# Radiation Oncology/Nephroblastoma

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## Epidemiology

* 450-650 new cases per year in North America
* 75% cases < 5y, Median age is 3-4 for unilateral and 2.5y for bilateral
* ~90% are unifocal/solitary, ~12% multifocal (unilateral), ~7% are bilateral
* Black children more than white
* Females more than males
* 4th most common pediatric cancer
* Most common renal malignancy
* 90% are favorable histology
* General prognosis has improved from high mortality in early 1900s to current cure rate of >90%

## Genetics

* 1% of Wilms is considered familial.
** WT1 is a tumor suppressor gene on 11p13. Associated syndromes:
*** WAGR syndrome: Wilms (57%), Aniridia (98%), GU malformations (76%), and mental Retardation (75%).
*** Denys-Drash syndrome triad: Wilms (90%), pseudohermaphroditism, renal failure (diffuse mesangial sclerosis)
** WT2 is a tumor suppressor gene on 11p15. Associated syndromes:
*** Beckwith-Wiedemann syndrome: Wilms (5-10%), gigantism/macrosomia, macroglossia, omphalocele, pancreatic hyperplasia, GU abnormalities, hemihypertrophy
* 1p & 16q Loss of heterozygosity. increased risk for relapse and death in NWTS-5. Grundy, JCO 2005 (PMID: 16129848)

## Presentation

* Healthy appearing child with abdominal swelling (remember, Wilms = Well, Neuroblastoma = Not well).
* Smooth nontender mass
* Gross hematuria ~25% cases
* Sometimes hypertension
* Calcifications in ~5-10% (compare with ~60-70% of neuroblastoma)
* Most common site of metastases: lymph nodes, liver, lungs
* Unifocal (one kidney) in ~82%
* Multifocal (one kidney) in ~12%
** Requires observation of contralateral kidney (nephrogenic rests)
* Bilateral in ~6%

## Staging

New COG Staging System (AREN0532):
* Stage I - Tumor limited to kidney, completely resected. The renal capsule is intact. The tumor was not ruptured or biopsied prior to removal. The vessels of the renal sinus are not involved. There is no evidence of tumor at or beyond the margins of resection. NOTE: For a tumor to qualify for certain therapeutic protocols as Stage I, regional lymph nodes must be examined microscopically.
* Stage II - The tumor is completely resected and there is no evidence of tumor at or beyond the margins of resection. The tumor extends beyond kidney, as is evidenced by any one of the following criteria:
** There is regional extension of the tumor (i.e. penetration of the renal capsule, or extensive invasion of the soft tissue of the renal sinus, as discussed below)
** Blood vessels within the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus, contain tumor.
** Note: Rupture of spillage confined to the flank, including biopsy of the tumor, is no longer included in Stage II and is now included in Stage III.
* Stage III - Residual non-hematogenous tumor present following surgery, and confined to abdomen. Any one of the following may occur:
** Lymph nodes within the abdomen or pelvis are involved by tumor. (Lymph node involvement in the thorax, or other extra-abdominal sites is a criterion for Stage IV)
** The tumor has penetrated through the peritoneal surface
** Tumor implants are found on the peritoneal surface
** Gross or microscopic tumor remains post-operatively (e.g., tumor cells are found at the margin of surgical resection on microscopic examination)
** The tumor is not completely resectable because of local infiltration into vital structures
** Tumor spillage occurring either before or during surgery
** The tumor is treated with preoperative chemotherapy (with or without a biopsy regardless of type- tru-cut, open or fine needle aspiration) before removal
** Tumor is removed in greater than one piece (e.g. tumor cells are found in a separately excised adrenal gland; a tumor thrombus within the renal vein is removed separately from the nephrectomy specimen). Extension of the primary tumor within vena cava into thoracic vena cava and heart is considered Stage III, rather than Stage IV even though outside the abdomen.
* Stage IV - Hematogenous metastases (lung, liver, bone, brain, etc.), or lymph node metastases outside the abdomino-pelvic region are present. (The presence of tumor within the adrenal gland is not interpreted as metastasis and staging depends on all other staging parameters present).
* Stage V - Bilateral renal involvement by tumor is present at diagnosis. An attempt should be made to stage each side according to the above criteria on the basis of the extent of disease.
National Wilms Tumor Study 5 Staging System:
* Stage I - Tumor limited to kidney and completely excised. No penetration of the renal capsule or involvement of renal sinus vessels.
* Stage II - Tumor extends beyond the kidney but is completely excised with negative margins and lymph nodes. At least one of the following has occurred:
** (a) penetration of the renal capsule
** (b) invasion of the renal sinus vessels
** (c) spillage of tumor locally during removal
* Stage III - Gross or microscopic residual tumor remains postoperatively, including inoperable tumor, positive surgical margins, diffuse tumor spillage involving peritoneal surfaces, regional lymph node metastasis, or transected tumor thrombus. Biopsy before resection.
* Stage IV - Hematogenous metastasis (lung, liver, bone, brain) or lymph node metastasis outside the abdominal or pelvic cavities.
* Stage V - Bilateral renal tumors at diagnosis.

## Pathology

* Reflects development of normal kidney, containing 3 components: blastemal, epithelial, and stromal elements
* Prognostically divided into favorable histology (FH) and unfavorable histology (UH)
* Favorable histology is present in ~90%
* Unfavorable histology includes anaplasia, and two further varieties no longer considered WT: Clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RTK)
* Anaplasia (~5%) may be focal (FA) or diffuse (DA), and reflects distribution of anaplastic cells within the tumor
* CCSK (~4%) tends to metastasize to bone and brain (need to do bone scan and brain MRI)
* RTK (~1%) is the most aggressive; it may have CNS PNET associated with it

## Treatment Overview

* National Wilms Tumor Study (NWTS) consortium was established in 1969 to more rigorously evaluate treatment strategies, given the rarity of the condition. The International Society of Pediatric Oncology (SIOP) began running trials in parallel in Europe in 1991
* The treatment strategies diverged, after the first SIOP trial, SIOP-1 showed benefit for neoadjuvant RT over adjuvant RT. SIOP has since then been using neoadjuvant therapy, followed by surgery and adjuvant therapy. In the US, NWTS continues to perform surgery first, and optimize adjuvant therapy.
* NWTS 1 showed that adjuvant RT is not necessary for young patients (<2 years) in Group I (tumor limited to kidney and completely resected) if they are treated with Actinomycin D x15 months. RT dose for the rest was age-adjusted, topping out at 40 Gy
* NWTS 2 showed that adjuvant RT is not necessary even in older patients (>2 years) in Group I, as long as they get Actinomycin D and vincristine. For the rest, same age-adjusted doses were used as NWTS 1
* By this time, NWTS determined that different histologies have different prognosis. Favorable Histology (FH) included tumors with no anaplasia; Unfavorable Histology (UF) included tumors with anaplasia, as well as clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RTK). CCKS and RTK were excluded from NWTS 3 onward.
* NWTS 3 showed that RT can also be eliminated from Stage II, and that dose can be reduced from as much as 40 Gy to 10 Gy in Stage III. Dose-adjusted RT was no longer necessary
** Stage III 10Gy with 3-drug chemo (added adriamycin), or 20Gy with two drugs
* Post-hoc analysis from NWTS 1-3 showed that delay in RT >10 days after surgery was associated with worse outcomes
* NWTS 4 didn't ask any RT questions; it attempted to optimize chemo delivery
** Also failed to verufy need to begin RT within 10 days
* NWTS 5 showed that loss of heterozygosity on chromosome 1p and 16q was associated with significantly worse DFS and OS
* Meanwhile, in Europe SIOP-5 showed that neoadjuvant chemo doublet is comparable to neoadjuvant RT with Actinomycin D; neoadjuvant chemo become the standard
* SIOP-6 began a risk-adapted strategy. No RT was used for Stage I patients
* SIOP-9 revealed that a short course of neoadjuvant chemotherapy is comparable to a long course; adjuvant RT was 15 Gy
* Finally, SIOP 93-01 demonstrated that in intermediate risk patients, short adjuvant chemo is comparable to long adjuvant chemo.
* The British were historically following the NWTS protocols, but in 1991 decided to compare the NWTS and the SIOP approach directly. A randomized trial showed that neoadjuvant chemotherapy downstaged significant number of patients, and allowed 20% children to avoid potentially toxic RT or doxorubicin, with same EFS and OS
* Editorial in JCO 2008 (PMID 18757319) provides a nice perspective on the two differing approaches (pre-op vs post-op therapy)
* In the US, Childrens Oncology Group (COG) is now managing clinical trials for Wilms
** Surgery is the primary approach
** Chemotherapy plays a critical role
* US RT Guidelines
** RT not necessary for Stage I
** RT not necessary for Stage II, if adequate chemotherapy (vincristine/dactinomycin) given
** Risk adapted dose as below; please see COG protocol for risk definitions
** RT start by day 9, FH at latest by day 14
** Care must be given to irradiate vertebral column uniformly to limit scoliosis
** Historically, pulmonary mets seen on CXR were treated with whole-lung RT 12 Gy; whether presumed mets seen on CT should be treated is controversial, since only 69% of multiple pulmonary lesions were tumor on bipsy
| Risk Group | RT |
| Low Risk | No RT |
| Intermediate Risk | Flank 10.8 Gy |
| High Risk | Flank 19.8 Gy |
| Unresected LNs | 19.8 Gy |
| Lung | 12 Gy |
| Brain | 25.2 Gy + 10 Gy boost |
| Bone | 25.2 Gy |

## Specific Situations
### NWTS Flank recurrence

* NWTS Flank recurrence; 2006 PMID 16542795 -- "Radiation therapy for favorable histology Wilms tumor: prevention of flank recurrence did not improve survival on National Wilms Tumor Studies 3 and 4." (Breslow NE, Int J Radiat Oncol Biol Phys. 2006 May 1;65(1):203-9.)
** NWTS Subset analysis. Stage I-IV FH, enrolled on NWTS-3 and NWTS-4.
** Recurrence: In flank 20 Gy 0%, 10 Gy 1.5%, no RT 1.8 % (SS); intra-abdominal 1.0%, 3.7%, 2.4% (SS). Composite flank NWTS-3 risk 1.0% increased to NWTS-4 (no 20 Gy RT) 2.1%, but EFS was unchanged 86% vs. 88% (NS), and OS was better 91% vs. 94% (SS)
** Conclusion: Due to lower post-recurrence mortality with more intense chemo, prevention of flank recurrence by RT did not improve survival
* Tumor spillage; 2010 (1979-1994) PMID 19395185 -- "Intraoperative spillage of favorable histology wilms tumor cells: influence of irradiation and chemotherapy regimens on abdominal recurrence. A report from the National Wilms Tumor Study Group." (Kalapurakal JA, Int J Radiat Oncol Biol Phys. 2010 Jan 1;76(1):201-6.)
** NWTS subset analysis. 450 patients, surgical tumor spillage (20% of total). Stage II-IV FH, enrolled on NWTS-3 and NWTS-4. Influence of tumor dose evaluated: NWTS-3 Stage II no RT vs RT 20 Gy to flank (1cm margin on involved kidney, cross midline), Stage III RT 10 Gy vs RT 20 Gy, Stage IV RT 20 Gy to tumor bed. NWTS-4 Stage II no RT, Stage III-IV RT 10 Gy or whole abdomen 10 Gy. If diffuse tumor spillage, WART 10 Gy or 20 Gy on NWTS-3 and 10 Gy on NWTS-4. Considered two types of failure, at flank and beyond-flank
** Outcome: Recurrent disease in abdomen in 7% overall; flank in 61%. Flank relapse no RT 12% vs RT 10 Gy 3% vs RT 20 Gy 0% (SS). Beyond-flank relapse 6% vs 3% vs 3%. Stage II unirradiated patients treated with 2-drug regimen 8-year RFS spillage- 87% vs spillage+ 79% (NS), 8-year OS 95% vs 90% (SS).
** Conclusion: RT reduced abdominal tumor recurrence after tumor spillage

### Anaplastic Histology

* NWTS Subset; 2006 PMID 16710034 -- "Treatment of anaplastic histology Wilms' tumor: results from the fifth National Wilms' Tumor Study." (Dome JS, J Clin Oncol. 2006 May 20;24(15):2352-8.)
** Subset analysis, 281 patients with anaplastic histology (11%). Stage I treatement AMD + VCR x4.5 months. Stage II-IV RT + VCR + doxorubicin + cyclophosphamide + etoposide x6 months
** 4-year Outcome: OS Stage I 83%, Stage II 83%, Stage III 65%, Stage IV 33%, bilateral 44%; compared with Stage I favorable histology 98%
** Conclusion: Novel strategies needed to improve outcomes for patients with AH

### Bilateral Wilms' Tumor

* NWTS experience (1974-86) - PMID 1650403, 1991 — "Extended followup of bilateral Wilms tumor: results of the National Wilms Tumor Study." Montgomery BT et al. J Urol. 1991 Aug;146(2 ( Pt 2)):514-8.
** 185 pts from NWTS 2 and NWTS 3 who were registered but not eligible for randomization.
** Overall outcome is good, with 90% survival at 5 and 10 yrs. Worse outcome with surgical substage III or IV disease and unfavorable histology. No difference in survival for initial tumor resection vs initial biopsy.

### Adults

* SIOP 93-01 Subset PMID 15542800 -- "Wilms' tumor in adults: results of the Society of Pediatric Oncology (SIOP) 93-01/Society for Pediatric Oncology and Hematology (GPOH) Study." (Reinhard H, J Clin Oncol. 2004 Nov 15;22(22):4500-6.)
** Subset analysis. 30 patients >16 years treated according to pediatric protocol. Predominance of higher stages, 33% Stage IV. 2/30 showed nephroblastoma and renal cell carcinoma in the same kidney. Mean F/U 4 years
** Outcome: 4-year EFS 57%, OS 83%
** Conclusion: Adults can be cured in high percentage by pediatric protocols. Toxicity higher but acceptable

## NWTS Trials

* NWTS 5 (1995-2002) - Prospective risk-adapted therapy
** Prospective non-randomized study. 2387 patients. Risk-adapted treatment attempting to reduce toxicity for low risk patients, and intensify treatment for high risk patients. Evaluation of loss of heterozygosity on chromosomes 1p and 16q. RT depending on risk: none, 10.8 Gy to flank, and possibly 10.8 Gy boost to residual disease, 12 Gy to whole lung
** 2005 PMID 16129848 -- "Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: a report from the National Wilms Tumor Study Group." (Grundy PE, J Clin Oncol. 2005 Oct 10;23(29):7312-21.)
*** 2021 children assayed for loss of heterozygosity (LOH) on chromosomes 1p and 16q
*** Outcome: Risk for relapse 1p 1.56 (SS), 16q 1.49 (SS); risk of death 1p 1.84 (SS), 16q 1.44 (NS). For Stage I-II, worse outcome for either 1p or 16q; for Stage III-IV, worse outcome only if LOH of both regions
*** Conclusion: LOH for 1p and/or 16q identifies subset of favorable histology who have significantly increased risk of relapse and death
* 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)
** 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)
** 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 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-2 (1974-1976)
** Prospective nonrandomized. 52 patients with small tumors had primary surgery, 86 patients had pre-op RT. Results described in PMID 6321673
** Outcome: tumor rupture pre-op RT 5% vs. surgery first 20% (SS)
** Conclusion: confirmed results of SIOP 1
* 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

* 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