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The Treatment of Stages I–IV Favorable Histology Wilms' Tumor

Department of Pediatrics, Roswell Park Cancer Institute, and the School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY

The prognosis for children with Wilms' tumor (WT) has improved dramatically. During the last three decades, the National Wilms Tumor Study Group (NWTSG), the International Society of Pediatric Oncology (SIOP), and the United Kingdom Children's Cancer Study Group (UKCCSG) conducted sequential studies of treatments for children with WT. The results will be reviewed in the light of long-term follow-up. Areas for future investigation will be identified.

Stage I/Favorable Histology
The National Wilms' Tumor Studies (NWTS) demonstrated abdominal radiation therapy was not necessary for children with stage I/favorable histology (FH) WT who received postoperative chemotherapy with vincristine and dactinomycin.^1–3 The postnephrectomy administration of the combination of agents was shown in NWTS-1 to significantly improve the relapse-free survival (RFS) percentage of children with group II/III tumors compared with treatment with either agent alone.¹ NWTS-2 randomly assigned children with group I/FH WT to treatment with vincristine and dactinomycin for either 6 (regimen E) or 15 (regimen F) months.² The 16-year RFS percentage was 98.9% for those treated for 6 months and was 90.5% for those treated for 15 months (P = .02; Table 1). NWTS-3 randomly assigned these children to treatment with vincristine and dactinomycin for 10 weeks (regimen L) or 6 months (regimen EE).³ The 16-year RFS percentage was 88.9% for those treated for 10 weeks and was 92.5% for those treated for 6 months (P = .08; Table 2).

Garcia et al⁵ suggested that those children with a combined weight of the affected kidney and tumor less than 550 g had a good prognosis. Children with stage I/FH WT on NWTS-1 who were younger than 24 months had an excellent outcome.⁶ There was not a significant improvement in the RFS for children younger than 24 months with tumors that weighed less than 550 grams treated with a single agent (NWTS-1) or combination chemotherapy (NWTS-2 and NWTS-3).⁷ These analyses supported treatment of this group of children with nephrectomy only. This study (NWTS-5) was designed with a stringent stopping rule that ensured closure of the study, with high probability, based on interim analysis, if the true RFS rate was 90% or less. The study was closed because this boundary was exceeded, but the 2-year OS rate was 100%.⁸ These children were more successfully retreated than prior stage I/FH children were, probably because they were naive to both radiation therapy and chemotherapy. Nephrectomy only should be re-evaluated for the treatment of children younger than 24 months with a stage I/FH WT weighing less than 550 grams.

Stage II–III/Favorable Histology
The prognosis for children with groups II–III/FH WT treated on NWTS-1 with radiation therapy and the combination of vincristine and dactinomycin (regimen C) was not as good as that for children with group I WT.¹ The reported response rate of WT to doxorubicin was 60% (31 of 52 patients, with eight complete responses and 23 partial responses).⁹ The investigators of the NWTSG developed a new chemotherapy regimen that included vincristine, dactinomycin, and doxorubicin (regimen D).

Children in groups II–IV were randomly assigned in NWTS-2 between regimens C and D. The 16-year RFS of children in group II-III/FH for regimens C and D were 72.4% and 86.4%, respectively (P = .05; Table 3). The 16-year OS percentages were 80.4% for those treated with two drugs and 86.7% for those treated with three drugs (P = .58; Table 4). The RFS percentages were approximately 70% for regimen C and 88% for regimen D when these results were reported in 1981 (P = .004).² Neither the original report nor these updated results demonstrated a statistically significant difference in survival percentages between those treated with two, compared with three drugs.

Children were randomly assigned in NWTS-3 using a 2 x 2 factorial design that compared treatment with (DD) or without (K) doxorubicin, and with radiation doses of 10 (K1 or DD1) or 20 Gy (K2 or DD2) (stage III) or 0 (K or DD) or 20 Gy (DD or DD2; stage II). The 16-year RFS percentages of children with stage II or III/FH WT were 85.4% for those treated with three drugs and 82.6% for those treated with two drugs (P = .30; Table 2). The 16-year OS percentages were 88.1% for those treated with two drugs and 88.8% for those treated with three drugs (P = .68; Table 5). These results are not different from those originally reported.³

The 4-year RFS and OS rates did not differ between patients with stage II/FH WT who received 20 Gy compared with 0 Gy.³ A subset analysis demonstrated a benefit for those stage III/FH children treated with three drugs compared with two drugs (P = .04).³ Fewer abdominal relapses occurred among those with stage III/FH WT treated with three (3%; four of 134) compared with two (7.8%; 11 of 141 patients) drugs.³ The data suggested that either a three-drug chemotherapy regimen or a higher radiation therapy dose (20 Gy) was necessary to successfully treat children with stage III/FH tumors. Concern about the late effects of the higher radiation therapy dose and the absence of data regarding the long-term effects of treatment with doxorubicin resulted in the selection of the three-drug regimen with the lower radiation therapy dose (10 Gy) as the standard for this group of children.

The results of NWTS-2 and NWTS-3 were used in the design of the sixth SIOP WT trial and study. Children with postoperative stage II FH WT and positive lymph nodes or postoperative stage III FH WT were randomly assigned to treatment with vincristine and dactinomycin or those drugs and doxorubicin. The RFS percentage was 49% for those treated with two drugs, compared with 74% for those treated with three drugs (P < .029), suggesting a benefit from the addition of doxorubicin to the treatment regimen for children who still had lymph node disease, and/or microscopic or macroscopic non-nodal residual disease after 4 weeks of prenephrectomy chemotherapy with vincristine and dactinomycin.¹⁰

Prolonged follow-up of anthracycline-treated children led to the identification of congestive heart failure and second malignant neoplasms as significant late treatment complications. These data were not available in 1985 when the decision to adopt the three-drug chemotherapy regimen as the standard for those with stage III/FH WT was made.

Breslow and his colleagues¹¹ reported that the second malignant neoplasm (SMN) standardized incidence ratio increased from 6.9 (95% CI, 3.2 to 13.2) among children treated with radiation therapy, but not doxorubicin to 12.4 (95% CI, 7.1 to 20.1) among those treated with radiation therapy and doxorubicin. This report was consistent with others demonstrating that anthracycline treatment was a significant risk factor for the occurrence of an SMN.^12,13

Anthracycline treatment produces abnormalities in cardiac function^14,15 that progress with increasing elapsed time from anthracycline exposure¹⁶ and may be associated with clinical congestive heart failure. The end systolic wall stress was reduced in 20% (eight of 40 patients) of children assessed 6.7 ± 1.9 years after treatment with 90 mg/M² of daunorubicin.¹⁷ Increased afterload was identified in 17% (three of 18) of children whose treatment included a single dose of doxorubicin of 45 mg/M².¹⁴ Serial endomyocardial biopsies from children receiving anthracycline therapy at Stanford University demonstrated cardiomyopathic effects in children treated with only 45 mg/m² of doxorubicin. Histological changes were observed at cumulative doxorubicin doses that did not increase the pre-ejection period/left ventricular ejection time ratio.¹⁸

Among children who received doxorubicin as part of their initial treatment for WT, the cumulative percentage who developed congestive heart failure was 4.4%. The relative risk (RR) of congestive heart failure is increased among females (RR, 4.5; 95% CI; 1.6 to 12.5; P = .004), and increases by 3.3 (95% CI, 1.8 to 5.9; P < .001) for every 100 mg/m² of doxorubicin, by 1.6 (95% CI, 1.0 to 2.4; P = .037) for every 10 Gy of lung irradiation, and by 1.8 (95% CI, 1.1 to 2.7; P = .013) for every 10 Gy of left abdominal irradiation.¹⁹ This is consistent with reports that lung irradiation is a risk factor for cardiac mortality,²⁰ and that anthracycline exposure and an initial disease-free interval of less than 15 years are significant risk factors for late mortality among 15-year childhood cancer survivors.²¹

The roles for doxorubicin and higher radiation therapy dose in the treatment of children with stage III/FH tumors are not clear. The administration of a three-drug chemotherapy regimen produces a marginal improvement in RFS but requires the treatment of almost 75% with a drug, doxorubicin, that does not improve their OS percentage and exposes them to potential long-term morbidity. Although the current NWTSG regimens use a lower cumulative dose of doxorubicin (150 mg/m² rather than 300 mg/m² used in NWTS-2, NWTS—3, and as part of the randomization in NWTS-4) and a lower dose of flank irradiation, factors that might reduce the risk of anthracycline related cardiomyopathy, the shorter follow-up of those who received lower cumulative doses prevents definitive statements regarding the relative morbidity of the two different cumulative anthracycline doses and of the lower abdominal radiation therapy doses. The use of doxorubicin and abdominal radiation therapy dose should be re-evaluated in these children.

Stage IV/Favorable Histology
Children with stage IV/FH WT with metastases restricted to the lung(s) have an excellent prognosis. More than 80% entered on NWTS-3 were alive 4 years after diagnosis.³ Treatment includes immediate nephrectomy and postnephrectomy whole-lung irradiation. Abdominal radiation therapy is restricted to those with a stage III tumor. All receive chemotherapy with vincristine, dactinomycin, and doxorubicin.

In NWTS-2, children with stage IV/FH WT were randomly assigned to treatment with regimen C or D (vide supra). All received abdominal and whole-lung irradiation.² The 4-year RFS percentages were 53.3% for those on regimen C and 57.7% for those on regimen D (P = .63). The 4-year OS rates were 53.3% for those on regimen C and 61.5% for those on regimen D (P = .62).²² The results for NWTS-3 children with stage IV/FH tumors demonstrated no statistically significant improvement in 4-year RFS or OS from the addition of cyclophosphamide to the three-drug regimen. The 16-year RFS percentages were 76.5% for the three-drug regimen (regimen DD) and 77.6% for the four-drug regimen (regimen J, P = .65). The 16-year OS percentages were 79.5% for the three-drug regimen and 80.1% for the four-drug regimen (P = .65; Table 5).

The UKCCSG and SIOP evaluated different approaches to the management of children with stage IV/FH WT, seeking to avoid the use of whole-lung irradiation because of its significant acute and long-term toxicity.²³ Those entered onto the UKCCSG Nephroblastoma Study-1 received cyclophosphamide, vincristine, dactinomycin, and doxorubicin administered for 12 months from the date of complete remission, whether induced by the initial period of drug treatment or whole-lung irradiation. Those who had complete resolution of the pulmonary metastases after 12 weeks of chemotherapy did not receive whole-lung irradiation. The 6-year RFS percentage was 50% for the 39 children so treated, only four of whom received whole-lung irradiation. The 6-year survival percentage was 65%.⁴ Children with stage IV WT entered onto the UKCCSG Nephroblastoma Study-2 received vincristine, doxorubicin, and dactinomycin. All underwent delayed nephrectomy and received 12 Gy of whole-lung irradiation. The 4-year EFS percentage was 70%, and the 4-year OS percentage was 75%.²⁴

Investigators from SIOP-treated children with stage IV WT with 6 weeks of prenephrectomy chemotherapy with vincristine, dactinomycin, and doxorubicin. Children whose pulmonary metastases did not respond completely to chemotherapy, with or without surgical excision of residual metastases, received postnephrectomy whole-lung irradiation. Seventy-five percent of the children had a complete response to the initial 6-week period of chemotherapy. The RFS and OS percentage was 83%. Seven children received whole-lung irradiation.^25,26

These results suggest that some children with stage IV/FH WT may be treated successfully without the use of an anthracycline and that some may be treated successfully without whole-lung irradiation. A study of therapy without an anthracycline or without whole-lung irradiation could be considered in a group with favorable biologic prognostic factors.

Prenephrectomy Chemotherapy
To decrease the need for postoperative abdominal radiation therapy to treat children who have tumor rupture during nephrectomy, SIOP conducted trials in which children received prenephrectomy chemotherapy or abdominal radiation therapy. Prenephrectomy abdominal irradiation decreased the percentage of nephrectomies complicated by tumor rupture from 33% (20 of 60 nephrectomies) to 4% (3 of 72 nephrectomies).²⁷ In a subsequent randomized trial (SIOP-5), the frequency of tumor rupture was nearly the same for children treated with prenephrectomy abdominal irradiation and dactinomycin (8%; 7 of 76 children) and for those treated with prenephrectomy chemotherapy with vincristine and dactinomycin (6%; 5 of 88 children). The RFS percentages were 76.5% for those who received prenephrectomy chemotherapy and 67.0% for those treated with prenephrectomy radiation therapy.

SIOP evaluated the role of postnephrectomy abdominal irradiation in children treated with prenephrectomy combination chemotherapy who had postchemotherapy stage II WT without regional lymph node involvement by tumor. All received chemotherapy with vincristine and dactinomycin. The trial was discontinued because a statistically significant excess of intra-abdominal recurrences occurred in the unirradiated children. The RFS percentage was 72.0% for those who received postnephrectomy abdominal irradiation and was 78.0% for those who did not receive radiation therapy (P = not significant).¹⁰ Eight of 59 unirradiated children had their first relapse in the abdomen, compared with one of the 64 irradiated children, suggesting that prenephrectomy chemotherapy did not destroy perinephric tumor extensions and/or tumor deposits in regional lymph nodes.¹⁰ Only seven of 59 unirradiated children had their first recurrence in the lungs, compared with 15 of 64 irradiated children.

The duration of prenephrectomy chemotherapy was evaluated in SIOP-9. Children were randomly assigned to receive 4 or 8 weeks of prenephrectomy chemotherapy with vincristine and dactinomycin. There was no difference in the proportion of tumors that were stage I at the time of nephrectomy following 4 (64%) or 8 weeks (62%) of chemotherapy. The 2-year EFS percentages were: stage I/standard or anaplastic histology, 88%; stage II/lymph node-negative/standard histology, 84%; stage II/lymph node-positive/standard histology and stage III/standard histology, 71%.²⁸

NWTSG investigators recommend immediate nephrectomy because prenephrectomy chemotherapy administration is associated with several risks, including: (1) administration of chemotherapy to a patient with a benign disease; (2) administration of chemotherapy to a patient with a different histological type of malignant tumor; (3) modification of tumor histology; and (4) loss of staging information.

The data do not permit an assessment of the risk and benefits of prenephrectomy chemotherapy compared with immediate nephrectomy in children who present with a unilateral renal tumor and no hematogenous metastases. Children with surgical emergencies due to tumor rupture are stage III in the NWTSG but are not recorded in the SIOP trials, artifactually decreasing the proportion of those with stage III tumors. Those with doubt in diagnosis, registration after nephrectomy, prior surgery, or chemotherapy and physician or patient refusal are excluded. The stage distribution of the excluded groups has not been reported. This would be of interest for the comparison of NWTSG to SIOP results.

DISCUSSION

The survival rate of children with Wilms' tumor has improved dramatically since the inception of the prospective randomized trials conducted by the NWTSG, SIOP, and the UKCCSG. Future research must address the several important remaining questions including treatment of young children with small, stage I/FH WT using nephrectomy only, the role of doxorubicin in combination with abdominal irradiation for the management of children with stage III/FH WT, the need for whole-lung radiation therapy for the management of children with stage IV/FH WT, and the identification and utilization of biologic features of the excised tumor for treatment stratification. Answers to these questions will continue the progress that has been achieved—improving the survival rate and minimizing the adverse acute and late effects of therapy.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

Acknowledgment

We thank the investigators of the Pediatric Oncology Group and the Children's Cancer Group and the many pathologists, surgeons, pediatricians, radiation oncologists, and other health professionals who managed the children entered onto the National Wilms' Tumor Studies; Sierra Li for performing the statistical analyses updating the results of NWTS-2 and NWTS-3; Giulio J. D'Angio, M.D, Norman E. Breslow, PhD, J. Bruce Beckwith, MD, Paul E. Grundy, MD, and Jeff Dome, MD, for their helpful reviews of this manuscript; and my colleagues on the National Wilms Tumor Study Group Committee, including Peter Coccia, MD, Max J. Coppes, MD, PhD, Milton Donaldson, MD, Audrey E. Evans, MD, Jerry Z. Finklestein, MD, Gerald M. Haase, MD, Vicki Huff, PhD, Panayotis P. Kelalis, MD (deceased), Tae Kim, MD, Morris Kletzel, MD, Roger Macklis, MD, Marcio Malogolowkin, MD, Robert Newbury, MD, Elizabeth Perlman, MD, Michael L. Ritchey, MD, Robert C. Shamberger, MD, Patricia Shearer, MD, Stephen J. Shochat, MD, Patrick R.M. Thomas, MD, Gail Tomlinson, MD, PhD, Douglas Weeks, MD, and Robert Weetman, MD.

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