Preoperative chemotherapy and resection

For patients with bilateral Wilms tumor, the goal of therapy is to preserve as much renal tissue as possible without compromising overall outcome. This approach is used to avoid the late effect of end-stage renal disease, which can be caused by underlying germline genetic aberrations and treatment-related loss of functional renal tissue. End-stage renal disease occurs more frequently in patients with bilateral Wilms tumor (12% nonsyndromic) than in patients with unilateral Wilms tumor (<1%). Functional renal outcome is considerably better after bilateral nephron-sparing surgery than after other types of surgery.[176]

Source links and citations

176

Traditionally, patients have undergone bilateral renal biopsies, with staging of each kidney followed by preoperative chemotherapy. In the first prospective multi-institutional treatment trial (COG AREN0534 [NCT00945009]), pretreatment biopsies were not required if results of imaging tests were consistent with Wilms tumor.[176] This approach was taken because the bilateral occurrence of non-Wilms renal tumors is very low. Also, core-needle and wedge biopsies are not highly successful in identifying anaplasia in Wilms tumor.[174] In the setting of an unusual clinical situation, such as age older than 10 years or atypical imaging features, when a diagnosis other than Wilms should be considered, a tissue diagnosis is obtained.[176]

Source links and citations

For patients who are treated with preoperative chemotherapy, the tumor pathology needs to be evaluated after 4 to 8 weeks. For patients not treated in a clinical trial, the ideal time to perform a biopsy or resection is unknown because minimal shrinkage may reflect chemotherapy-induced differentiation or anaplastic histology. A planned attempt at resection or biopsy of apparently unresectable tumor is undertaken no later than 12 weeks from diagnosis. Continuing therapy without evaluating tumor pathology in a patient with bilateral Wilms tumor may miss anaplastic histology or chemotherapy-induced differentiation (including rhabdomyomatous differentiation) and thus increase toxicity for the patient without providing additional benefit for tumor control. Anaplastic histology occurs in 10% of patients with bilateral Wilms tumor, and these tumors respond poorly to chemotherapy.[204]

Source links and citations

204

Once the diagnosis is confirmed, a complete resection is performed. Histological confirmation of the diagnosis is not straightforward. In a series of 27 patients from the NWTS-4 study, discordant pathology (unilateral anaplastic tumor) was seen in 20 cases (74%), which highlights the need to obtain tissue from both kidneys. Seven children who were later diagnosed with diffuse anaplastic tumors had core biopsies performed to establish the diagnosis; however, anaplasia was not found. Anaplasia was identified in only three of the nine patients when an open-wedge biopsy was performed and in seven of nine patients who had a partial or complete nephrectomy.[204]

Source links and citations

204

The decision to administer chemotherapy and/or radiation therapy after biopsy or a second-look operation is dependent on the tumor's response to initial therapy. More aggressive therapy is required for patients with inadequate response to initial therapy observed at the second procedure or in the setting of anaplasia.[216,290,291]

Source links and citations

End-stage renal disease is the most clinically significant morbidity in patients with bilateral Wilms tumor and can be caused by underlying germline genetic aberrations, as well as treatment-related loss of functional renal tissue. Long-term monitoring of renal function is required after treatment for bilateral disease.

Evidence (preoperative chemotherapy and resection for bilateral Wilms tumor):

The first prospective study in bilateral Wilms tumor (AREN0534 [NCT00945009]) aimed to improve EFS and OS while preserving renal tissue by intensifying preoperative chemotherapy (using three drugs—vincristine, dactinomycin, and doxorubicin), completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histological response.[176]; [292][Level of evidence C2]

Source links and citations

The first prospective study in bilateral Wilms tumor (AREN0534 [NCT00945009]) aimed to improve EFS and OS while preserving renal tissue by intensifying preoperative chemotherapy (using three drugs—vincristine, dactinomycin, and doxorubicin), completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histological response.[176]; [292][Level of evidence C2]

For the arm that treated children with bilateral Wilms tumor, results showed that central review of imaging, surgical resection within 12 weeks of diagnosis, and response-based and histology-based postoperative therapy improved EFS and OS, when compared with the historical outcomes of children with bilateral Wilms tumor.

The first prospective study in bilateral Wilms tumor (AREN0534 [NCT00945009]) aimed to improve EFS and OS while preserving renal tissue by intensifying preoperative chemotherapy (using three drugs—vincristine, dactinomycin, and doxorubicin), completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histological response.[176]; [292][Level of evidence C2]

For the 180 patients with bilateral Wilms tumor, the 4-year EFS rate was 81% (95% confidence interval [CI], 74%–87%), and the OS rate was 95% (95% CI, 91%–99%). The above-described approach with risk assignment for treatment based on both staging and postoperative histopathology yielded excellent outcomes for patients with bilateral Wilms tumors but did not improve outcome for patients with diffuse anaplasia. Seven patients who had completely necrotic tumors had a 4-year EFS rate of 100%. Of 118 patients who had tumors with intermediate-risk histopathology, the 4-year EFS rate was 82% and the OS rate was 97%. Fourteen patients with blastemal-type tumors had a 4-year EFS rate of 79% and an OS rate of 93%. Patients who had complete necrosis were assigned to the low-risk category and those with blastemal-type histopathology to the high-risk category for subsequent treatments. For 18 patients who had diffuse anaplasia, the 4-year EFS rate was 61% and the OS rate was 72%. For seven patients who had focal anaplasia, the EFS rate was 71% and the OS rate was 100%.[292][Level of evidence C2] Because biopsy was not performed before treatment in this series, some of the patients enrolled may have had only nephrogenic rests and not a true Wilms tumor. This finding may have improved these survival figures over historical controls.

Source links and citations

The first prospective study in bilateral Wilms tumor (AREN0534 [NCT00945009]) aimed to improve EFS and OS while preserving renal tissue by intensifying preoperative chemotherapy (using three drugs—vincristine, dactinomycin, and doxorubicin), completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histological response.[176]; [292][Level of evidence C2]

Participants in the AREN0534 trial were followed for up to 10 years. The overall 8-year EFS rate was 75% (95% CI, 69%–83%), with a median follow-up of 8.6 years. The highest risk of an EFS event was immediately after diagnosis, with a declining rate over the following 2 years. Over 25% of first recurrences occurred more than 2 years after diagnosis. These late events tended to occur in year 3, with a smaller number of events after year 6. The risk of late recurrences was higher in female patients, patients with anaplastic histology tumors, and patients with negative lymph nodes or margins. Distant relapses in the lungs, liver, or abdomen tended to occur early, while relapses after 2 years were usually in kidney tissue (80% of recurrences). Based on this study, the investigators suggested that observation of patients with bilateral Wilms tumor continue beyond 4 years after diagnosis.[293]

Source links and citations

293

The first prospective study in bilateral Wilms tumor (AREN0534 [NCT00945009]) aimed to improve EFS and OS while preserving renal tissue by intensifying preoperative chemotherapy (using three drugs—vincristine, dactinomycin, and doxorubicin), completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histological response.[176]; [292][Level of evidence C2]

One of the aims of the study was that 75% of patients undergo definitive surgery by 12 weeks. After induction chemotherapy, 163 of 189 patients (84%) underwent definitive surgical treatment in at least one kidney by 12 weeks, and 39% of patients retained parts of both kidneys.

The first prospective study in bilateral Wilms tumor (AREN0534 [NCT00945009]) aimed to improve EFS and OS while preserving renal tissue by intensifying preoperative chemotherapy (using three drugs—vincristine, dactinomycin, and doxorubicin), completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histological response.[176]; [292][Level of evidence C2]

Chemotherapy after surgery was tailored according to histological response. The 4-year EFS rate was 84.1% for FH tumors, 58.2% for anaplastic histology tumors, and 82% for blastemal-type tumors.

The first prospective study in bilateral Wilms tumor (AREN0534 [NCT00945009]) aimed to improve EFS and OS while preserving renal tissue by intensifying preoperative chemotherapy (using three drugs—vincristine, dactinomycin, and doxorubicin), completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histological response.[176]; [292][Level of evidence C2]

Because of the higher risk of renal failure in patients with bilateral Wilms tumor than in patients with unilateral Wilms tumor, one of the goals of the study was that 50% of the patients undergo bilateral nephron-sparing surgery. This threshold was not met, with only 39% of patients successfully treated with bilateral nephron-sparing surgery.

The first prospective study in bilateral Wilms tumor (AREN0534 [NCT00945009]) aimed to improve EFS and OS while preserving renal tissue by intensifying preoperative chemotherapy (using three drugs—vincristine, dactinomycin, and doxorubicin), completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histological response.[176]; [292][Level of evidence C2]

Based on the above study, the recommendation was to continue with three-drug preoperative chemotherapy for 6 to 12 weeks followed by nephron-sparing surgery whenever possible. After resection, postoperative therapy is based on the histology of the resected specimen. The disappointing use of nephron-sparing surgery in this study may have been because of the level of experience of the surgeons in this multi-institutional study.

Outcomes of patients with anaplasia and bilateral Wilms tumor were examined in the AREN0534 study. Twenty-seven patients were enrolled (17 had diffuse anaplasia and 10 had focal anaplasia). Twenty-six patients had bilateral disease. One patient presented with unilateral disease (within the patient's solitary kidney).[294]

Source links and citations

294

Outcomes of patients with anaplasia and bilateral Wilms tumor were examined in the AREN0534 study. Twenty-seven patients were enrolled (17 had diffuse anaplasia and 10 had focal anaplasia). Twenty-six patients had bilateral disease. One patient presented with unilateral disease (within the patient's solitary kidney).[294]

Twenty-one of the 26 patients with bilateral disease had discordant pathology. This suggests that if a biopsy is needed, both kidneys should be sampled.

Outcomes of patients with anaplasia and bilateral Wilms tumor were examined in the AREN0534 study. Twenty-seven patients were enrolled (17 had diffuse anaplasia and 10 had focal anaplasia). Twenty-six patients had bilateral disease. One patient presented with unilateral disease (within the patient's solitary kidney).[294]

The 4-year and 8-year EFS rates were both 53% for patients with diffuse anaplasia. The 4-year EFS rate was 80%, and the 8-year EFS rate was 70% for patients with focal anaplasia.

Outcomes of patients with anaplasia and bilateral Wilms tumor were examined in the AREN0534 study. Twenty-seven patients were enrolled (17 had diffuse anaplasia and 10 had focal anaplasia). Twenty-six patients had bilateral disease. One patient presented with unilateral disease (within the patient's solitary kidney).[294]

The EFS and OS did not differ by margin status.

Outcomes of patients with anaplasia and bilateral Wilms tumor were examined in the AREN0534 study. Twenty-seven patients were enrolled (17 had diffuse anaplasia and 10 had focal anaplasia). Twenty-six patients had bilateral disease. One patient presented with unilateral disease (within the patient's solitary kidney).[294]

All children who died experienced prior relapse or progression within 18 months of study enrollment.

In a retrospective review of 49 patients with Wilms tumor who received preoperative therapy according to the SIOP-93-01 (NCT00003804) guidelines, the timing of surgery was determined when there was no longer imaging evidence of tumor regression. The mean treatment duration was 80 days before renal-sparing surgery.[295]

Source links and citations

In a retrospective review of 49 patients with Wilms tumor who received preoperative therapy according to the SIOP-93-01 (NCT00003804) guidelines, the timing of surgery was determined when there was no longer imaging evidence of tumor regression. The mean treatment duration was 80 days before renal-sparing surgery.[295]

The 5-year EFS rate was 83.4%, and the OS rate was 89.5%.

In a retrospective review of 49 patients with Wilms tumor who received preoperative therapy according to the SIOP-93-01 (NCT00003804) guidelines, the timing of surgery was determined when there was no longer imaging evidence of tumor regression. The mean treatment duration was 80 days before renal-sparing surgery.[295]

All but one of the patients had renal-sparing surgery in at least one kidney.

In a retrospective review of 49 patients with Wilms tumor who received preoperative therapy according to the SIOP-93-01 (NCT00003804) guidelines, the timing of surgery was determined when there was no longer imaging evidence of tumor regression. The mean treatment duration was 80 days before renal-sparing surgery.[295]

Despite the good survival, 14% of the patients developed end-stage renal disease.