1. IMMEDIATE VS DELAYED NEPHRECTOMY IN WILMS TUMOR Kevin Sullivan, MD UW General Surgery, R1 June 11, 2015

2. Wilms Tumor  Most common tumor of renal origin in children, second most common solid abdominal tumor, and 6% of all tumors  Clinical presentation  Mean age of 3 years old, most common 1-4yo  Large smooth, round, nontender flank mass  Hematuria (~20%)  Hypertension (20-25%)  Fever, anorexia, weight loss (~10%)  Coagulopathy (~10%)  Associated abnormalities in about 13-28%  WAGR (Wilms, aniridia, genitourinary abnormalities, mental retardation)  Beckwith-Wiedemann, Klippel-Treynaunay, Denys-Drash

3. AB  3 month old female with 1 month of abdominal distention found to have palpable abdominal mass

4. What’s next?  Abdominal Ultrasound to evaluate for IVC or atrial extension (4%) or renal vein extension (11%)  Primary resection vs pre-operative chemotherapy?  National Wilms Tumor Society Group (NWTSG) and Children’s Oncology Group (COG) US, Canada  International Society of Pediatric Oncology (SIOP) Europe

5. NWTS  Staging (before chemotherapy) ILimited to kidney and completely excised, capsule intact No extension into vessels No tumor rupture IIExtends beyond kidney but is completely excised with negative margins IIIResidual tumor confined to the abdomen (eg lymph nodes, peritoneal surfaces, beyond margins, not completely resectable) Tumor spill IVHematogenous metastasis Metastasis beyond regional lymph nodes VBilateral renal involvement at the time of diagnosis

6. NWTS Metzger ML, Dome JS. Current therapy for Wilms' tumor. Oncologist 2005; 10:815.  Adjuvant treatment, favorable histology IVincristine and dactinomycin x 18 weeks IIVincristine and dactinomycin x 18 weeks IIIVincristine, dactinomycin, doxorubicin x 24 weeks Radiation therapy IVVincristine, dactinomycin, doxorubicin x 24 weeks Radiation therapy *No postop chemotherapy given if <2yo AND tumor <550g AND stage I

7. SIOP  Staging (after 4 weeks chemotherapy) ILimited to kidney or surrounded by fibrous pseudocapsule May dip into ureter but not infiltrating walls No renal sinus involvement IIExtends beyond kidney or pseudocapsule but margins clear Infiltrates local vessels or lymphatics but completely excised IIIIncomplete excision (grossly or microscopically) Penetration of peritoneal surface Any abdominal lymph nodes Tumor rupture before or intraoperatively IVHematogenous metastasis Metastasis beyond regional lymph nodes VBilateral renal involvement at the time of diagnosis

8. SIOP Metzger ML, Dome JS. Current therapy for Wilms' tumor. Oncologist 2005; 10:815.  Adjuvant treatment, favorable histology IVincristine and dactinomycin x 4 weeks IIVincristine, dactinomycin, doxorubicin x 27 weeks IIIVincristine, dactinomycin, doxorubicin x 27 weeks Radiation therapy IVChemotherapy x 27-34 weeks Radiation therapy if lung lesions remain present at 9 weeks therapy

9. NWTS vs SIOP  No obvious difference in outcome was apparent between contemporaneous studies such as NWTS 5 and SIOP 9

10. NWTS vs SIOP Mitchell C, Pritchard-Jones K, Shannon R, 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; 42:2554.  UKW3 Trial: Randomized controlled trial of immediate nephrectomy vs percutaneous needle biopsy, 6 weeks preoperative chemotherapy, and delayed nephrectomy

11. UKW3 Trial – Overall Survival Event Free Survival 79.6% at 5 years regardless of regimen Hazard ratio 1.25 (95% CI 0.68-2.30, p = 0.52) Overall Survival at 5 years was 89.0% combined HR 0.84 (95% CI 0.38- 1.88, p = 0.18

12. UKW3 Trial  Relapses  10 local relapses in of 91 patients in delayed surgery group (11%)  5 local relapses in 93 immediate surgery group (5.4%)  This 5.6% difference did not reach statistical significance (95% CI -2.6% - 14.2%)

13. UKW3 Trial

14.  Significant improvement in stage distribution in children receiving delayed surgery compared with immediate nephrectomy (stage I: 65.2% versus 54.3%; stage II: 23.9% versus 14.9%; stage III: 9.8% versus 29.8%, χ 2 test for trend = 7.02, P = 0.008)  Reduced the need for abdominal radiation and anthracycline in 20% of patients

15. Biopsy? Hall G, Grant R, Weitzman S, et al. Predictors of surgical outcome in Wilms' tumor: a single-institution comparative experience. J Pediatr Surg 2006; 41:966.  Considered tumor spillage with the potential for tumor cells to seed the abdomen  Upstaging to stage III  Irtan et al examined the results of the UKW3 trial with respect to risk factors for local recurrence  Univariate analysis: Biopsy increased risk of local recurrance (HR 1.91, 95% CI: 1.08–3.36, p = 0.026)  Multivariate analysis adjusting for anaplastic histology and large tumor size: Biopsy trended toward increase risk but lost statistical significance (HR 1.54, CI: 0.99– 2.43, p = 0.062)  Small sample size, biopsy group contained higher number of stage IV tumors (29.8% vs 6.6%), tumor rupture more frequent in no-biopsy group (14% vs 8%), older age in biopsy group (median 3.5 versus 2.8 years)

16. Surgical Complications Powis M, Messahel B, Hobson R, et al. Surgical complications after immediate nephrectomy versus preoperative chemotherapy in non-metastatic Wilms' tumour: findings from the 1991-2001 United Kingdom Children's Cancer Study Group UKW3 Trial. J Pediatr Surg 2013; 48:2181.  Fewer overall complications as well as fewer episodes of tumor rupture in children undergoing delayed nephrectomy

17. Summary

18. AB  Final path  Wilms tumor, favorable histology (no anaplasia)  No extracapsular or renal sinus invasion  Negative LN and soft tissue excisions  427.7 grams