Medical Therapy

Chemotherapy is essential in the treatment of Wilms tumor (WT). Refinements in the combination, length, and mode of administration of the various chemotherapeutic agents have resulted from the successive NWTS trials and have helped to optimize survival rates while minimizing acute and chronic toxicities. Chemotherapy protocols vary from study to study; however, the main agents administered include vincristine, dactinomycin, and doxorubicin. Cyclophosphamide can be added in the presence of unfavorable histology and advanced stage. In the SIOP trials, chemotherapy is administered up front to reduce tumor volume, thereby decreasing the risk of surgical spillage of tumor. Radiation therapy is restricted to treatment of higher-stage (stage II with unfavorable histology and stages III and IV) disease.

Surgical Therapy
According to the NWTSG protocol, the first step in the treatment of Wilms tumor is surgical staging followed by radical nephrectomy, if possible. Begin the abdominal exploration through a transverse incision. The kidney is explored by mobilizing the ipsilateral colon and opening the Gerota fascia. Exploration of the contralateral kidney is currently not recommended because of the improvement in imaging techniques (CT scan, MRI). If bilateral disease is diagnosed, nephrectomy is not performed, but biopsy specimens are obtained. New protocols in the management of bilateral Wilms tumor are being explored. If the disease is unilateral, radical nephrectomy and regional lymph node dissection or sampling are performed. The role of partial nephrectomy remains controversial. Although end-stage renal disease after unilateral radical nephrectomy is uncommon (0.25% in NWTSG trial), preserving healthy renal tissue may prevent this complication, especially in patients with an underlying intrinsic renal disease (eg, WAGR syndrome, Denys-Drash syndrome). Partial nephrectomy may be feasible in only 10%-15% of patients, as most tumors are too large at initial diagnosis. The main concern regarding a nephron-sparing procedure is that of local recurrence. The NWTS-4 study showed an 8% local recurrence rate following partial nephrectomy for patients with bilateral disease.[3] In the presence of bilateral Wilms tumors, solitary kidney, or renal insufficiency, partial nephrectomy is a reasonable consideration. If the tumor is unresectable, biopsies are performed and the nephrectomy is deferred until after chemotherapy, which, in most cases, will shrink the tumor. Contiguous involvement of adjacent organs is frequently overdiagnosed. The overall surgical complication rate for Wilms tumor is approximately 20%. If IVC thrombus is present, preoperative chemotherapy will reduce the cavotomy rate by 50%. With bilateral Wilms tumor (6% of cases), surgical exploration, biopsies from both sides, and accurate surgical staging (including lymph node biopsy of both sides) are performed. This is followed by 6 weeks of chemotherapy that is appropriate to the stage and histology of the tumor. Then, reassessment is performed using imaging studies, followed by definitive surgery with (1) unilateral radical nephrectomy and partial nephrectomy on the contralateral side; (2) bilateral partial nephrectomy; and (3) unilateral nephrectomy only, if the response was complete on the opposite side. This approach dramatically reduces the renal failure rate following bilateral Wilms tumor therapy. The overall 2-year survival rate is higher than 80% with this approach, and the nephrectomy rate drops by 50% in patients with bilateral Wilms tumor. Bilateral partial nephrectomy is possible after chemotherapy or, if the tumor on one side responds completely to chemotherapy, with no subsequent need for nephrectomy. Tumor biomarkers, histology, and stage are the most important prognostic factors in cases of unilateral disease. Bilateral high-stage tumors with unfavorable histology are associated with a poor prognosis in spite of the multimodal therapy.

Preoperative Details
Multimodal therapy (ie, surgery, radiation, chemotherapy) is the key to success when treating Wilms tumor. The NWTSG recommends preoperative chemotherapy (after initial exploratory laparotomy and biopsy) in the following situations:[4] Intracaval tumor extension: This occurs in 5% of cases of Wilms tumor. It is associated with a 40% rate of surgical complications, even in experienced hands. Upfront chemotherapy after staging and biopsy reduces tumor and thrombus size, which account for 25% of surgical complications. Inoperable tumors: Large tumors that involve vital structures make resection difficult. The complication rate is high, and the incidence of tumor spill soilage is also high. Upfront chemotherapy reduces soilage by 50%. Bilateral Wilms tumor SIOP advocates upfront chemotherapy without previous laparotomy and biopsy. The NWTSG suggests that this approach comprises a 1%-5% risk of treating a benign disease. Chemotherapy without proper surgical staging (eg, staging by means of imaging studies only) may alter the actual initial stage of the disease by the time of surgery and may subsequently alter decisions regarding the adjuvant chemotherapy and radiation therapy, which is based on the surgical staging.

Intraoperative Details
Through a transperitoneal approach, enter the Gerota (perinephric fascia) fascia to examine the kidney. In cases of unilateral tumor, perform a radical nephrectomy if the opposite side is normal. Evaluate the liver, lymph nodes, and peritoneum for metastases. The renal vein and IVC should be palpated to assess intravascular extension (present in 6% of the cases). In cases of bilateral disease, excisional biopsy of visible tumor is indicated, followed by re-resection with nephron-preservation after chemotherapy. Identify the involved nodes with clips to facilitate postoperative radiation therapy. Integrity of the surgical specimen is of paramount importance, as tumor spillage has a deleterious impact on prognosis (6-fold increase in local abdominal recurrence).

Postoperative Details
Postoperative chemotherapy and radiotherapy protocols are based on the surgical staging and follow the guidelines of the NWTSG. o o o o o o o o o o o o Stage I favorable histology and unfavorable histology or stage II favorable histology Nephrectomy Postoperative vincristine and actinomycin D (18 wk) Stage II focal anaplasia or stage III favorable histology and focal anaplasia Nephrectomy Abdominal radiation (1000 cGy) Vincristine, actinomycin D, and doxorubicin (24 wk) Stage IV favorable histology or focal anaplasia Nephrectomy Abdominal irradiation according to local stage Bilateral pulmonary irradiation (1200 cGy) with sulfamethoxazole and trimethoprim (Bactrim) prophylaxis for Pneumocystis carinii Chemotherapy with vincristine, actinomycin D, and doxorubicin Stage II and stage IV diffuse anaplasia Nephrectomy Abdominal irradiation Whole lung irradiation for stage IV

Chemotherapy for 24 months with vincristine, actinomycin D, doxorubicin, etoposide, and cyclophosphamide

Follow-up
Follow-up care after treatment must be long (if possible, lifelong) because Wilms tumor may recur after several years. Follow-up consists of chest radiography and abdominal ultrasonography, CT scan, or MRI every 3 months for the first 2 years, every 6 months for another 2 years, and once every 2 years thereafter.

Complications
Surgical complications
Small-bowel obstruction (7%) Hemorrhage (6%) Wound infection, hernia (4%) Vascular complications (2%) Splenic and intestinal injury (1.5%)

Long-term complications
Renal function: The rate of chronic renal failure is 1% overall. Of these cases, 70% are children with bilateral Wilms tumor (WT). In unilateral Wilms tumor, the rate is 0.25%. Bilateral nephrectomy is the most common cause of chronic renal failure, followed by treatment-related causes such as radiation or surgical complications. Unrecognized renal disease, such as Denys-Drash syndrome, is rare but should be kept in mind. The damage produced by radiation is dose-dependent, and the rate of impairment in creatinine clearance is approximately 20% with total abdomen irradiation with less than 1200 rads. Cardiac function: Anthracyclines such as doxorubicin produce cardiac muscle impairment in 5% of those receiving a cumulative of 400 mg/m2. The overall incidence rate of some form of cardiac damage is 25% in those treated with anthracycline. The overall incidence of cardiac failure is 1.7%. The mean time to the onset of cardiac failure is 8 years (according to NWTSG-2 and NWTSG-3). If lung irradiation is added, the rate of cardiac failure is 5.4%. Pulmonary function: Radiation pneumonitis is encountered in 20% of the cases receiving total pulmonary radiation. The rate of diffuse interstitial pneumonitis with varicella and Pneumocystis infection is 13%. Hepatic function: Actinomycin D and radiation may damage the liver, with an overall incidence rate of 10%. Hepatic venoocclusive disease (VOD) is a clinical syndrome of hepatotoxicity and consists of jaundice,ascites, hepatomegaly, and weight gain. The incidence rate is 8%. Patients younger than 1 year have double the incidence of VOD. Gonadal function: Chemotherapy may affect gonadal function in boys but rarely affects the function of ovaries. Abdominal irradiation may induce ovarian failure if ovaries were in the target field. Musculoskeletal function: Clinical rickets is possible due to renal tubular Fanconi syndrome caused by drugs that are too cytotoxic. Skeletal sequelae of radiation, including scoliosis or kyphosis, result from uneven growth when the radiation was unilaterally targeted to the vertebral bodies and the dose was higher than 2000 rads. Second malignant neoplasm: These may result from inherited disposition and treatment, bone tumors, breast cancer, and thyroid cancer. The rate after a medium follow-up of 15 years is 1.6%, which is 5 times the expected rate. Second malignant neoplasm can possibly be limited by limiting the intensive chemotherapy and radiotherapy and reserving the intensive treatment regimens only for the high stages and the cases with unfavorable histology.

Outcome and Prognosis

With the advent of multimodal therapy, the prognosis of Wilms tumor (WT) is good, and it is considered an example of success in cancer therapy. The overall survival rate of Wilms tumor is 90%. Cases that involve diffuse anaplasia and stage III or IV disease that recur despite complex therapy have a much poorer prognosis. However, the addition of newer chemotherapeutic agents such as cyclophosphamide, ifosfamide, cisplatin, carboplatin, and etoposide, especially the ICE combination (ifosfamide, carboplatin, etoposide), have contributed to significantly increased postrelapse survival rates to 50%-60%.

Future and Controversies

The purpose of NWTSG-5, which is now closed for patient accrual, was to increase the cure rate in patients with unfavorable histology by using chemotherapy regimens based also on cyclophosphamide and etoposide (VP-16). Another goal of NWTSG is to reduce the rate of adverse effects of treatment by modifying the radiotherapy delivery technique to the abdomen and lung. In addition, using risk stratification based on tumor molecular profile may allow treatment to be tailored for each patient individually. Clinical outcomes may be further improved through promising new cytotoxic agents such as the camptothecin analogue topotecan. Another promising class of chemotherapeutic agents are the antiangiogenesis agents, which target the vascular endothelial growth factor (VEGF) pathway.