Pharmacotherapeutic Management of Wilms Tumor: An Update
Although differences exist in treatment and risk-stratification strategies for children with Wilms tumor (WT) between the European [International Society of Paediatric Oncology (SIOP)] and American [Children’s Oncology Group (COG)] study groups, outcomes are very similar, with an overall survival of > 85%. Future strategies aim to de-intensify treatment and reduce toxicity for children with a low risk of relapse and intensify treatment for children with high-risk disease. For metastatic WT, response of lung nodules to chemotherapy is used as a marker to modify treatment intensity. For recurrent WT, a unified approach based on the use of agents that were not used for primary therapy is being introduced. Irinotecan is being explored as a new strategy in both metastatic and relapsed WT. Introduction of biology-driven approaches to risk stratification and new drug treatments has been slower in WT than in some other childhood cancers. While several new biological pathways have been identified recently in WT, their individual rarity has hampered their translation into clinical utility. Identification of robust prognostic factors requires extensive international collaborative studies because of the low proportion who relapse or die. Molecular profiling studies are in progress that should ultimately improve both risk classification and signposting to more targeted therapies for the small group for whom current therapies fail. Accrual of patients with WT to early-phase trials has been low, and the efficacy of these new agents has so far been very disappointing. Better in vitro model systems to test mechanistic dependence are needed so available new agents can be more rationally prioritized for recruitment of children with WT to early-phase trials.
The authors thank Suzanne Tugnait for her contribution to the final editing of the manuscript.
Compliance with Ethical Standards
RMO is funded by the Great Ormond Street Hospital Children’s Charity (grant reference W1090). KPJ is funded in part by the National Institute for Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Hospital Children’s Charity, Cancer Research UK (grant no. C1188/A4614) and the Children’s Cancer and Leukaemia Group (Bethany’s Wish, grant reference CCLGA 2017 02).
Conflict of interest
Radna Minou Oostveen and Kathy Pritchard-Jones have no conflicts of interest that might be relevant to the contents of this manuscript.
- 9.Mitchell C, Pritchard-Jones K, Shannon R, Hutton C, Stevens S, Machin D, et al. Immediate nephrectomy versus preoperative chemotherapy in the management of non-metastatic Wilms’ tumour: results of a randomised trial (UKW3) by the UK Children’s Cancer Study Group. Eur J Cancer. 2006;42(15):2554–62.PubMedCrossRefGoogle Scholar
- 15.Grundy PE, Breslow NE, Li S, Perlman E, Beckwith JB, Ritchey ML, et al. Loss of heterozygosity for chromosomes 1p and 16q Is an Adverse prognostic factor in favorable-histology Wilms tumor: a report from the national Wilms tumor study group. J Clin Oncol. 2005;23(29):7312–21.PubMedCrossRefPubMedCentralGoogle Scholar
- 18.Randolph J. Treatment of mixed tumors of the kidney in childhood. In: Gross RE, Neuhauser EBD, editors. Pediatrics, vol. 6. 1950. p. 843–52 (1998;102(Supplement 1):209–10).Google Scholar
- 25.Fernandez CV, Perlman EJ, Mullen EA, Chi Y-Y, Hamilton TE, Gow KW, et al. Clinical outcome and biological predictors of relapse after nephrectomy only for very low-risk Wilms tumor: a report from children’s oncology group AREN0532. Ann Surg. 2017;265(4):835–40.PubMedPubMedCentralCrossRefGoogle Scholar
- 34.Pritchard-Jones K, Kelsey A, Vujanic G, Imeson J, Hutton C, Mitchell C. Older age is an adverse prognostic factor in stage I, favorable histology Wilms’ tumor treated with vincristine monochemotherapy: a study by the united kingdom children’s cancer study group, Wilm’s Tumor Working Group. J Clin Oncol. 2003;21(17):3269–75.PubMedCrossRefGoogle Scholar
- 37.Lindsay FA, Shamberger RC, Henderson TO, Lisa D. Decision analysis to compare treatment strategies for stage I/favorable histology Wilms tumor. Pediatric Blood Cancer. 2010;54(7):879–84.Google Scholar
- 45.Pritchard-Jones K, Bergeron C, de Camargo B, van den Heuvel-Eibrink MM, Acha T, Godzinski J, et al. Omission of doxorubicin from the treatment of stage II–III, intermediate-risk Wilms’ tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial. Lancet. 2015;386(9999):1156–64.PubMedCrossRefGoogle Scholar
- 47.Chagtai T, Zill C, Dainese L, Wegert J, Savola S, Popov S, et al. Gain of 1q As a prognostic biomarker in Wilms Tumors (WTs) treated with preoperative chemotherapy in the International Society of Paediatric Oncology (SIOP) WT 2001 Trial: A SIOP Renal Tumours Biology Consortium Study. J Clin Oncol. 2016;34(26):3195–203.PubMedPubMedCentralCrossRefGoogle Scholar
- 48.The SRTSG, Spreafico F, van den Heuvel-Eibrink MM, Pritchard-Jones K, Bergeron C, Godzinski J, et al. Paediatric renal tumours: perspectives from the SIOP–RTSG. Nature Rev Urol. 2016;14:3.Google Scholar
- 56.Grundy PE, Green DM, Dirks AC, Berendt AE, Breslow NE, Anderson JR, et al. Clinical significance of pulmonary nodules detected by CT and Not CXR in patients treated for favorable histology Wilms tumor on national Wilms tumor studies-4 and 5: a report from the Children’s Oncology Group. Pediatric Blood Cancer. 2012;59(4):631–5.PubMedPubMedCentralCrossRefGoogle Scholar
- 59.Daw NC, Anderson JR, Hoffer FA, Geller JI, Kalapurakal JA, Perlman EJ, et al. A phase 2 study of vincristine and irinotecan in metastatic diffuse anaplastic Wilms tumor: results from the Children’s Oncology Group AREN0321 study. J Clin Oncol. 2014;32(15_suppl):10032.Google Scholar
- 62.Pein F, Pinkerton R, Tournade MF, Brunat-Mentigny M, Levitt G, Margueritte G, et al. Etoposide in relapsed or refractory Wilms’ tumor: a phase II study by the French Society of Pediatric Oncology and the United Kingdom Children’s Cancer Study Group. J Clin Oncol. 1993;11(8):1478–81.PubMedCrossRefGoogle Scholar
- 67.Hol JA, den Heuvel-Eibrink MM, Graf N, Pritchard-Jones K, Brok J, Tinteren H, et al. Irinotecan for relapsed Wilms tumor in pediatric patients: SIOP experience and review of the literature—a report from the SIOP Renal Tumor Study Group. Pediatric Blood Cancer. 2018;65(2):e26849.CrossRefGoogle Scholar
- 68.Mavinkurve-Groothuis AMC, van den Heuvel-Eibrink MM, Tytgat GA, van Tinteren H, Vujanic G, Pritchard-Jones KLP, et al. Treatment of relapsed Wilms tumour (WT) patients: experience with topotecan. A report from the SIOP Renal Tumour Study Group (RTSG). Pediatric Blood Cancer. 2015;62(4):598–602.PubMedCrossRefPubMedCentralGoogle Scholar
- 71.Malogolowkin M, Cotton CA, Green DM, Breslow NE, Perlman E, Miser J, et al. Treatment of Wilms tumor relapsing after initial treatment with vincristine, actinomycin D, and doxorubicin. A report from the National Wilms Tumor Study Group. Pediatric Blood Cancer. 2008;50(2):236–41.PubMedCrossRefGoogle Scholar
- 72.Hale J, Hobson R, Moroz V, Sartori P. Results of UK children’s cancer and leukemia group (CCLG) protocol for relapsed Wilms tumor (UKWR): unified relapse strategy improves outcome. In: Proceeding of the 40th Meeting of International Society of Pediatric Oncology (Abstract O154). 2008:16.Google Scholar
- 74.Perotti D, Hohenstein P, Bongarzone I, Maschietto M, Weeks M, Radice P, et al. Is Wilms tumor a candidate neoplasia for treatment with WNT/β-catenin pathway modulators?—a report from the renal tumors biology-driven drug development workshop. Mol Cancer Ther. 2013;12(12):2619–27.PubMedCrossRefGoogle Scholar
- 77.Geller JI, Pressey JG, Smith MA, Kudgus RA, Schoon R, McGovern RM, et al. ADVL1522: a phase 2 study of IMGN901 (lorvotuzumab mertansine; IND# 126953, NSC# 783609) in children with relapsed or refractory Wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, malignant peripheral nerve sheath tumor (MPNST), and synovial sarcoma: a Children’s Oncology Group study. J Clin Oncol. 2017;35(15_suppl):10537.CrossRefGoogle Scholar
- 78.Malempati S, Weigel B, Ingle AM, Ahern CH, Carroll JM, Roberts CT, et al. Phase I/II Trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(3):256–62.PubMedCrossRefGoogle Scholar
- 80.Fouladi M, Perentesis JP, Wagner LM, Vinks AA, Reid JM, Ahern C, et al. A phase I study of cixutumumab (IMC-A12) in combination with temsirolimus (CCI-779) in children with recurrent solid tumors: a Children’s Oncology Group Phase I Consortium Report. Clin Cancer Res. 2015;21(7):1558–65.PubMedCrossRefGoogle Scholar
- 83.Geoerger B, Chisholm J, Le Deley M-C, Gentet J-C, Zwaan CM, Dias N, et al. Phase II study of gemcitabine combined with oxaliplatin in relapsed or refractory paediatric solid malignancies: an innovative therapy for children with Cancer European Consortium Study. Eur J Cancer. 2011;47(2):230–8.PubMedCrossRefGoogle Scholar
- 85.Muscal JA, Thompson PA, Horton TM, Ingle AM, Ahern CH, McGovern RM, et al. A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: a Children’s Oncology Group phase I consortium study (ADVL0916). Pediatric Blood Cancer. 2013;60(3):390–5.PubMedCrossRefGoogle Scholar
- 89.Adamson PC, Matthay KK, O’Brien M, Reaman GH, Sato JK, Balis FM. A phase 2 trial of all-trans-retinoic acid in combination with interferon-α2a in children with recurrent neuroblastoma or Wilms tumor: a Pediatric Oncology Branch, NCI and Children’s Oncology Group Study. Pediatric Blood Cancer. 2007;49(5):661–5.PubMedCrossRefGoogle Scholar
- 90.Mossé YP, Lipsitz E, Fox E, Teachey DT, Maris JM, Weigel B, et al. Pediatric phase I trial and pharmacokinetic study of MLN8237, an investigational oral selective small-molecule inhibitor of aurora kinase A: a Children’s Oncology Group Phase I Consortium Study. Clin Cancer Res. 2012;18(21):6058–64.PubMedPubMedCentralCrossRefGoogle Scholar