to improve convenience, reduce in-clinic time and overall cost of treatment. Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan. We will report on an ongoing Phase 1-2 first-in-human clinical trial of VAL-413, designed to test the hypothesis that VAL-413 improves palatability without significant pharmacokinetic differences from IRN-IVPO using intra-patient comparison of pharmacokinetic profiles. The evaluation of two dose levels will help to formally define a recommended dose for advanced clinical studies. Trial Design: Patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option, are eligible. Up to 20 eligible patients will receive VAL-413 90mg/m2/day or 110mg/m2/day using a standard 3 + 3 design. During the first cycle of treatment, each patient will receive four daily doses of VAL-413 and one daily dose of IRN-IVPO, together with five (5) days of concurrent temozolomide. Pharmacokinetic assessments will follow both VAL-413 and IRN-IVPO administration using a limited sampling strategy. During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days. Up to 17 cycles of treatment may be administered on this study. Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; and comparative intrapatient pharmacokinetics of irinotecan and its metabolites will be assessed in all patients. Citation Format: James Geller, Patrick Thompson, Javier Oesterheld, Dennis M. Brown, Jeffrey Bacha, Sarath Kanekal, Lorena Lopez, Markos Leggas, Neil Sankar, Noymi Yam, Lars M. Wagner. A pilot clinical study of VAL-413 (Orotecan®, oral irinotecan HCl) in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT256.

A pilot clinical study of VAL-413 (oral irinotecan HCl) in patients with recurrent pediatric solid tumors.

TPS10063 Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label for a range of adult and pediatric solid tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days, every 21 days has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001 ). Protracted administration schedule of intravenous irinotecan is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed (Wagner. ClinSarcRes, 2015 ). Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet clinical need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan. Methods: Eligibility: Up to 20 patients ≥ 1 year and ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled. Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 100mg/m2/day will be studied in combination with a fixed-dose of temozolomide using a standard 3 + 3 phase I design. In the event that the starting dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented. Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated. Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; and comparative intrapatient pharmacokinetics of irinotecan and its metabolites will be assessed in all patients. This trial is ongoing (CT.gov: NCT04337177). Enrolment of the first dose level is ongoing, with no DLT observed to date. Clinical trial information: NCT04337177.

Recurrent unilateral Wilms tumor: Lessons learned based on a prospective cohort study from India

Recurrent unilateral Wilms tumor: Lessons learned based on a prospective cohort study from India

S-049 再発のみられたWilms腫瘍における外科的治療の意義(小児腫瘍学-再発・進行例に対する外科手術のフロンティアII.頭頚部,肝,腎腫瘍および再発腫瘍に対する外科治療戦略, 第44回日本小児外科学会学術集会)

S-049 再発のみられたWilms腫瘍における外科的治療の意義(小児腫瘍学-再発・進行例に対する外科手術のフロンティアII.頭頚部,肝,腎腫瘍および再発腫瘍に対する外科治療戦略, 第44回日本小児外科学会学術集会)

Chromosomal anomalies at 1q, 3, 16q, and mutations of SIX1 and DROSHA genes underlie Wilms tumor recurrences.

Approximately half of children suffering from recurrent Wilms tumor (WT) develop resistance to salvage therapies. Hence the importance to disclose events driving tumor progression/recurrence. Future therapeutic trials, conducted in the setting of relapsing patients, will need to prioritize targets present in the recurrent lesions. Different studies identified primary tumor-specific signatures associated with poor prognosis. However, given the difficulty in recruiting specimens from recurrent WTs, little work has been done to compare the molecular profile of paired primary/recurrent diseases. We studied the genomic profile of a cohort of eight pairs of primary/recurrent WTs through whole-genome SNP arrays, and investigated known WT-associated genes, including SIX1, SIX2 and micro RNA processor genes, whose mutations have been recently proposed as associated with worse outcome. Through this approach, we sought to uncover anomalies characterizing tumor recurrence, either acquired de novo or already present in the primary disease, and to investigate whether they overlapped with known molecular prognostic signatures.Among the aberrations that we disclosed as potentially acquired de novo in recurrences, some had been already recognized in primary tumors as associated with a higher risk of relapse. These included allelic imbalances of chromosome 1q and of chromosome 3, and CN losses on chromosome 16q. In addition, we found that SIX1 and DROSHA mutations can be heterogeneous events (both spatially and temporally) within primary tumors, and that their co-occurrence might be positively selected in the progression to recurrent disease. Overall, these results provide new insights into genomic and genetic events underlying WT progression/recurrence.

The impact of surveillance imaging on overall survival in patients with recurrent Wilms tumor: A report from the Children’s Oncology Group.

9536 Background: Surveillance imaging during and after therapy is employed to detect relapse in patients with Wilms tumor (WT). The use of more sensitive imaging modalities such as CT and MRI scans...

Acute pancreatitis induced by ifosfamide therapy

Ifosfamide used in the treatment of pediatric solid tumors is known to have serious adverse effects, including acute pancreatitis, a rare complication of therapy. This report describes a young girl who developed acute pancreatitis while being treated for recurrent Wilms tumor with the ifosfamide, carboplatin, and etoposide regimen. She recovered completely and without sequelae from ifosfamide-induced pancreatitis soon after the drug was stopped. Abdominal pain in patients on anticancer treatment is a common occurrence, but it is rarely investigated. Patients who receive ifosfamide as part of a chemotherapy regimen should be carefully monitored, and symptoms or signs suggestive of acute pancreatitis should be promptly investigated. Withholding the drug usually leads to complete recovery.

Successful Treatment of Late, Recurrent Wilms Tumor With High-dose Chemotherapy and Autologous Stem Cell Rescue in Third Complete Response

Wilms tumor relapses are infrequent, occurring in approximately 15% of favorable histology patients. Very few cases of late recurrent relapse exist in the literature. Long-term survival after autologous stem cell rescue ranges from 40% to 73%, but there are very few reports of patients transplanted in their third complete response. We report a late recurrent relapse of Wilms tumor successfully treated with high-dose chemotherapy and autologous stem cell rescue in his third complete response who remains disease free 15 months posttransplant.

Treatment of relapsed Wilms tumors: lessons learned

Treatment regimens for recurrent Wilms tumor (WT) are currently designed to include drugs that are not used during primary chemotherapy, using a risk-stratified approach. Therapy of recurrent disease depends on the nature of initial treatment, and of recognized prognostic indicators inherent in the primary tumor. Several highly effective chemotherapy regimens, including ifosfamide–carboplatin–etoposide, cyclophosphamide–etoposide and carboplatin–etoposide, are considered first treatment choice for recurrent disease. While intense-dose chemotherapy is uniformly accepted to treat high-risk recurrent WTs, the optimal therapy for standard-risk children has yet to be defined, owing to the small number of such patients and their relatively better prognosis compared with high-risk recurrences. Recurrent tumors among those defined as very-high risk are likely to develop chemoresistant disease, and novel therapeutic strategies will be necessary to cure these patients. Evidence on how to properly administer surgery and radiotherapy at relapse is more fragmentary. The authors have reviewed the available experiences concerning the treatment of recurrent WT, and have attempted to provide the most up-to-date recommendations regarding the optimal risk-based treatment for these patients.

Phase 2 Trial of Recombinant Tumor Necrosis Factor-α in Combination With Dactinomycin in Children With Recurrent Wilms Tumor

Tumor necrosis factor (TNF), a peptide produced by macrophages with cytostatic and cytolytic effects, demonstrated single agent antitumor activity and synergistic effect when administered with dactinomycin in in vitro tumor cell lines, in vivo xenograft models, and adult and pediatric phase 1 clinical trials. This phase 2 pediatric trial evaluated the efficacy and further defined the toxicity profile of recombinant TNF (rTNF) and dactinomycin in patients with recurrent or refractory Wilms tumor. On this 2 stage Children's Cancer Group trial, dactinomycin (15 microg/kg/d, IV) immediately followed by rTNF (200 microg/m/d, IV), once daily for 5 consecutive days, was administered to patients with recurrent or refractory Wilms tumor. Cycles repeated every 21 days to a maximum of 12 courses. Nineteen of 21 consecutive patients, ranging 0.9 to 16.5 years of age at the time of initial diagnosis, were evaluable for response and toxicity. Three patients (15.8%) had a complete response, 5 (26.3%) had stable disease, and 11 (57.9%) had progressive disease. Following 59 patient treatment cycles, the most commonly observed grade 3/4 toxicities were thrombocytopenia (40.7%), elevated liver transaminases (23.7%), neutropenia (20.3%), leucopenia (13.6%), anemia (11.9%), and myalgias (10.2%). Before completion of stage 2, the study closed due to unavailability of rTNF. The documented complete responses and disease stabilization suggest antitumor activity of rTNF with dactinomycin in patients with recurrent Wilms tumor. The combination was well tolerated. Although grade 3/4 adverse events were reported, dose adjustments were not required. Toxicities resolved without significant interventions.

Wilms Tumor

Wilms Tumor

Treatment of high‐risk relapsed Wilms tumor with dose‐intensive chemotherapy, marrow‐ablative chemotherapy, and autologous hematopoietic stem cell support: Experience by the Italian association of pediatric hematology and oncology

We evaluated an intensified chemotherapy strategy in children with Wilms tumor who relapsed with high-risk features. From January 2001 to June 2006, we treated 20 consecutive children with reinduction chemotherapy (using ifosfamide/carboplatin/etoposide in 15/20 cases), with (n = 15) or without (n = 5) subsequent high-dose chemotherapy and hematopoietic stem cell support, surgery where feasible, and radiation therapy. The median time to relapse was 10 months after nephrectomy. All but two children initially received doxorubicin as first-line therapy. All patients were assessed for outcome: 13 are currently alive, 12 of them in remission a median 25 months since their relapse, one with progressing tumor. The treatment was unsuccessful in eight children: the disease progressed during reinduction in three, and relapsed in five. There was one toxic death. All transplanted patients engrafted to a neutrophil count >0.5 x 10(3)/microl after a median 11 days, and to an unsustained platelet count >25,000/microl after a median of 13 days. Three-year disease-free and overall survival rates were 56 +/- 12% and 55 +/- 13%, respectively. Neither recurrence within 12 months of nephrectomy nor extra-lung recurrence negatively affected outcome. A survival advantage was demonstrated in patients without disease evidence prior to transplant. A disease-free survival rate nearing 50% is a realistic target in children with high-risk recurrent Wilms tumor. The benefit of autologous hematopoietic stem cell transplantation for consolidation deserves to be investigated in a randomized, controlled study.

Recurrent Adult Wilms Tumor With Extensive Metastases on FDG PET-CT

Abstract: We report the PET-CT appearance of recurrent Wilms tumor in the surgical bed with multiple metastatic sites in a 30-year-old man. He was initially diagnosed with Wilms tumor in the right kidney with involvement of the right adrenal gland and right renal vein into the inferior vena cava, for which he underwent a right nephrectomy, right adrenalectomy, and retroperitoneal lymph node dissection. Three months later, a restaging PET-CT study demonstrated multiple hypermetabolic lesions in the surgical bed region, the left adrenal gland, liver, thoracolumbar spine, retroperitoneal lymph nodes, and peritoneum.

Renal Function Outcomes in Patients Treated With Nephron Sparing Surgery for Bilateral Wilms Tumor

Management of bilateral Wilms tumor represents a particular challenge in the consideration of long-term renal function for affected patients. Aggressive surgical resection to prevent recurrence must be balanced with the desire to preserve renal function. We evaluated our institutional experience with nephrological outcomes in patients treated with nephron sparing surgery for bilateral Wilms tumor. We identified all patients with synchronous bilateral Wilms tumors presenting to St. Jude Children's Research Hospital between October 1987 and February 2004. We also included patients with Wilms tumor involving a solitary kidney presenting during the same period. A total of 17 patients were identified who underwent nephron sparing surgery, including 16 with bilateral tumors and 1 with tumor in a solitary kidney. Institutional review board approval was obtained to retrospectively review records and analyze outcomes based on long-term renal function, hypertension, proteinuria, need for dialysis and indications for renal transplantation. Eight of the 17 patients initially underwent bilateral nephron sparing surgery and 9 initially underwent a combination of nephrectomy and contralateral nephron sparing surgery. Two patients were eventually rendered anephric following further resections secondary to local recurrence. Before the initiation of therapy all patients had normal baseline creatinine clearance, which was calculated using the Schwartz formula. At a median followup from diagnosis of 72 months (range 15 to 207) 1 patient had renal insufficiency and another 3 had renal failure requiring dialysis. One of the 3 patients on dialysis died of metastatic Wilms and 2 await renal transplantation. None of the remaining patients had evidence of proteinuria. Ten of the 17 patients (58.8%) had hypertension at diagnosis and 9 (52.9%) required antihypertensive medications at the most recent followup. The overall survival rate in this group of patients was 88.2% with no evidence of disease in survivors at the most recent followup. When combined with adjuvant radiation and/or chemotherapy, nephron sparing surgery provides an opportunity to preserve renal function, while maintaining excellent long-term oncological outcomes for patients with bilateral Wilms tumor.

Tandem high dose therapy with hematopoietic progenitor cell rescue in children with high-risk solid tumors

A major advance in the treatment of high-risk patients with solid tumors has been to intensify therapy. We hypothesize that the use of tandem high dose chemotherapy followed by stem cell rescue will improve survival in children with high-risk solid tumors. Fifteen patients were enrolled from March 2000 to August 2004 with a median age of 6 years (2–19). Each had received at least 2 courses of chemotherapy prior to study enrollment. Patients (Table 1) had the following diagnoses: recurrent Wilms tumor (n = 5), high-risk Ewing’s sarcoma (n = 3), recurrent hepatoblastoma (n = 2), recurrent retinoblastoma (n = 2), recurrent germ cell tumor (n = 2), and undifferentiated sarcoma (n = 1).

Improved Survival in Patients with Recurrent Wilms Tumor: the Experience of the Seoul National University Children's Hospital

The survival in cases with relapsed Wilms tumor is dismal. Recently, however the introduction of new therapeutic agents and experimental strategies has improved the survival. We analysed the survival of patients with relapsed Wilms tumor according to the treatment period. During the early period 1983-1993, patients who had received two drugs were treated with doxorubicin and the others were treated with cisplatin and etoposide, whereas during the late period 1994-2004, patients were treated with combinations of cyclophosphamide/etoposide and carboplatin/etoposide. During the early period, 8 of 57 experienced relapse, and 8 of 41 relapsed during the late period. Only 2 patients treated during the early period survived in complete response (CR), whereas during the late period, 5 patients remained alive in CR, and 3 of those received high-dose chemotherapy (HDC) with autologous peripheral stem cell rescue (SCR). The estimated 5 yr event-free survival rate was 37.5% in the entire study group, 50% for patients in the late period, and 25% for patients in the early period (p=0.38). The survival in patients with relapsed Wilms tumor dramatically improved during the late period and HDC with SCR was one of the effective salvage strategies.

Combined Endoscopic Resection and Brachytherapy for Recurrent Intrapelvic Wilms Tumor

A 6-year-old boy presented elsewhere with stage V Wilms tumor and was treated with left nephrectomy, chemotherapy (vincristine, actinomycin and doxorubicin) and external beam radiation. The right kidney tumor responded completely radiologically. Sixteen months later a small tumor was identified in the right kidney and the patient was referred to our center, where he underwent partial right nephrectomy. Pathologically clear margins and favorable histology were confirmed. One year later the patient presented with acute right flank pain, gross hematuria, anuria and an enlarged solitary kidney. Computerized tomography demonstrated a mass within the renal pelvis causing hydronephrosis (fig. 1). At exploration no parenchymal lesions were evident. The renal pelvis was opened and found to contain tumor. An adult resectoscope was used to resect all visible tumor and revealed the source as being a lower pole calix. A nephrostomy tube was placed under endoscopic guidance through the affected calix. The nephrostomy tube was used postoperatively to implant radioactive iridium seeds (17 Gy.) with great accuracy, followed by rescue chemotherapy (ifosfamide, carboplatin and etoposide) and concomitant external beam radiation (33 Gy.). The patient has now been disease-free for 10 years, with

Combined Endoscopic Resection and Brachytherapy for Recurrent Intrapelvic Wilms Tumor

Combined Endoscopic Resection and Brachytherapy for Recurrent Intrapelvic Wilms Tumor

Secondary acute myelogenous leukemia in patients previously treated for childhood renal tumors: a report from the National Wilms Tumor Study Group.

This review characterized cases of secondary acute myelogenous leukemia (AML) occurring after treatment of renal neoplasms on protocols of the National Wilms Tumor Study Group (NWTSG) between October 1969 and December 1991. The NWTSG database was reviewed for cases of secondary AML and for WT1 status of the affected patients. Referring institutions were contacted by a confidential letter requesting pathology reports, results of immunophenotyping, cytogenetic, and molecular analyses, and details concerning treatment of AML. Of the 5,278 patients treated during the study period, 43 had second malignant neoplasms, and 7 of these 43 had AML. At the time of diagnosis of Wilms tumor, the median age of the seven patients (4 boys) was 3.2 years. Five of the seven renal neoplasms had favorable histologic characteristics. The most common French-American-British morphology was M5. One patient had bilateral tumors, and two were treated for recurrent Wilms tumor. All patients received chemotherapy regimens that included doxorubicin (6) or etoposide (1), and six were treated with infradiaphragmatic irradiation. The median latency period from initial diagnosis of the renal neoplasm to development of secondary AML was 3 years (range, 1.2-4 yrs). One patient had the translocation t(9:11)(p22;q23); WT1 status was not noted for any of the seven patients. The development of secondary AML in this subset of patients after treatment of renal neoplasms may reflect the interaction of the effects of treatment and possible genetic predisposition toward cancer.

The Management of Relapsed Wilms Tumor

Relapsed Wilms tumor is often very responsive to re-treatment, and cures are possible in many cases. Recurrent Wilms tumor forms a heterogeneous group because initial therapies vary widely. Given the complexity of the problem, there is a great need for an organized clinical investigative approach. Ideally, the treatment of initial relapse should be specified by the primary treatment protocol in order to better evaluate overall survival as an end-point for new primary therapy strategies. This is especially appropriate for Wilms tumor, because the investigations of this tumor over the last 20 years have attempted to determine the minimal therapy necessary for cure. Thus, survival rather than relapse-free survival is the most appropriate criterion for the success of a primary retreatment regimen. This investigative approach would also allow evaluation of treatment strategies tailored to a specific patient population. Important questions remain for those who treat recurrent Wilms tumor. Defining the role of high-dose therapy, defining the role of total body irradiation in high-dose therapy regimens, and defining the benefit and toxicity of cyclophosphamide compared with ifosfamide are three current questions under investigation. Developing new agents and regimens effective against Wilms tumor, especially against anaplastic tumors, RTK, and CCSK, is extremely important if progress is to be made in treating these tumors after relapse. Finally, there is a strong need to develop biologic information about tumors that recur, so not only will we better understand why patients relapse but also we can develop therapy tailored specifically to the biology of the recurrent tumor.