Background
Phase III RCT (UK Children's Cancer Study Group Wilms Tumor Study 3, UKW-3). 439 children with Wilms tumor enrolled in the United Kingdom. Compared pre-operative chemotherapy (vincristine + dactinomycin) vs immediate surgery (North American COG approach) for localized Wilms tumor. Evaluated rates of tumor rupture, stage distribution post-preoperative therapy, and ultimate outcomes.
Interventions and follow up
Arm A: Pre-operative chemotherapy: vincristine + dactinomycin × 4 weeks → nephrectomy → post-operative chemotherapy ± RT
Arm B: Immediate surgery → post-operative chemotherapy ± RT per NWTS staging criteria
Primary endpoint: EFS, OS
mFollow up: 5.0 year
Arm B: Immediate surgery → post-operative chemotherapy ± RT per NWTS staging criteria
Primary endpoint: EFS, OS
mFollow up: 5.0 year
Results
Tumor rupture rate (pre-op chemo): 2.5% vs immediate surgery 8.5%, P=.01
5-yr OS: Pre-op 90% vs immediate surgery 87% (P=NS)
Stage III rate: Significantly lower in pre-op arm (less intraoperative spillage)
Consequence: Less whole abdomen RT required in pre-op arm
5-yr OS: Pre-op 90% vs immediate surgery 87% (P=NS)
Stage III rate: Significantly lower in pre-op arm (less intraoperative spillage)
Consequence: Less whole abdomen RT required in pre-op arm
Adverse events
Main adverse events: Pre-op chemotherapy: pre-operative myelosuppression mild. Immediate surgery group: higher rupture rate requiring whole abdominal RT — increased late effects (scoliosis, bowel obstruction, ovarian dysfunction). Chemotherapy late effects similar in both arms.
Conclusions
Pre-operative chemotherapy significantly reduces intraoperative tumor rupture and downstages tumors, resulting in less whole-abdominal RT with equivalent long-term survival. This supported the SIOP European approach of routine preoperative chemotherapy vs the North American COG upfront surgery approach.
Key Limitations
Key Limitations: Upfront biopsy required in preoperative arm — misdiagnosis (non-Wilms) occurred in ~1%. No randomization of post-operative RT based on pathologic response to pre-op chemo (which is now recognized as important). Blastemal predominance in residual tumor post-pre-op chemo is associated with inferior prognosis.
Clinical Context
UKW-3 supports the SIOP European approach of preoperative chemotherapy for Wilms tumor, which reduces tumor rupture and whole-abdominal RT. COG continues upfront surgery approach. Current SIOP 2016 protocol uses blastemal predominance in post-preoperative nephrectomy specimen to risk-stratify chemotherapy intensity.
References
References: Pritchard J et al, Eur J Cancer 1995 (UKW-3)