Radiation Oncology Synopsis

Wilms Tumor

Background, Natural History and Epidemiology

Wilms tumor was first described in 1814. By 1828 a second case was identified. Wilms wrote a treatise on the disease in 1899. Radiation therapy was used early on in the treatment of the disease and by the mid 20th century, radiation oncologists were well experienced with its treatment.

Epidemiology

Wilms tumor is aan embryonic kidney tumor and is the most common childhood abdominal tumor, representing 6% of childhood cancer. The incidence rate is 6.1/million-year. About 500 cases per year are diagnosed in the US. The median age is 3-4 years and 95% are less than 10 years old. Females are more frequently affected than males. Wilms patients are older than neuroblastoma patients with neuroblastoma patients presenting at < 2 years. Hereditary tumors present at a younger age than sporadic tumors with an average age of 2.5 years. There are three genetic syndromes associated with Wilms:

Denys-Drash Syndrome is associated with the 11p WT1 gene. It describes a cluster of diseases including Wilms tumors, renal disease (proteinuria during infancy), nephritic syndrome, progressive renal failure, male pseudohermaphroditism.

Beckwith-Wiedemann Syndrome is a cluster of macrosomia, macroglossia, omphalocoele, hemihypertrophy and is also associated with 11p chromosome alterations.

Other genetic defects include loss of heterozygosit of 1p and 16q, FWT1 (17q) and FWT2 (19q).

Other potential risk factors are fathers who work with metals, such as welders and machinists and mothers who use hair dyes.

Poor prognostic factors include:


The NWTS-5 analysis in 2005 demonstrated the prognostic importance of LOH 1p+16q for Wilms. This is associated with a significant increase in the relative risk of relapse. Loss of heterozygosity of both increase the risk of relapse and death.

Pathology

Histologies are favorable or unfavorable. Unlike rhabdomyosarcoma there are no distinctions of favorable or unfavorable sites.

The unfavorable histologies are:


Focal anaplasia is defined as sharply localized within the primary tumor without atypia in the remainder of the tumor. Diffuse anaplasia is:

Rhabdoid histology has the worst prognosis.

By stage, the 4 year overall survival for anaplastic/unfavorable histology Wilms tumors is:

Stage I 83%
Stage II 83%
Stage III 65%
Stage IV 33%

The 4 year overall survival for focal v. anaplastic Wilms tumors is:

Stage Focal
OS-4		 Anaplastic
OS-4
Overall 97% 50%
Stage I 100% 100%
Stage II 93% 55%
Stage III 90% 45%
Stage IV 80% 4%

Presentation, Workup and Staging

Presentation

The typical presenting signs of Wilms Tumor are a painless abdominal mass in 83% of all patients. This will eventually progress to abdominal pain in 37%, hypertension in 25% due to increased renin production, hematuria in 25%, and fever and anemia due to decreased erythropoetin production. Unlike Wilms, neuroblastoma most commonly presents with systemic symptoms.: Wilms are well, Neuroblastomas are not well.

Workup

Work up for an abdominal mass of uncertain etiology typically involves H&P, focused assessment of congenital GU and other defects (WAGR -- Wilms/aniridia/genito-urinary abnormalities/retardation. Lab studies including a urinary catecholamine assessment, abdominal ultrasound, chest XR and CT of the Chest/abdomen and pelvis.

Ultrasound is the preferred abdominal first line imaging study for an abdominal mass. Once an ultrasound demonstrates the mass, CT/MR of the head, (for rhabdoid and clear cell histologies) and a bone scan for clear cell histology are recommended. Both Chest X-ray and CT of the chest are used for chest imaging. Lesiosn seen on CT but not visible on CXR may be treated more conservatively than lung mets visible on CXR.

Patients with rhabdoid and clear cell histologies require additional imaging:

DO NOT BIOPSY! unless the tumor is unresectable or bilateral in presentation. If a biopsy is necessary, a posterior approach is preferred to avoid contamination of the abdomen. Biopsy of these lesions automatically makes them a Stage IV disease.

At the time of surgical staging, the surgeon's report should specifically describe the extent of disease in detail. In particular a discussion of whether or not there was tumor spillage is essential.

On presentation, 7% have bilateral disease, 12% have multi-focal disease, 10% have renal vein invasion, and 20% have regional lymphatic involvement.

On presentation, 10% present with distant metastases. Most of these are pulmonary metastases at 80%, followed by liver and bone. Clear cell histologies can metastasize to the brain. Non-local lymph nodes are also found in metastatic cases.

Wilms occasionally has calcifications, which are seen in only 15-20%. Neuroblastoma frequently has calcifications which are seen in 85% of all neuroblastomas. .

Staging

There are five stages in the Wilms Staging system:

Adrenal involvement is considered local involvement and is not considered metastatic disease.

Treatment

The initial treatment paradigm in the United States for Wilms is initial surgical resection and staging → risk adapted chemotherapy ± radiation therapy. There are two study groups for Wilms tumors: the NWTS (National Wilms Tumor Study) and SIOP. In Europe, the SIOP trials are based on neoadjuvant treatment prior to surgery. The usual pre-op therapy is chemo/radiation therapy. In the US, under conditions of initally inoperable Wilms, pre-operative chemotherapy is used, similar to SIOP. Conditions making Wilms unresectable include bilateral involvment, or disease such that it would be not possible to get a complete resection.

COG Protocols -- AREN0532 and AREN0533 recommend radiation therapy based on the biology and stage of disease.

Radiation is recommended in the following circumstances:

  1. FAVORABLE histology: Stages III-IV
  2. UNFAVORABLE histology: Stages I-IV

Evidence for Treatment Selections: National Wilms Tumor Study group and SIOP

SIOP's philosophy is that neoadjuvant therapy would render a Wilms tumor less vulnerable to intraopeartive rupture and surgery related tumor seeding. SIOP also hoped that neoadjuvant treatment would downstage the tumor, thus reducing the total amount of treatment and consequent morbidity. SIOP was willing to sacrifice potential prognostic information to gain these goals.

In the US, the NWTS studies elected surgical management as initial management to gain as much information as possible about the disease characteristics and use that as a guide to adjuvant therapies.

NWTS-1 1969 - 1974 This study asked several important treatment questions:

Radiation therapy doses were age adjusted:

Radiation therapy appeared unnecessary in Group I babies and combined drug therapy was superior in groups II and III. Pre-operative vincristine was not helpful in Group IV.

In patients > 2 years with Group I tumors, had an advantage with radiation, but these patients in Group II did as well, suggesting that vincristine + actinomycin D could substitute for post-operative radiation therapy.

The NWTS-1 study clearly demonstrated the difference between unfavorable and favorable histology with 2 year relapse free survival rates of 29% in unfavorable histology and 89% in favorable histology. Larger tumor size, lymph node involvement and age ≥ 2 years were confirmed as poor prognostic indicators. No dose-response relationship was seen in the 10 - 40 Gy range and delays of up to 10 days in initiating post-operative radiation therapy appeared to be acceptable. Whole abdomen radiation therapy was found not to be necessary for tumor spills confined to the flank, or for prior tumor biopsy. Limited radiotherapy fields sufficed.

NWTS-2 (1974 - 1979). The NWS-2 study explored three major questions:

Radiotherapy was given according to the same age dependent dosing scheme as NWTS-1. Flank RT was given in groups II- IV disease, and whole abdominal RT was given only when diffuse abdominal seeding was present. Lung metastases were initially treated with 14 Gy of whole lung irradiation but a 10% rate of pneumonitis developed and the dose was reduced to 12 Gy.

Study results: OS-2 was 54% for unfavorable histology, 90% for favorable histology, and 54% for positive lymph nodes, and 84% for negative lymph nodes. Excellent outcomes without RT were noted for Group I and adriamycin added considerable benefit in Group II-III favorable histology and some benefit in Group II-III unfavorable histology and Group IV.

NWTS-3 (1979 - 1985) This study incorporated two major changes in treatment planning:

  1. Patients were stratified by Stages rather than by groups
  2. The distinction between favorable and unfavorable histology was incorporated into the treatment algorithm

NWTS-3 considered 5 major questions:

  1. Can the duration of chemotherapy be shortened for Stage I favorable histology?
  2. Can radiation therapy be eliminated in Stage II favorable histology?
  3. What is the minimum effective dose for Stage III favorable histology?
  4. Is adriamycin clearly beneficial and necessary in Stage II and III favorable histology?
  5. Will the addition of cyclophosphamide improve survival in Stage I-III unfavorable histology and in Stage IV any histology?

NWTS-3 findings include:

  1. Short course therapy appeared equivalent to long course therapy in Stage I favorable histology.
    • Patients in this group can be treated successfully with 10 weeks of VA without radiation and can achieve a 4 year relapse free survival of 89% and overall survival of 96%.
    • Radiation can be eliminated in Stage II favorable histology. 4 year RFS was 87% and OS-4 was 91%.
  2. In Stage III favorable histology 10 Gy was equivalent to 20 Gy
    • There was no statistically significant difference between 10 Gy and 20 Gy although a trend favored the addition of adriamycin.
  3. The addition of adriamycin was beneficial in Stage III but not clearly beneficial in stage II favorable histology.
  4. Cyclophosphamide did not benefit Stage IV favorable histology. The OS-4 for Stage IV favorable histology treated with vincristine, actinomycin D, adriamycin and abdominal and lung radiation was 81%.
  5. Cyclophosphamide seemed to help patients with focal anaplasia.

NWTS-4 (1986 - 1994) Focused on Minimization of therapy and reduction in toxicity. This trial was the first to assess economic impact of two approaches and was customized by stage and histology. NWTS-4 introduced pulse intense chemotherapy. This compressed the standard 15 months of chemotherapy into 6 months. The main advantages of pulse intense chemotherapy include decreased hematologic toxicity and decreased total cost due to the reduction in drug use.

NWTS-3 demonstrated that Stage I-II favorable histology, compromising 62% of Wilms patients needed no radiation or adriamycin.

NWTS-4 examined RFS and OS rates of patients with stage I and II favorable histology and Stage I anaplastic tumors treated with conventional vincristine and actinomycin D. Stage II and IV favorable histology and Stages I-IV CCSK were treated with VA/A (vincristine/actinomycin D/adriamycin) compared with pulsed intensive VA/A. All patients received radiotherapy which consisted of 10.8 Gy to the abdomen for favorable histology and 12 Gy to the lungs where appropriate. For Stage II-IV anaplastic tumors appropriate radiation followed by actinomycin D, vincristine and adraimycin was the treatment.

NWTS-4 evaluated the rate of intra-abdominal recurrences in the setting of tumor spillage in favorable histology disease. It found flank irradiation (but not adriamycin) reduced abdominal relapse rates. The odds ratio for recurrence risk was 0.35 for 10 Gy and 0.08 for 20 Gy. Tumor spillage resulted in higher relapse rates and significantly lower survival among Stage II patients.

Because of these findings, NWTS-4 moved patients with tumor spillage from Stage II to Stage III.

For Stage II patients in NWTS-4, Relapse free survival at 8 years was 79% with tumor spillage and 87% without spillage. In addition OS was lower at 90% over 95% (with no spillage) p-0.04.

NWTS-5 (1995-2001) Looked at chemotherapy doses and agents and evaluated the LOH 1p and 16q as prognostic factors. Radiotherapy was as in NTWS-4 except NTWS-5 recommended 10.8 Gy for anaplastic tumors instead of the age adjusted doses used in NWTS 1-4.

NWTW-5 demonstrated an increased rate of relapse for Stage I favorable histology patients who were < 2 years old and had tumors < 550 g, treated with nephrectomy alone. The relapse rate was 13.5% without adjuvant chemotherapy. Most of these recurrences were salvaged at 70%.

For Stage II-IV with diffuse anaplasia NWTS-5 demonstrated an improvement in outcomes with VACE (vincristine adriamycin, cyclophosphamide, etoposide) chemotherapy.

Stage I unfavorable histology patients were not offered radiation therapy in NWTS-5.

The COG Protocols

The COG is the successor to the NWTS. COG has introduced several studies in the light of the NWTS studies. Presently, AREN0532 and AREN0533 is examining treatment intensification based on the LOH 1p and 16q status. Stage I patients with anaplastic disease (UH) get radiation, VA/A chemotherapy..

COG changed the staging mechanism into risk groups. These Risk groups are based on the following factors:

These risk groups are divided into:

  1. very low
  2. low
  3. standard
  4. higher
  5. high
  6. bilateral

COG Radiotherapy Protocols

Under the current COG protocols, patients in the very low risk group would forego radiotherapy. These patients include:

Flank Irradiation

The standard flank dose is 10.8 Gy. Indications for radiation therapy to the flank include

For unresected positive lymph nodes, the entire lymphatic chain is treated to 19.8 Gy → boost with optional 5.4 Gy - 10.8 Gy (total dose 25.2 Gy to 30.6 Gy) Use 30.6 Gy in children ≥ 16.

For resected positive lymph nodes 10.8 Gy is the recommended dose.

For Wilms patients with Stage III favorable histology, Stage I-III focal anaplasia, Stage I-II diffuse anaplasia, Stage I - III clear cell, age < 16, and infants with rhabdoid or diffuse anaplasia are all given 10.8 Gy

For Wilms Patients ≥ 16 years and/or those with rhabdoid and/or diffuse anaplastic disease the present COG recommendations are flank irradiation to 19.8 Gy for Stage III/DA (diffuse anaplasia) or rhabdoid pathologies, Stages I-III. A 10.8 Gy boost is given to metastatic or gross disease, bringing the total dose to 30.6 Gy.

Flank irradiation fields should include the entire vertebral body to the contralateral side + 1 cm margin. The preferred radiation therapy fields, margins and techniques include the GTV + 1 cm margin, APPA for flank with 3D conformal RT for the boost. The boost field should encompass any residual disease + 2 cm margins.

Liver metastases

For patients with isolated liver metastases, surgery is the preferred first line therapy. For patients with diffuse liver mets, 19.8 Gy to the entire liver, with boost options of 5.4 - 10.8 Gy.

Whole Lung Irradiation

Formerly, a CT positive lung metastatic case was treated as lung negative if a chest x-ray was negative. Recently this has changed and CXR or CT positive lungs are treated as positive cases.

Whole lung irradiation is indicated when lung disease is demonstrated and treated with VA/Adriamycin and there is not a complete response by CT at week 6 after the three drug regimen. It is not based on CT or CXR detectability. The whole lung dose is 12 Gy for age > 1 year or 10.5 Gy for age < 1 year at 1.5 Gy/fraction. If disease persists after whole lung irradiation, consider a 7.5 Gy boost. Patients should be given Bactrim DS for PCP prophylaxis when being treated with whole lung irradiation.

Brain Metastases

For brain metastases:

Bone metastases

Total dose for bone metastases is 25.2 Gy or 30.6 Gy if older than 16.

Patients with metastatic disease are treated exactly like those without mets. Mets are treated concurrently with abdominal RT if abdominal RT is also necessary.

Timing of Radiation

Radiation should be started by Post operative Day 9 and should begin no later than POD 14. Secondary analysis of NWTS 1 and 2 demonstrated worse outcomes if treatment was delayed beyond POD 10.

Radiation Dose limits/Normal Tissue Complication Limits

Chemotherapy

For Stage I-II favorable histology, Standard chemotherapy is 18 weeks of VA.

For Stage III-IV favorable histology, Standard chemotherapy is 24 weeks of VA/Adriamycin

Relapse/Salvage Therapy

For Stage I/II relapsed disease treated with VA only the EFS-4 is 71% and OS-4 is 82%. Patients are salvaged with surgery, radiation therapy and chemotherapy with VAdriaCE. For lung metastases only recurrences, the 4 year EFS is 68% and OS-4 is 81%.

For Stage III/IV prognosies is worse, with 42% EFS-4 and 48% OS-4. Lung only metastases are only slightly better at EFS-4 49% and OS-4 52%,.