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 PMID 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 PMID 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 PMID 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 PMID 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 intermediatee 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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