Radiation Oncology/Nephroblastoma/Randomized

Nephroblastoma (Wilms Tumor) Randomized Evidence NWTS Trials NWTS 4 (1986-94) -- no RT randomizations; chemo randomizations Randomized. 1638 patients. Compared standard schedule (STD) of AMD + ADR vs pulse-intensive (PI), and short (5-6 months) vs long courses (15-16 months) Stage I, FH or anaplastic: AMD + VCR, STD vs PI Stage II, FH: 2x2 design: AMD + VCR, STD vs. PI, and short vs long High risk (FH Stage III-IV or CCSK): 2x2 design: AMD + VCR + ADR STD vs PI, and short vs long 2-years 1998 9440748 — "Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms' tumor: a report from the National Wilms' Tumor Study Group." (Green DM et al. J Clin Oncol. 1998 Jan;16(1):237-45.) Fractionation outcome: RFS for STD 91% vs. PI 91% (NS) Conclusion: Pulse-intense chemothereapy equivalent to standard fractionated chemotherapy, less toxic, and logistically much easier NWTS 3 (1979-1985) -- High dose RT vs. low dose RT; low dose RT vs. no RT Randomized. 1439 patients. Treatment adapted by Stage and histology; FH in 90%, anaplastic 4%, CCSK 4%, RTK 2%. 2x2 design for Stage II and III. RT given in 1.8 Gy/fx, large fields 1.5 Gy/fx. Evaluated RT dose and chemo intensity Stage I, FH: No RT. AMD + VCR x 10 weeks vs 6 months. Stage II, FH: No RT vs 20 Gy. AMD+VCR+ADR vs intensive AMD+VCR, both for 15 months. Stage III, FH: RT 10 Gy vs 20 Gy. AMD+VCR+ADR vs intensive AMD+VCR, both for 15 months. Stage IV and All UH: RT per NWTS 2 followed by AMD+VCR+ADR vs AMD+VCR+ADR+ cyclophosphamide, both for 15 months. 4-years: 1989 2544249 — "Treatment of Wilms' tumor. Results of the Third National Wilms' Tumor Study." (D'Angio GJ et al. Cancer. 1989 Jul 15;64(2):349-60.) Stage I FH Outcome: RFS 10 weeks 89% vs. 6 months 91% (NS) Stage II FH Outcome: No difference between no RT and RT 20 Gy. Also no difference between chemo regimens Stage III, FH Outcome: No difference between RT 10 Gy and RT 20 Gy. Also no difference between chemo regimens Stage IV and UH Outcome: Cyclophosphamide didn't improve outcomes RT Conclusion: Stage II FH doesn't require RT; Stage III FH RT 10 Gy sufficient with doublet chemotherapy NWTS 2 (1974-78) -- chemo randomizations Randomized. 513 patients. Surgery first. RT within 10 days of surgery, same dose schedule as NWTS 1. If pulmonary mets, 12 Gy whole thorax (had toxicity at 14 Gy); if liver/brain mets 30 Gy Group I (35%): Actinomycin D + vincristine x6 months, then Arm 1) observation vs. Arm 2) additional 9 months of chemo. No RT for anyone, assume addition of VCR in age >2 will obviate need for adjuvant RT, and compare to historical outcomes Group II-IV: RT everyone, then Arm 1) Actinomycin D + vincristine vs. Arm 2) Actinomycin + vincristine + doxorubicin. Total 15 months both arms 2-years; 1981 6164480 — "The treatment of Wilms' tumor: results of the Second National Wilms' Tumor Study." D'Angio GJ et al. Cancer. 1981 May 1;47(9):2302-11. Group I Outcome: No difference in RFS or OS between arms. Age >2 2-year OS comparison: NWTS2 (AMD+VCR, no RT) 89% vs. NWTS1 (AMD+RT) 77% vs. NWTS1 (AMD, no RT) 51%. Abdominal relapse <5% Group II-IV Outcome: DFS AMD + VCR 62% vs. AMD + VCR + doxorubicin 77% (SS) RT Conclusion: RT not necessary in Group I with chemo doublet NWTS 1 (1969-74) -- Group I Adjuvant RT vs. adjuvant chemo Randomized. 259 patients. Surgery first. RT given within 2 days of surgery. Dose 0-18 months 18-24 Gy, 18-30 months 24-30 Gy, 30-40 months 30-35 Gy, >40 months 35-40 Gy. Fields: Group I/II flank, Group III whole abdomen Group I (n=163): Arm 1) RT + Actinomycin D vs. Arm 2) Actinomycin D only Group II/III (n=100): Surgery + RT and Arm 1) Actinomycin D vs. Arm 2) Vincristine vs. Arm 3) Actinomycin D + Vincristine Group IV (n=26): Arm 1) Surgery + RT + adjuvant chemo vs. Arm 2) Neoadjuvant vincristine + surgery + RT + adjuvant chemo 2-years; 1976 184912, 1976 — "The treatment of Wilms' tumor: Results of the national Wilms' tumor study." D'Angio GJ et al. Cancer. 1976 Aug;38(2):633-46. Group I Outcome: Age <2 years: RT 90% vs. no RT 88% (NS); age >2 years RT 77% vs. 58% (SS). More infradiaphragmatic failures without RT, leading to worse survival Group II/III Outcome: Actinomycin D 57% vs. Vincristine 55% vs. Combination 81% (SS) RT Conclusion: Adjuvant RT not necessary for Group I patients <2 years treating with Actinomycin D, but important for patients >2 years. SIOP Trials SIOP 93-01 (1993-2000) -- short vs. long adjuvant chemo Randomized. 847 patients, excluding Stage IV and bilateral. Preop chemo, followed by surgery, followed by risk-adapted therapy. In Stage I intermediate risk/anaplasia, randomized to adjuvant chemo 3 courses vs. 1 course. Benign tumors treated 1.3%, surgical Stage I 61%, Stage II LN0 24%, Stage II LN+ 5%, Stage III 7%. Histology low risk 3%, intermediate risk 90%, high risk 7% 2004 15175957 -- "Results of the SIOP 93-01/GPOH trial and study for the treatment of patients with unilateral nonmetastatic Wilms Tumor." (Reinihard H, Klin Padiatr. 2004 May-Jun;216(3):132-40.) Outcome: short adjuvant chemo 90% vs. long adjuvant chemo 91% (NS) Conclusion: Post-op chemo in Stage I intermediate risk (44% patients) can be reduced to 4 weeks SIOP-9 (1987-1993) -- Short vs. long neoadjuvant chemo Randomized. 382 patients. Arm 1) 4 weeks of Actinomycing D + vincristine vs. Arm 2) 8 weeks of same chemo. Then surgery and risk-stratified therapy: Stage I FH observation, Stage I SH/anaplasia VCR+AMD x4 months; Stage II-III FH/SH VCR + AMD + anthracycline x6 months. Stage II-III Anaplastic/CCSK AMD + VCR + anthracycline + ifosfamide 9 months. RT given: Stage II LN0 no RT, Stage II LN+/Stage III 15 Gy 2001 11208843 -- "Optimal duration of preoperative therapy in unilateral and nonmetastatic Wilms' tumor in children older than 6 months: results of the Ninth International Society of Pediatric Oncology Wilms' Tumor Trial and Study." (Tournade MF, J Clin Oncol. 2001 Jan 15;19(2):488-500.) Outcome: No benefit for longer pre-op course Abdominal recurrence: Stage II LN0 (no RT): 7% Conclusion: 4-week neoadjuvant chemo should be standard SIOP-6 (1980-1987) -- Risk adapted randomization Randomized. 509 patients. Risk adaptive therapy. Neoadjuvant chemo (AMD+VCR), surgery, then assigned based on stage, LN involvement. Stage I: 4 months (short) vs. 9 months (long) adjuvant chemo Stage II LN0: adjuvant RT 20 Gy vs. no RT (Stopped prematurely due to high failures in no RT arm Stage II LN+/Stage III: intensified VCR + AMD vs. VCR + AMD + doxorubicin. RT 30 Gy + 5 Gy boost dose to residual disease 5-years; 1993 8388918 -- "Results of the Sixth International Society of Pediatric Oncology Wilms' Tumor Trial and Study: a risk-adapted therapeutic approach in Wilms' tumor." (Tournade MF, J Clin Oncol. 1993 Jun;11(6):1014-23.) Outcome: 2-year DFS and 5-year OS Stage I: DFS short 92% vs. long 88% (NS); OS 95% vs. 92% (NS) Stage II LN0: DFS RT+ 72% vs. RT- 78%; OS 88% vs. 855 (NS) - (trial stopped early in favor of RT+, due to first year 6 consecutive failures in RT- arm vs none in RT+ arm) Stage II LN+/III: DFS VCR+AMD 49% vs. VCR+AMD+doxorubicin 74% (SS); OS 77% vs. 80% (NS) Conclusion: Risk-adapted therapy possible. Continued RT or more chemo necessary for LN+ SIOP-5 (1977-1979) -- neoadjuvant chemo vs. chemo-RT Randomized. 164 patients. Arm 1) Preop RT 20 Gy + concurrent Actinomycin D then surgery then post-op RT 15 Gy vs. Arm 2) Pre-op Actinomycin D + vincristine then surgery then post-op RT 30 Gy. Both arms maintenance Actinomycin D + vincristine. Primary criterion was effectiveness of pre-op therapy on surgical outcome 4-years; 1983 6321673 -- "Effectiveness of preoperative chemotherapy in Wilms' tumor: results of an International Society of Paediatric Oncology (SIOP) clinical trial." (Lemerle J, J Clin Oncol. 1983 Oct;1(10):604-9.) Outcome: No difference in tumor size or intra-op tumor rupture; chemo resulted in less necrosis and tumor histology distortion. 4-year RFS chemo 76% vs. chemo-RT 69% (NS), OS chemo 89 vs. chemo-RT 83% (NS). No difference in failure patterns Downstaging: 43% of patients were Stage yI at surgery, and thus may not need post-op RT Conclusion: Neoadjuvant chemo alone comparable to neoadjuvant chemo-RT SIOP-1 (1971-1974) -- Pre-op vs. Post-op RT Randomized. 195 patients. 2x2 design. Arm 1) Pre-op RT 20 Gy + surgery + post-op RT (Stage I none, Stage II-III 15 Gy) vs. Arm 2) post-op RT (Stage I 20 Gy, Stage II-III 30 Gy). Post-op RT arm ended prematurely due to worse outcome. Actinomycin D single course vs. 15 months 1976 184913 -- "Preoperative versus postoperative radiotherapy, single versus multiple courses of actinomycin D, in the treatment of Wilms' tumor. Preliminary results of a controlled clinical trial conducted by the International Society of Paediatric Oncology (S.I.O.P.)." (Lemerle J, Cancer. 1976 Aug;38(2):647-54.) RT outcome: Tumor rupture during surgery pre-op RT 4% vs. post-op RT 31% (SS). No difference in RFS or OS. Post-op arm stopped, because massive tumor rupture in 11 patients during surgery necessitated upstaging and whole-abdomen RT Chemo outcome: No difference between single course and multiple courses Conclusion: Pre-op RT superior, as it leads to less tumor rupture during surgery UK CCSG Trials UKW3 (1991-2001) Randomized. 205 patients with renal tumors. Arm 1) immediate surgery vs. Arm 2) biopsy, then 6 weeks preoperative chemotherapy (AMD+VCR) followed by surgery. Both groups received risk-adjusted post-op therapy. Post-op RT FH 20 Gy, UH 30 Gy. Wilms confirmed in 91%, CCSK 4%. 2006 16904312 -- "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." (Mitchell C, Eur J Cancer. 2006 Oct;42(15):2554-62.) Stage distribution: surgery vs. chemo Stage I 65% vs. 54%, Stage II 24% vs. 15%, Stage III 10% vs. 30%, (SS). This resulted in 20% fewer children receiving RT or doxorubicin Outcome: 5-year EFS both groups 80% (NS), OS both groups 89% (NS) Conclusion: Neoajduvant chemotherapy shifts patients to better stage, and hence reduction in adjuvant therapy