Oncological and Renal Functional Outcomes After Nephron-Sparing Surgery versus Nephrectomy for Unilateral Wilms Tumor: A Matched Pairs Analysis

Project location: Italy, Rome
Project start date: September 2017 - Project end date: September 2018
Project number: 2018-006
Beneficiary: Dipartimento Di Pediatria E Neuropsichiatria Infantile - Sapienza Universit

Wilms tumor (WT) or nephroblastoma is the second most common intraabdominal cancer of childhood and the fifth most common pediatric malignancy overall. It represents the most frequent primary renal tumor, accounting for 6% to 7% of childhood cancer [1]. Clinical onset occurs before 5 years of age in 75% of cases. Rarely, this malignancy affects also young adults [1]. Synchronous disease in both kidneys at presentation occurs in approximately five percent of children with WT. Most patients with WT can be cured with treatment and subsequently lead normal life. The multidisciplinary management of WT has resulted in a striking improvement in survival rate as high as 90%, and has become a paradigm for successful cancer therapy. Most of the dramatic improvements in survival of these children have been achieved by results from randomized clinical studies conducted primarily by two large collaborative groups, i.e. the National Wilms Tumor Study (NWTS) Group, which is now part of the Children's Oncology Group (COG), and the Société Internationale d'Oncologie Pédiatrique (SIOP).

Over the past decades, the Dipartimento di Pediatria e Neuropsichiatria Infantile's (DP) research group has focused on the potential detrimental effects following nephrectomy (i.e., removal of one entire kidney), which is still considered as the surgical procedure of choice for unilateral WT [2,3]. Meanwhile, the DP has produced robust data supporting the oncologic efficacy and safety of nephron-sparing surgery (NSS) in children/survivors treated for unilateral WT, along with the positive effect on long-term renal function [4-7].

References
1. Pizzo PA, Poplack DG (eds). Principles and Practice of Pediatric Oncology. 3rd Edition, Lippincott-Raven, Philadelphia, 1997;733-59.
2. Cozzi DA, Ceccanti S, Frediani S, et al. Chronic kidney disease in children with unilateral renal tumor. J Urol. 2012;187:1800-5.
3. Cozzi DA, Ceccanti S, Frediani S, et al. Renal function adaptation up to the fifth decade after treatment of children with unilateral renal tumor: a cross-sectional and longitudinal study. Pediatr Blood Cancer. 2013;60:1534-8.
4. Cozzi F, Schiavetti A, Bonanni M, et al. Enucleative surgery for stage I nephroblastoma with a normal contralateral kidney. J Urol. 1996;156:1788-91; discussion 1791-3.
5. Cozzi DA, Schiavetti A, Morini F,et al. Nephron-sparing surgery for unilateral primary renal tumor in children. J Pediatr Surg. 2001;36:362-5.
6. Cozzi F, Schiavetti A, Morini F, et al. Renal function adaptation in children with unilateral renal tumors treated with nephron sparing surgery or nephrectomy. J Urol. 2005; 174:1404-8.
7. Cozzi DA, Ceccanti S, Cozzi F. Renal Function Recovery after Nephrectomy or Nephron-Sparing Surgery in Children with Unilateral Renal Tumor. Eur J Pediatr Surg. 2017;27:74-80.

Amongst the well-standardized multimodal treatment of WT, surgery still plays a pivotal role. Radical nephrectomy is currently considered as the procedure of choice, because it allows excision of the primary tumor with a wide surgical margin and most of the patients are believed to have another good kidney. Nephron-sparing surgery (NSS) plays instead a lesser role, and such type of surgery is predominantly confined to patients with bilateral WT. Indeed, the rationale for NSS is to limit potential long-term morbidity by maximizing the preservation of functioning renal parenchyma. However,
whether NSS is a reasonable alternative to nephrectomy in children with WT in the setting of a normal contralateral kidney remains controversial. Main issue against such clinical scenario is that there is no convincing evidence that 50% reduction of renal mass is associated with increased risk of renal failure. Additionally, it is a well accepted that the benefit of NSS in terms of renal function must to be weighed against the potential risk of leaving cancer behind (i.e., positive surgical margins), which implies a rather aggressive adjuvant treatment regimen. As a matter of fact, prospective
randomized trials have not yet been designed to evaluate the efficacy of NSS over nephrectomy in terms of both oncological and renal functional outcomes in children with non-metastatic unilateral WT. Therefore, current evidence must depend on data derived from carefully designed observational studies.
In the pediatric population, there is a certain reluctance to consider NSS as an advantage over radical nephrectomy in terms of residual renal function.That is because the risk of developing renal failure following radical nephrectomy is currently believed to be low. However, there is an increasing evidence that a renal dysfunction is significantly associated with the amount of renal parenchyma excised and with aging, especially from the fifth decade of life onwards.

The DP's working hypothesis is that nephrectomized children for unilateral renal tumor may present during adulthood a progressive decline of renal function associated with an ominous high prevalence of mild-to-severe renal dysfunctions. Since healthy life expectancy in these children has dramatically improved due to the very high cure rates nowadays achieved for pediatric kidney tumors, the DP's main concern is that the renal dysfunction which may develop following radical nephrectomy in children is currently underestimated. Additionally, several population studies have found that the occurrence of such renal dysfunction is strongly associated with morbid cardiac events and all causes mortality.
Therefore, in this context NSS may have a renal function advantage over radical nephrectomy. However, very few data are currently available and the DP is amongst the few centers which have accumulated experience with such innovative surgery in children with primary renal tumor and normal contralateral kidney.

The present research project is a continuation of a previous project financed by the Nando and Elsa Peretti Foundation, which has always encouraged and promoting medical and scientific research, especially when proposed issues pertain child health.

The aims of present study project can be summarized as follows:
- To determine residual renal function and relative renal volume of the kidney remnants after NSS.
- To compare oncologic and nephrological outcomes of patients with primary renal tumor receiving either radical nephrectomy or NSS. Matched case-control analysis will be employed to control for known potential confounding variables.
The obtained results from the proposed study will be very innovative and will contribute to expand the currently limited role of NSS for select children with unilateral WT and normal opposite kidney.