Pediatric: Wilms Tumor > Evidence Based Questions > Flashcards
Evidence Based Questions Flashcards
What did the early NWTS-1 and NWTS-2 studies show?
- Vincristine and actinomycin D (VA) are better together than either alone.
- RT is not needed for stage I FH pts if they rcv chemo, but when RT given, it should preferably start within 9 days of Sg (but no later than postop day 14).
- There was no RT dose response from 10–40 Gy.
Which study demonstrated that whole abdomen irradiation (WAI) is not needed for local spillage?
NWTS-1; flank fields suffice if spillage is local.
Which study demonstrated that adding Adr to VA benefited group 2–4 pts?
NWTS-2; adding Adr benefited group 2–4 FH, especially group 2–4 UH pts (OS 38% vs. 78%).
Which study demonstrated that 10 wks was equal to 6 mos of chemo for stage I pts?
NWTS-3; 4-yr OS was 96%–97%.
Which study showed that stage II FH pts do not need RT as long as VA is given?
NWTS-3 (4-arm: vincristine/Actinomycin D/Adr [VAAdr] vs. VA vs. +/– RT → 4-yr OS ∼90%–95%, no difference)
Which study eliminated Adr from stage II FH?
NWTS-3. VA alone was sufficient.
Which study demonstrated that 10 Gy was equal to 20 Gy if Adr was added to stage III pts?
NWTS-3 demonstrated the noninferiority of lower RT doses with Adr.
Which study addressed the addition of Cytoxan to VAAdr for high-risk pts?
NWTS-3. Cytoxan improved outcome in UH stage II–IV but not FH stage IV.
Which study addressed pulse-intense (PI) chemo?
NWTS-4. 6 mos of PI was equal to 15 mos of conventional chemo.
What are the main advantages of PI chemo?
With PI chemo, there is ↓ hematologic toxicity and ↓ total cost b/c fewer drugs are used.
Which study found that local spillage (old stage II) without RT results in a ↑ LR?
NWTS-4; ↑ LR, but no difference in OS; so, moved to stage III for FH (need adj RT)
What question does NWTS-5 address? (Dome JS et al., JCO 2006)
Nonrandomized, assesses prognostic importance of LOH 1p16q
For which pts did NWTS-5 show ↑ (13.5%) rates of relapse with nephrectomy alone and without adj chemo?
Stage I FH, pts <2 yo, and tumors <550 g. Most (>70%) were salvaged successfully, however.
What chemo regimen in NWTS-5 improved outcomes for stages II–IV with DA?
Vincristine/Adr/cyclophosphamide/etoposide
Did stage I anaplastic tumors qualify for RT in NWTS-5?
No. Anaplastic tumors did not qualify for RT in NWTS-5.
What do the current protocols (COG AREN0532, 0533) address?
Tx intensification based on LOH 1p16q status; stage I anaplastic pts get RT + Adr (with VA).
What were the factors that determine risk groups in the COG AREN0532/0533?
Age (>2 yo worse), tumor weight (550 g), stage, LOH 1p16q, and chemo response
What subset of pts on the current COG protocol could get Sg alone without adj Tx?
Very low risk group (stage I FH, pts <2 yo, and tumors <550 g) and if there is central pathology review and LN sampling
What are the RT doses to the postop bed for Wilms pts ≥16 yo and/or those with rhabdoid and/or DA? How about for other pts?
19.8 Gy to flank for stage III DA or rhabdoid stages I–III (+10.8 Gy boost to mets/gross Dz = 30.6 Gy), 10.8 Gy for the rest (stage III FH, stages I–III FA, stages I–II DA, stages I–III clear cell, age <16 yrs, infants with DA or rhabdoid histology)
What are the indications and the RT doses for WAI?
Seeding/rupture/diffuse spill; 10.5 Gy (1.5 Gy/fx), boost to 21 if bulky (but 19.8 Gy for DA or rhabdoid)
What are the indications for flank RT?
Stage III FH, localized spill, stages I–III UH, and recurrent Wilms (also done for certain stage IV pts)
What is the standard flank RT dose?
The standard flank RT dose is 10.8 Gy in 6 fx.
What is the dose to unresected +LNs?
19.8 Gy to entire chain → boost with optional 5.4–10.8 Gy; 30.6 Gy if >16 yo
What is the preferred Tx for localized liver mets? Diffuse liver mets?
Sg is preferred for localized liver mets. For diffuse liver mets, 19.8 Gy to the entire liver (with optional boost of 5.4–10.8 Gy) is an option.
What dose is given to resected +LNs?
Resected +LNs get a dose of 10.8 Gy.
At what age can pts rcv greater flank doses and greater doses to mets?
≥16 yo (19.8 Gy to flank or WAI and 30.6 Gy to mets in bone, LNs, and brain)
When is whole lung irradiation (WLI) not required in a Wilms pt with lung mets?
WLI is not required in these pts if mets are seen only on CT and not on CXR or if a CR is seen after VAAdr at wk 6.
When is WLI indicated? What are the doses?
WLI is indicated when there is no CR seen on CT at wk 6 after 3-drug chemo (per current protocol); it is not based on # of mets, size, or detectability on CT or CXR. The dose for WLI is 12 Gy (>1 yo) or 10.5 Gy (<1 yo) in 1.5 Gy/fx. If there is persistent Dz after WLI, consider a 7.5 Gy boost.
What med should pts take when treated with WLI?
Trimethoprim/sulfamethoxazole (Bactrim) for PCP prophylaxis
How is bilat Wilms treated?
Initial Sg or Bx to stage each side → chemo → 2nd-look Sg at 6 wks for a max safe resection (spare two-thirds of 1 kidney if possible) → continuation of chemo. RT is given after Sg based on the final local stage.
RT should preferably start by which day and should begin no later than which day after Sg?
RT should preferably start by day 9 and should begin no later than day 14. Secondary analyses of NWTS-1and NWTS-2 showed worse outcomes when RT was delayed >10 days.
How long is the chemo regimen for stages I–II and III–IV FH?
18 wks (VA); 24 wks (VAAdr)
What is the medial border of a flank field?
1 cm from the contralat vertebral body edge. Be aware of the intact kidney location.
What are the preferred RT margins/techniques for a flank field?
Preop GTV + 1 cm; AP/PA for flank; conformal for boost (residual + 2 cm)
What is the dose for brain mets?
The dose for brain mets is WBRT to 21.6 Gy if <16 yo (+ 10.8 Gy boost = 32.4 Gy) or 30.6 Gy (–boost) if >16 yo.
What is the dose for bone mets?
The dose for bone mets is 25.2 Gy (30.6 Gy if > 16 yo).
How do you manage a pt who presents with mets and a resectable tumor?
These pts are treated the same way as nonmetastatic pts, except mets are treated at the same time as abdominal RT, if needed.
What is the outcome for relapsed Wilms treated with VA only for stage I or II Dz?
4-yr EFS/OS: 71% (stage I) vs. 82% (stage II). Pt salvaged with Sg, RT, and chemo with vincristine/Adr/Cytoxan/etoposide. Lung mets only, 4-yr EFS/OS: 68% (stage I) vs. 81% (stage II).
What about relapsed stages III–IV Dz?
Relapse after stages III–IV Tx is worse (4-yr EFS/OS: 42% vs. 48%, respectively), lung only mets: 4-yr EFS/OS: 49% vs. 53%, respectively. (Green DM et al., Ped Blood Cancer 2007; Malogolowkin M et al., Ped Blood Cancer 2008)
What are the main findings of the National Wilms Tumor Studies (NWTS) I-V?
NWTS-1 (1969–1974): D’Angio (Cancer 1976 PMID 184912)
Postop RT is not needed for group I <2 y/o, but did improve DFS for pts ≥2 y/o (p = .002).
VCR + AMD are better than either agent alone in groups II and III.
For group III w/ local spillage or pre-op biopsy, no need for WAI.
Pre-op VCR does not help stage IV.
Age ≥2 y/o, the presence of anaplastic or sarcomatous features and LN involvement were found to be poor prognostic factors.
NWTS-2 (1974–1979): D’Angio (Cancer 1981 PMID 6164480)
Excellent survival rates for group I pts receiving VA CHT; thus RT is not needed for stage I FH patients.
Six months of VA is equal to 15 months for stage I.
ADR in addition to VCR and AMD helped for groups II-IV.
No dose response from 18 to 40 Gy for flank RT.
Total lung RT dose should be 12 Gy, due to 10% risk of “pneumonopathy” w/ 14 Gy.
Unfavorable histology, small RT field size, and RT delay of ≥10 days are poor prognostic factors for LR.
NWTS-3 (1979–1985): D’Angio (Cancer 1989 PMID 2544249)
(Note: Changed from grouping system to staging system; however, until after NWTS-4, local spillage was considered stage II rather than III)
Distinction between FH and UH was incorporated into treatment algorithm.
For stage I FH, 10 weeks of AMD + VCR is equal to 6 mos, OS 96%.
For stage II FH, there was no benefit to the addition of ADR (VA alone sufficient) or RT.
For stage III FH, 10 Gy is equal to 20 Gy if ADR is added.
Cyclophosphamide improves outcomes in UH (focal anaplasia) stages II–IV but not FH stage IV.
NWTS-4 (1986–1994): Green (JCO 1998 PMID 9440748; Green JCO 1998 PMID 9850017).
For stage I FH or anaplastic pts, pulse-intense (PI) VCR + AMD x 18 weeks is equivalent to standard VCR + AMD x 25 weeks.
For stage II FH, PI VCR + AMD for 6 months is as effective, less costly, and less toxic (hematologic) than standard VCR + AMD for 15 months.
For stages III-IV FH, PI VCR + AMD + ADR for 6 months is as effective, less costly, and less toxic than standard VCR + AMD + ADR for 15 months.
Seibel (JCO 2004 PMID 14752069): Long-term update shows long-course CHT associated with better RFS in CCSK, but OS no different.
Local spillage without RT has unacceptable LR risk; moved to stage III for FH (need adjuvant RT).
NWTS-5 (1995–2001):
Shamberger (Ann Surg 2010 PMID 20142733): Stage I FH, pts <2 y/o, and tumors <550 g had an increased rate of relapse with nephrectomy alone (without adjuvant CHT) but no difference in OS with or without CHT.
Dome (JCO 2006 PMID 16710034): Vincristine/Adriamycin/cyclophosphamide/etoposide improved outcomes for stages II-IV with DA.
Grundy (JCO 2005 PMID 16129848): For stages I-II FH pts, risk of relapse and death were increased with LOH at 1p, 16q, or both. For stages III-IV FH, risk of relapse and death were increased only with LOH for both 1p and 16q (RR = 2.4, p = .01 and RR = 2.7, p = .04
What is the impact of RT in the setting of tumor spillage?
Helps with decreasing abdominal tumor recurrence rates.
Kalapurakal, NWTS 4 & 5 Pooled (IJROBP 2010 PMID 19395185): Analyzed influence of irradiation (Flank and WAI) and CHT regimens on abdominal recurrence after intraoperative spillage of FH Wilms on NWTS-4 and 5. OR for recurrence after RT versus no RT was 0.35 (0.15–0.78) for 10 Gy and 0.08 (0.01–0.58) for 20 Gy. OR for CHT after adjusting for RT was not significant. For stage II pts (NWTS-4), 8-yr RFS with and without spillage, respectively, was 79% versus 87% (p = .07) and OS was 90% versus 95% (p = .04). Conclusion: RT (10 Gy or 20 Gy) reduced abdominal tumor recurrence rates after tumor spillage. Tumor spillage in Stage II patients associated with decreased RFS and significantly decreased OS.
What is the role of WLI in patients with FH Wilms who have pulmonary metastases detected by CT only? What is the role of Adriamycin in this setting?
No OS benefit with ADR, no benefit with WLI.
Grundy, NWTS 4 & 5 Pooled (Pediatr Blood Cancer 2012, PMID 22422736): 417 pts with FH WT and isolated lung metastases on NWTS-4 and -5. Compared outcomes by method of detection (CXR vs. CT only), use of WLI, and two- or three-drug CHT (AMD and VCR +/− ADR). For pts with CT-only lung mets (negative CXR), 5-yr EFS was greater with three drugs (including Adriamycin) with or without WLI versus only two drugs (80% vs. 56%; p = .004); OS was not impacted (87% vs. 86%; p = .91). For pts with CT-only lung mets, WLI showed a trend for benefit with regard to 5-yr EFS (81.0% vs. 70.1%; p = .11), but this disappeared when the analysis was adjusted for the CHT regimen (p = .52).
58: WILMS TUMOR
Yvonne D. Pham, John H. Suh, and Erin S. Murphy
QUICK HIT: Wilms tumor (WT) is the most common abdominal tumor in children. WT is managed with initial resection followed by risk-adapted CHT +/− RT. CHT is variable and usually consists of vincristine, actinomycin-D, and Adriamycin (with carboplatin/etoposide/cyclophosphamide added on protocol for higher risk patients). If indicated, deliver RT by postoperative day 10 (i.e., start by day 10, no later than day 14 with surgery day 0). RT is delivered based on pathologic findings as listed in Table 58.1. For stage IV, RT can be directed to the abdomen and whole lung separately, based on indications.
TABLE 58.1: General Strategy of Postoperative RT for Wilms Tumor
Indication
Target
Dose
Stage III, Favorable Histology
Stage IV, Favorable Histology with Hilar Lymph Nodes
Stage I-IV, Unfavorable Histology
Recurrent Disease
Residual Flank Disease
Flank
10.8 Gy/6 fx
(+9 Gy/5 fx boost for diffuse anaplasia)
Surgical Spillage
Peritoneal Seeding
Malignant Ascites
Preoperative Rupture
Whole Abdomen
10.5 Gy/7 fx
(+9 Gy/6 fx flank boost for diffuse anaplasia age>12 months or +10.5 Gy/7 fx boost for diffuse unresectable implants)
Lung Metastases on Chest X-ray
Whole Lung Irradiation
12 Gy/8 fx
(10.5 Gy/7 fx if age <1)
EPIDEMIOLOGY: WT accounts for 6% of childhood cancers with about 470 to 500 new cases per year in the United States. It is the most common abdominal tumor in children with a median age at diagnosis between 3 and 4 years of age for unilateral tumors. Bilateral cases occur in 4% to 8% at presentation and tend to present earlier at a median age of 2 to 3 years of age. 75% of pts present before 5 years of age. Females are more commonly affected; F:M is 1.09:1 for unilateral tumors and 1.67:1 for bilateral tumors.1
RISK FACTORS: Paternal occupation as a machinist or a welder and maternal use of hair dye.2 Also associated with congenital anomalies in 10% to 13% of cases:
WAGR: Wilms tumor, Aniridia, GU malformations, mental Retardation. Caused by alteration of 11p13 with deletion of WT1 gene (Wilms tumor suppressor gene, important for normal kidney/gonadal development) and PAX6 (aniridia gene). 30% risk of developing WT.
Beckwith–Wiedemann: Macrosomia, hemihypertrophy, macroglossia, omphalocele, abdominal organomegaly, ear pits/creases. Caused by alteration of 11p15 locus, which causes loss of imprinting of genes. 5% risk of developing WT.
Denys–Drash syndrome: Renal disease (proteinuria during infancy, nephrotic syndrome, renal failure), male pseudohermaphroditism, and Wilms. Caused by alteration of 11p13 locus, causing point mutation in zinc-finger regions of WT1 gene. 50% to 90% risk of developing WT.3
ANATOMY: Wilms tumor originates from the kidney parenchyma and drains to perinephric and para-aortic lymph nodes.
PATHOLOGY: WT is an embryonic kidney tumor, classically triphasic with blastemal, epithelial, and stromal elements. WT tend to be lobulated and solid, lack calcifications, and may have soft and cystic areas. These tumors tend to be very large and often can compress adjacent structures but only the minority of cases show pathologic evidence of organ invasion.1
TABLE 58.2: Pathologic Types of Renal Tumors in Children
Favorable histology (FH) Wilms tumor
Typical features (blastemal, epithelial, and stromal elements) without anaplastic or sarcomatous components.
Unfavorable histology (UH) Wilms tumor; anaplastic Wilms tumor
Anaplasia refers to enlargement of nuclei, hyperchromatism of nuclei, and increased mitotic figures.
Focal anaplasia (FA): sharply localized in the primary tumor.
Diffuse anaplasia (DA): nonlocalized or localized with significant nuclear unrest in remainder of tumor or found outside tumor capsule, in metastases, or on random biopsy of the tumor.
Rhabdoid tumor of the kidney (RTK)
Typically diagnosed before 2 years of age with eosinophilic cytoplasm and hyaline globular inclusions (+vimentin and cytokeratin), associated with primary CNS neoplasms (i.e., ATRT) and INI1 mutations.
Clear cell sarcoma of the kidney (CCSK)
4% of all childhood renal tumors.4 About 5% present with metastases and 40%–60% with bone metastases compared to those with WT (2% incidence).5 Tumor cells w/ abundant intracytoplasmic vesicles. No specific tumor markers but classically described as “chicken-wire” pattern with undifferentiated cells separated by fibrovascular septa.6
Renal cell carcinoma
Approximately 6% of renal tumors in children, not included in classic studies; treatment is surgery alone, no clear role for adjuvant RT.
All subtypes except FH are considered “high-risk” tumors.
GENETICS: Poor prognosis associated with loss of heterozygosity (LOH) of 1p and/or 16q (worse if both). Those with early stage disease and loss of 1p16q are treated more aggressively with three-drug regimen (as for stage III/IV).
Gain of 1q is associated with inferior survival for unilateral FH WT.7
Although Wilms is associated with inactivation of the WT1 tumor-suppressor gene in 5% to 10% of cases, about 1/3 of Wilms cases are associated with inactivation of a more recently described tumor suppressor gene referred to as WTX (unknown gene on X chromosome), which may be involved with normal kidney development. Tumors with WTX mutation lack WT1 mutation. In contrast to WT1-associated Wilms, which required biallelic (two-hit) inactivation, WTX requires only one hit (i.e., the single X chromosome in males or the active X chromosome in females).1
SCREENING: If children present with worrisome physical exam findings that are associated with the predisposing genetic syndromes listed earlier, then screening may be appropriate with periodic abdominal ultrasounds.1
CLINICAL PRESENTATION: Abdominal mass (83%), fever (23%), hematuria (21%), abdominal pain (37%).1 Can also have anemia (due to decreased EPO) and hypertension (from increased renin). See Table 58.3 for comparison between Wilms and neuroblastoma.
TABLE 58.3: Comparison Between Neuroblastoma and Wilms Tumor
Neuroblastoma
Wilms
Classic eggshell calcifications on x-ray in 85%
No tumor calcifications (but may have calcifications from hemorrhage)
Displaces kidney (“drooping lily” sign) but does not distort renal architecture
Disrupts renal architecture
Mets to LNs, bone marrow, liver, skin (rarely to lung or brain)
Mets to lung, liver, bone
Frequently crosses midline
Often does not cross midline
WORKUP: H&P (including assessment for congenital anomalies)
Labs: Urinalysis including urinary catecholamines (to rule out neuroblastoma)
Imaging: Abdominal ultrasound including contralateral kidney and evaluation of thrombosis/extension into renal vein or IVC. MRI, CT chest, abdomen, pelvis, and CXR (studies have relied on whether pulmonary metastases are visible on CXR; positive CT with a negative CXR can present controversy). Do not biopsy unless unresectable or bilateral disease to avoid local tumor spillage. If biopsy is necessary, use posterior approach to avoid abdominal contamination and contain bleeding or spillage if they occur. Once pathology available, obtain further workup if CCSK or RTK (bone scan, skeletal survey, bone marrow biopsy, MRI brain).
PROGNOSTIC FACTORS: LOH 1p and/or 16q, gain of 1q, higher stage, unfavorable histology, and age >24 months portend a worse prognosis.
STAGING: Two systems exist: National Wilms Tumor Study Group (NWTSG, often referred to as simply NWTS) versus Société Internationale d’Oncologie Pédiatrique (SIOP) staging. NWTS system emphasizes postsurgical, pre-CHT staging to obtain most “unadulterated” information (extent of primary, degree of anaplasia, presence of unusual histology, +/− LN). SIOP philosophy is neoadjuvant treatment with CHT and/or RT in an effort to reduce extent of disease and increase en bloc resection, but at the expense of losing or obscuring some of the information listed earlier. NWTS staging is currently in use by the COG and listed in Table 58.4.1
TABLE 58.4: NWTS/COG Staging for Wilms Tumor1
I
Tumor limited to kidney, completely excised. The renal capsule is intact. 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.
II
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). Blood vessels within the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus, contain tumor.
III
Residual nonhematogenous 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)
- Tumor has penetrated through the peritoneal surface
- Tumor implants are found on the peritoneal surface
- Gross or microscopic tumor remains postoperatively (e.g., tumor cells are found at the margin of surgical resection on microscopic examination)
- Tumor is not completely resectable because of local infiltration into vital structures
- Tumor spillage occurring either before or during surgery
- Tumor was biopsied (whether 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)
Helpful Mnemonic for Stage III Wilms (SLURPPIB):
SSTR/+Margin
LLN (abdominal)
UUnresectable
RRupture/Spillage
PPiecemeal resection (including thrombus not removed en bloc)
PPreoperative CHT required (unresectable)
IImplant (i.e., peritoneal involvement, including peritoneal penetration)
BBiopsy
IV
Hematogenous metastases (lung, liver, bone, brain, etc.) or lymph node metastases outside the abdominopelvic region are present
V
Bilateral renal involvement by tumor present at diagnosis
TREATMENT PARADIGM
Surgery: Radical nephrectomy is the initial definitive treatment of choice for WT in the United States. Historically, nephrectomy alone (1930s) achieved cure in only 15% to 30%. Surgery alone is being investigated for very low-risk patients on protocol (COG AREN 0532). 90% to 95% of patients are resectable at diagnosis via wide transverse abdominal incision and radical nephrectomy with assessment of surgical margins and avoidance of spillage via a transperitoneal approach. Tumors that are marginally resectable or with large central necrosis, which may portend increased risk for spillage, may benefit from neoadjuvant therapy with CHT or RT. This is a complex surgery (10% tumors involve renal vein; 15% tumors involve IVC/atrium). Inspect/palpate abdominal cavity, liver and LN for extent of tumor spread; examine and palpate opposite kidney; inspect and palpate renal vein to exclude tumor thrombus. Regional LN sampling for accurate staging. Tumor spillage incidence is 15% to 30% in the literature1and is significantly associated with abdominal recurrence and mortality.8 Incidence of surgical complications with nephrectomy (as per NWTS-4) is 11%. Most common complications are hemorrhage and SBO. Quality of surgery has prognostic importance (e.g., degree of LN sampling, spillage, unnecessary biopsies) and QA among COG surgeons is underway.
Chemotherapy: CHT has improved overall results for WT in the past two decades via NWTS and SIOP studies. In Europe, CHT is typically given preoperatively. In North America, it is given adjuvantly following initial nephrectomy. Preoperative CHT can be required if there is bulky, unresectable disease, bilateral WT, WT in a solitary kidney, or tumor thrombus in IVC. The use of specific agents varies with stage. Lower stages (I and II) typically are treated with vincristine and actinomycin-D. Stage III/IV disease and UH are typically treated with three or more agents including Adriamycin.
Radiation: RT formerly played a much larger role in WT and was historically used postoperatively to the tumor bed at 2 Gy/day to 40–50 Gy. Now, approximately 25% of patients with WT are treated with RT (only 15%, if metastatic disease is excluded). Traditional start for RT is by day 10 after surgery, no later than day 14, if surgery is designated day 0. A later radiation start is linked to increased risk of abdominal recurrence in some studies. RT is given concurrently with vincristine and actinomycin-D.
Indications: See Table 58.1. Typically, at least flank RT is indicated for stage III disease, unfavorable histology or positive margins. Whole abdomen irradiation (WAI) indicated for mnemonic “SPAR” (Spillage during surgery, Peritoneal seeding, malignant Ascites, or preoperative Rupture).
Dose: Dose for flank RT is 10.8 Gy/6 fx with boost to any residual gross disease to 21.6 Gy. Give flank RT to 19.8 Gy if ≥16 years of age or if stage III diffuse anaplasia or I-III rhabdoid (+10.8 Gy boost to gross disease; total 30.6 Gy). WAI typically 10.5 Gy/7 fx or 21 Gy/14 fx for diffuse unresectable peritoneal implants. Whole lung irradiation (WLI) indicated for lung metastases on CXR (not if mets only visible on CT) at a dose of 12 Gy/8 fx (10.5 Gy if <1 year of age). If WLI and flank are indicated together, can treat flank to 10.5 Gy simultaneous with WLI to 12 Gy/8 fx or at separate times (do not feather or block to adjust for overlap).
Procedure: See Treatment Planning Handbook, Chapter 12 for details.9
Toxicities
Renal: ~1% of pts with unilateral WT will have end-stage renal disease from chronic renal failure 20 yrs from diagnosis; 3.1% for pts with bilateral WT.10
Premature mortality: Risk of death from all causes increased from 5.4% to 22.7% at 30 and 50 years of age, respectively, after WT diagnosis. 50% of excess deaths beyond 30 yrs from diagnosis were attributable to secondary neoplasms and 25% from cardiac diseases.11
Cardiac: The risk of CHF increases with increasing total dose of Adriamycin received, increasing amount of RT received by the heart, and female gender. 1.7% of pts treated w/ ADR on NWTS-1-4 developed CHF compared to 5.4% in pts treated with WLI.1,12
Pulmonary: 10% of pts w/ pulmonary mets treated on NWTS-3 developed “diffuse interstitial pneumonitis of unknown etiology” (possibly radiation pneumonitis) after WLI. There were four additional cases of diffuse pneumonitis secondary to varicella and PJP. Give trimethoprim/sulfamethoxazole for PJP prophylaxis with WLI. The incidence of pneumonitis has subsequently decreased by reducing the dose of Adriamycin and actinomycin-D given concurrently with RT.
Hepatic: In SIOP-9, 8% of children developed hepatotoxicity consistent with veno-occlusive disease with the combination of CHT and RT.13
Reproductive: Females who receive RT or CHT during childhood for unilateral WT had an increased risk for hypertension complicating pregnancy, fetal malpositioning, and premature labor.14
Musculoskeletal: RT is associated with development of scoliosis and reduction in height with severity increasing with younger age and increasing dose to the spine.15
Second malignancies: GI, soft tissue sarcomas, and breast cancers are the most frequent secondary neoplasms to develop after treatment.16 Cumulative incidence of invasive breast cancer for survivors who received lung RT is almost 15% by 40 years of age.17
EVIDENCE-BASED Q&A
What are the main findings of the National Wilms Tumor Studies (NWTS) I-V?
Note that early NWTS studies used a grouping system that was a predecessor to the current NWTS staging system. Groups I and V are essentially the same as the corresponding stages, although group V included patients who develop contralateral tumors at some point after diagnosis (whereas stage V currently is limited to those with bilateral disease at diagnosis). Group II included PA LN involvement, while group III included any LN beyond the abdominal PA chains. Group IV included only hematogenous metastases.
NWTS-1 (1969–1974): D’Angio (Cancer 1976 PMID 184912)
Postop RT is not needed for group I <2 y/o, but did improve DFS for pts ≥2 y/o (p = .002).
VCR + AMD are better than either agent alone in groups II and III.
For group III w/ local spillage or pre-op biopsy, no need for WAI.
Pre-op VCR does not help stage IV.
Age ≥2 y/o, the presence of anaplastic or sarcomatous features and LN involvement were found to be poor prognostic factors.
NWTS-2 (1974–1979): D’Angio (Cancer 1981 PMID 6164480)
Excellent survival rates for group I pts receiving VA CHT; thus RT is not needed for stage I FH patients.
Six months of VA is equal to 15 months for stage I.
ADR in addition to VCR and AMD helped for groups II-IV.
No dose response from 18 to 40 Gy for flank RT.
Total lung RT dose should be 12 Gy, due to 10% risk of “pneumonopathy” w/ 14 Gy.
Unfavorable histology, small RT field size, and RT delay of ≥10 days are poor prognostic factors for LR.
NWTS-3 (1979–1985): D’Angio (Cancer 1989 PMID 2544249)
(Note: Changed from grouping system to staging system; however, until after NWTS-4, local spillage was considered stage II rather than III)
Distinction between FH and UH was incorporated into treatment algorithm.
For stage I FH, 10 weeks of AMD + VCR is equal to 6 mos, OS 96%.
For stage II FH, there was no benefit to the addition of ADR (VA alone sufficient) or RT.
For stage III FH, 10 Gy is equal to 20 Gy if ADR is added.
Cyclophosphamide improves outcomes in UH (focal anaplasia) stages II–IV but not FH stage IV.
NWTS-4 (1986–1994): Green (JCO 1998 PMID 9440748; Green JCO 1998 PMID 9850017).
For stage I FH or anaplastic pts, pulse-intense (PI) VCR + AMD x 18 weeks is equivalent to standard VCR + AMD x 25 weeks.
For stage II FH, PI VCR + AMD for 6 months is as effective, less costly, and less toxic (hematologic) than standard VCR + AMD for 15 months.
For stages III-IV FH, PI VCR + AMD + ADR for 6 months is as effective, less costly, and less toxic than standard VCR + AMD + ADR for 15 months.
Seibel (JCO 2004 PMID 14752069): Long-term update shows long-course CHT associated with better RFS in CCSK, but OS no different.
Local spillage without RT has unacceptable LR risk; moved to stage III for FH (need adjuvant RT).
NWTS-5 (1995–2001):
Shamberger (Ann Surg 2010 PMID 20142733): Stage I FH, pts <2 y/o, and tumors <550 g had an increased rate of relapse with nephrectomy alone (without adjuvant CHT) but no difference in OS with or without CHT.
Dome (JCO 2006 PMID 16710034): Vincristine/Adriamycin/cyclophosphamide/etoposide improved outcomes for stages II-IV with DA.
Grundy (JCO 2005 PMID 16129848): For stages I-II FH pts, risk of relapse and death were increased with LOH at 1p, 16q, or both. For stages III-IV FH, risk of relapse and death were increased only with LOH for both 1p and 16q (RR = 2.4, p = .01 and RR = 2.7, p = .04).
What is the impact of RT in the setting of tumor spillage?
Helps with decreasing abdominal tumor recurrence rates.
Kalapurakal, NWTS 4 & 5 Pooled (IJROBP 2010 PMID 19395185): Analyzed influence of irradiation (Flank and WAI) and CHT regimens on abdominal recurrence after intraoperative spillage of FH Wilms on NWTS-4 and 5. OR for recurrence after RT versus no RT was 0.35 (0.15–0.78) for 10 Gy and 0.08 (0.01–0.58) for 20 Gy. OR for CHT after adjusting for RT was not significant. For stage II pts (NWTS-4), 8-yr RFS with and without spillage, respectively, was 79% versus 87% (p = .07) and OS was 90% versus 95% (p = .04). Conclusion: RT (10 Gy or 20 Gy) reduced abdominal tumor recurrence rates after tumor spillage. Tumor spillage in Stage II patients associated with decreased RFS and significantly decreased OS.
What is the role of WLI in patients with FH Wilms who have pulmonary metastases detected by CT only? What is the role of Adriamycin in this setting?
No OS benefit with ADR, no benefit with WLI.
Grundy, NWTS 4 & 5 Pooled (Pediatr Blood Cancer 2012, PMID 22422736): 417 pts with FH WT and isolated lung metastases on NWTS-4 and -5. Compared outcomes by method of detection (CXR vs. CT only), use of WLI, and two- or three-drug CHT (AMD and VCR +/− ADR). For pts with CT-only lung mets (negative CXR), 5-yr EFS was greater with three drugs (including Adriamycin) with or without WLI versus only two drugs (80% vs. 56%; p = .004); OS was not impacted (87% vs. 86%; p = .91). For pts with CT-only lung mets, WLI showed a trend for benefit with regard to 5-yr EFS (81.0% vs. 70.1%; p = .11), but this disappeared when the analysis was adjusted for the CHT regimen (p = .52). There was no difference in OS with or without WLI. Conclusion: Pts with CT-only lung mets have improved EFS but not OS with the addition of ADR; they do not seem to benefit from WLI.
What are the early outcomes of omission of WLI from AREN 0533 (higher risk favorable histology study)?
WLI may not be necessary for patients with FH WT with CR of lung nodules after 6 weeks of CHT.
Dix, AREN 0533 (ASCO 2015, Abstract 10011): Examined whether pts w/ stage IV pulmonary mets only without LOH 1p and 16q who have a CR of lung nodules after 6 weeks of CHT can maintain excellent EFS without the use WLI. The null hypothesis is that 4-year EFS is 85% for CR after vincristine/actinomycin-D/Adriamycin and WLI. Among 391 pts enrolled, 296 had lung-only metastases, of which 105 (39%) had CR. At interim analysis in June 2014, 20 events were observed: 19/20 were recurrences and 1 was a second malignancy. Recurrences were in the lung only (17), lung and liver (1), and abdomen (1). 4-yr EFS and OS estimates for the CR patients were 78% (95% CI: 68%–86%) and 95% (95% CI: 83%–98%). Conclusions: EFS was slightly less than historical standards although not statistically significant. Omission of WLI may be an acceptable treatment approach for this patient subgroup.
