Friday, August 29, 2014

Partial nephrectomy for Wilms tumor: reducing the morbidity of cancer treatment in children

Wilms tumor is a relatively rare form of kidney cancer, but the most common kidney cancer in children, and the fourth most common cancer in children with approximately 500 new cases per year.[1] Historically Wilms tumor carried a poor prognosis, with survival around 30%. Largely due to the efforts of the National Wilms Tumor Study group (NWTS) and the International Society of Pediatric Oncology (SIOP) survival has improved to around 90%. However, treatment often involves radical nephrectomy (surgical removal of an entire kidney) and chemotherapy. Fortunately the improved prognosis of Wilms tumor allows surgeons and oncologists to shift their focus to reducing the morbidity of treatment. Partial nephrectomy (or removing just a tumor and the portion of kidney that surrounds it) has been proposed as a means to reduce the burden of therapy in children with Wilms tumor.

The NWTS group recently released treatment protocol AREN0534, the first official protocol to recommend partial nephrectomy for Wilms tumor. In this protocol, neoadjuvant chemotherapy (chemotherapy given prior to surgery) followed by partial nephrectomy is recommended only for patients in whom preserving renal tissue is essential.  These patients include those with Wilms tumor in both kidneys, a tumor in a solitary kidney, or unilateral disease with predisposing syndromes that increase the risk of recurrence in any remaining kidney.[2]  While partial nephrectomy in lieu of radical nephrectomy is gaining popularity, partial nephrectomy for children with unilateral nonsyndromic Wilms tumor is still considered experimental.


Why partial nephrectomy?

The use of partial nephrectomy in adult patients with renal cell carcinoma has shown improved renal function and comparable oncological outcomes in select patients.[3,4] The benefits of partial nephrectomy (i.e. saving kidney function) in children with Wilms may be of paramount importance given the long expected survival given their young age at diagnosis, possible need for chemotherapy and significant risk of recurrence (2-3%) in the remaining kidney.[5] Surprisingly, the incidence of end-stage renal disease in Wilms tumor patients is low at 0.7%.[6] However, a group in Italy followed a small group of children with Wilms tumor that were treated with a partial nephrectomy and found that at 6 and 12 years of follow-up, patients had better renal function and lower blood pressures than their counterparts that received a radical nephrectomy.[7,8]


Oncologic outcomes

Unfortunately current oncologic data is limited to retrospective studies that are limited by small numbers and selection bias. The largest study examined a European cohort of 807 patients in a protocol that called for neoadjuvant chemotherapy and radical nephrectomy. Fortunately for the purposes of this study, 5% of patients actually received a partial nephrectomy. The relapse rate and relapse-free survival were similar in the partial nephrectomy and radical nephrectomy group, suggesting oncological outcomes were similar in the partial nephrectomy group (figure 1).[9]


Figure 1. Relapse events and Relapse free survival in Wilms tumor patients with 
partial nephrectomy vs radical nephrectomy. Neoadjuvant = Neoadjuvant 
chemotherapy.   Nx = nephrectomy.  Adapted from: Haecker, F., J Urology, 2003.

A group at UTSW (University of Texas Southwestern) reviewed current available literature and identified 82 patients that underwent partial nephrectomy for unilateral Wilms tumor and compared them to 121 of their own patients that underwent radical nephrectomy. They found that recurrence-free survival and overall survival were not significantly different between the partial and radical nephrectomy groups (figure 2). Selection of patients for partial and radical nephrectomy likely played a role in these outcomes (so called selection bias), as the children undergoing partial nephrectomy group had significantly lower stage tumors than patients undergoing radical nephrectomy.[10] Regardless, both studies discussed above suggest that Wilms tumor may be treated with partial nephrectomy without a significant compromise in cancer outcomes.

Cost, N., Pediatric Blood & Cancer, 2012

How many Wilms tumor patients are candidates for partial nephrectomy?

Resectability, or the ability of the tumor to be removed, is subjective and relies on the judgment of surgeons and radiologists. A group at UCONN (University of Connecticut) retrospectively reviewed CT scans and MRIs from Wilms tumor patients that underwent radical nephrectomy. A Cancer Oncology Group (COG) surgeon and radiologist reviewed the image and judged whether partial nephrectomy was feasible. They found that only 8% of patients were amenable to partial nephrectomy.[11] A similar study from UTSW reviewed surgical pathology from children that underwent radical nephrectomy. They determined 24.4% would have been amenable to partial nephrectomy.[12] European studies utilizing neoadjuvant chemotherapy in their protocols demonstrate that tumors can shrink 50 – 60% preoperatively.[13,14] Therefore, it is hypothesized that preoperative chemotherapy could increase the proportion of tumors amenable to partial nephrectomy. Further studies from the new AREN0534 protocol should enhance our grasp of this question.
Location of Wilms tumors in radiographic determination of partial 
nephrectomy feasibility study.  Ferrer, FA., J Urology, 2013


Is Partial Nephrectomy Worth the risk?

Partial nephrectomy does not come without risk. It is technically challenging operation requiring careful dissection and control of the renal vasculature (the kidney gets approximately 25% of the body's blood flow per minute), as well as removal of a tumor with a clean margin, and reconstruction of the kidney – all within a time period that prevents permanent kidney damage. Tumor spillage and positive margins are more common, which result in upstaging of Wilms tumor in these children. Upstaging has implications for prognosis and morbidity. According to COG protocols, positive surgical margins result in radiation and longer chemotherapy, while spillage results in a longer chemotherapy regimen. The risks and benefits must be carefully considered before proceeding with partial nephrectomy which, once again, remains an experimental therapy for unilateral nonsyndromic Wilms tumor.

Summary

Wilms tumor survival has increased significantly allowing urologists to focus on reducing the burden of therapy. The increasing use of partial nephrectomy in adults opened the door for consideration in children. A small portion of Wilms tumor patients are potential candidates for partial nephrectomy. Future data from partial nephrectomy patients in protocol AREN0534 will help us learn about the affect and feasibility of partial nephrectomy for unilateral Wilms tumor. Current data indicate oncologic outcomes appear similar with improved kidney function compared to radical nephrectomy patients.


This blog was written by Kyle Ericson, Medical Student at the University of Chicago.  Kyle recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Partial Nephrectomy for Wilms Tumor" from which this blog is inspired. Kyle is looking forward to a career in urology.


 






References
1.    Grovas A, Fremgen A, Rauck A. The National Cancer Data Base report on patterns of childhood cancers in the United States. Cancer. 1997;80(12):2321 -­‐ 2332. Available at: http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-­‐ 0142(19971215)80:12%3C2321::AID-­‐CNCR14%3E3.0.CO;2-­‐W/full. Accessed August 17, 2014.
2.    Nakamura L, Ritchey M. Current management of wilms' tumor. Curr Urol Rep. 2010;11(1):58-­‐65. doi:10.1007/s11934-­‐009-­‐0082-­‐z.
3.    Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective randomized EORTC intergroup phase 3 study comparing the complications of elective nephron-­‐sparing surgery and radical nephrectomy for low-­‐stage renal cell carcinoma. Eur Urol. 2007;51(6):1606-­‐15. doi:10.1016/j.eururo.2006.11.013.
4.    Scosyrev E, Messing EM, Sylvester R, Campbell S, Van Poppel H. Renal function after nephron-­‐sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904. Eur Urol. 2014;65(2):372-­‐7. doi:10.1016/j.eururo.2013.06.044.
5.    Moorman-­‐Voestermans C. Is Partial Nephrectomy Appropriate Treatment for Unilateral Wilms' Tumor? J Pediatr ….1998;33(2):165-­‐170. Available at: http://www.sciencedirect.com/science/article/pii/S0022346898904250. Accessed August 17, 2014.
6.    Harel M, Makari JH, Ferrer F a. Oncology: the role of partial nephrectomy in Wilms tumor. Curr Urol Rep.
2013;14(4):350-­‐8. doi:10.1007/s11934-­‐013-­‐0330-­‐0.
7.    Cozzi F, Schiavetti A, Morini F, Zani A. Renal function adaptation in children with unilateral renal tumors treated with nephron sparing surgery or nephrectomy. J Urol. 2005;174(December 2003):1404-­‐1408. doi:10.1097/01.ju.0000173132.19010.ff.
8.    Cozzi DA, Ceccanti S, Frediani S, Schiavetti A, Cozzi F. Chronic Kidney Disease in Children With Unilateral Renal Tumor. J Urol. 2012;187(5):1800-­‐1805. doi:10.1016/j.juro.2011.12.109.
9.    Haecker F-­‐M, von Schweinitz D, Harms D, Buerger D, Graf N. Partial nephrectomy for unilateral Wilms tumor: results of study SIOP 93-­‐01/GPOH. J Urol. 2003;170(3):939-­‐42; discussion 943-­‐4. doi:10.1097/01.ju.0000073848.33092.c7.
10.    Cost NG, Lubahn JD, Granberg CF, et al. Oncologic outcomes of partial versus radical nephrectomy for unilateral Wilms tumor. Pediatr Blood Cancer. 2012;58(6):898-­‐904. doi:10.1002/pbc.23240.
11.    Ferrer F a, Rosen N, Herbst K, et al. Image based feasibility of renal sparing surgery for very low risk unilateral Wilms tumors: a report from the Children's Oncology Group. J Urol. 2013;190(5):1846-­‐51. doi:10.1016/j.juro.2013.05.060.
12.    Cost NG, Lubahn JD, Granberg CF, et al. Pathological review of Wilms tumor nephrectomy specimens and potential implications for nephron sparing surgery in Wilms tumor. J Urol. 2012;188(4 Suppl):1506-­‐10. doi:10.1016/j.juro.2012.02.025.
13.    Bogaert GA, Heremans B, Renard M, Bruninx L, De Wever L, Van Poppel H. Does preoperative chemotherapy ease the surgical procedure for Wilms tumor? J Urol. 2009;182(4 Suppl):1869-­‐74. doi:10.1016/j.juro.2009.03.022.
14.    Reinhard H, Semler O, Bürger D, et al. Results of the SIOP 93-­‐01/GPOH trial and study for the treatment of patients with unilateral nonmetastatic Wilms Tumor. Klin Pädiatrie. 216(3):132-­‐40. doi:10.1055/s-­‐2004-­‐822625.

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