Second malignant neoplasms in survivors of Wilms' tumor: a report from the National Wilms' Tumor Study.

Between October 1969 and December 1982, 2,438 patients were enrolled in the National Wilms' Tumor Study and contributed 14,381 person-years of observation to a follow-up study for the occurrence of second malignant neoplasms (SMNs). Fifteen SMNs were observed, whereas 1.77 would have been expected from U.S. incidence rates for 1973-1977 [relative risk = 8.5; 95% confidence interval (CI) = 4.7, 14.0]. Ten years after the Wilms' tumor diagnosis, the cumulative risk of SMN was 1%. The relative risks compared to standard rates were 12/1.11 = 10.8 (95% CI = 5.6, 18.9) for those who received radiation as part of the initial course of treatment and 3/0.60 = 5.0 (95% CI = 1.0, 14.6) for those who did not, but this difference was not statistically significant. Preliminary data suggest that substantial numbers of SMNs occur as patients are followed greater than 10 years from diagnosis.

Acute toxicities associated with radiation in the second National Wilms' Tumor Study.

Twenty-three of 303 patients (7.6%) entered into National Wilms' Tumor Study Number 2 (NWTS-2) with groups II, III, and IV disease experienced 26 toxic events thought to be related to radiotherapy (RT). The randomization between vincristine (VCR) plus dactinomycin (AMD) and the same two drugs plus doxorubicin (ADR) had a minimal effect on RT toxicity. Five (1.6%) fatalities were recorded and the surviving 18 patients recovered without discernible residua. Sixteen patients had hepatic, four had pulmonary, and three had cardiac toxicity. Hepatic toxicity was significantly more common when the right side of the abdomen or the whole abdomen was irradiated than when the left side was treated (P = .01). We conclude that acute RT-related toxicity in NWTS-2 was very similar to that in NWTS-1, in which 26 (7.2%) of 359 randomized patients developed RT-related toxicity and three died. This acceptable rate was maintained despite more intensive chemotherapy (CT) in NWTS-2.

Anaplastic Wilms' tumor: clinical and pathologic studies.

A review of almost 1,200 children participating in the first and second National Wilms' Tumor Study (NWTS-1 and -2) has demonstrated a number of significant differences in the clinical presentation and response to therapy of anaplastic and nonanaplastic Wilms' tumor. Compared to their counterparts, children with anaplastic Wilms' tumor were generally one to two years older at diagnosis, more were non-white, and more had lymph node metastases at diagnosis. Consistent with previous studies, children with anaplastic Wilms' tumor survived for a significantly shorter time than those with non-anaplastic Wilms' tumor. A hopeful outlook, however, was suggested by the NWTS-2 experience since the more aggressive chemotherapies used in this study appear to have substantially improved the survival of patients with diffusely anaplastic tumors. Also, the survival of NWTS-2 patients with anaplastic Wilms' tumor was determined in part by clinicopathologic stage. It may be possible therefore to refine therapy according to stage so as to provide children with localized disease a chance for cure with fewer untoward treatment-related sequelae.

Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: a report from the National Wilms' Tumor Study.

To evaluate the effect of dactinomycin (AMD) dose and schedule on the frequency of severe hepatic toxicity in unirradiated National Wilms' Tumor Study-4 (NWTS-4) patients, we reviewed the records of 154 children randomized to single-dose AMD and 176 children randomized to divided-dose AMD administration. All the children also received vincristine in identical dose schedules for the first 10 weeks. The frequency of severe hepatic toxicity encountered in the early weeks of therapy was 14.3% (five of 35) among patients treated with 60 micrograms/kg of AMD, 3.7% (four of 108) among patients given 45 micrograms/kg, and 2.8% (five of 176) among patients treated with 15 micrograms/kg per dose times five doses (P = .025). The data suggest an increased frequency of severe hepatic toxicity with the higher, single-dose schedule of administration. However, the frequency of severe hepatic toxicity among the patients in the two remaining groups is markedly higher than the 0.4% observed among similar unirradiated patients in NWTS-3. The relationship of this toxicity to factors such as anesthetic agents, blood transfusions, intercurrent viral infection, or other presently unrecognized causes can be further evaluated only with a detailed investigation such as a case-control study.

The treatment of Wilms' tumor patients with pulmonary metastases detected only with computed tomography: a report from the National Wilms' Tumor Study.

To evaluate the prognosis of patients with Wilms' tumor who have pulmonary densities identified on a computed tomographic (CT) scan of the chest, but have a negative plain chest radiograph, we reviewed the treatments and outcome of 32 patients randomized or followed on National Wilms' Tumor Study (NWTS)-3. The 4-year event-free and overall survival percentages of 18 of these patients who had a favorable histology tumor and were treated as stage IV tumors with three or four drugs plus whole-lung irradiation were 88.1% and 94.0%, respectively. The 4-year event-free and overall survival percentages for nine favorable histology patients treated less aggressively based on the extent of locoregional disease with two or three drugs and without whole-lung irradiation were 88.9% and 88.0%, respectively. There were no statistically significant differences in the 4-year event-free or overall survival percentages between the two groups. The current data do not demonstrate improved survival for favorable histology patients treated with whole-lung irradiation for pulmonary metastases identified only on chest CT scan. However, due to the small number of patients included, no statistically valid conclusions regarding the roles of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and/or whole-lung irradiation in the treatment of these patients can be drawn from the present analysis. Additional patients need to be systematically studied to determine if these preliminary observations can be confirmed.

Abdominal relapses in irradiated second National Wilms' Tumor Study patients.

Ten of 259 (3.8%) irradiated patients with group 2 and 3 tumors in the second National Wilms' Tumor Study experienced initial clinical relapse either in the operative site or elsewhere in the abdomen, excluding the liver and opposite kidney. Analysis of factors associated with abdominal recurrences has shown the independent significance of unfavorable histology, field size of the radiotherapy portals, and a postoperative delay of ten or more days before starting irradiation.

Congestive heart failure after treatment for Wilms' tumor: a report from the National Wilms' Tumor Study group.

PURPOSE: We determined the frequency of and risk factors for congestive heart failure following treatment for Wilms' tumor that included doxorubicin. PATIENTS AND METHODS: Flow sheets and medical records were reviewed to identify cases of congestive heart failure in a cohort of patients treated on National Wilms' Tumor Studies (NWTS)-1, -2, -3, and -4. The frequency of congestive heart failure was estimated using the Kaplan-Meier method. A case-control study was conducted to determine the relationship among cumulative doxorubicin dose, site(s), total dose of abdominal and thoracic irradiation, sex, and the frequency of congestive heart failure. RESULTS: The cumulative frequency of congestive heart failure was 4.4% at 20 years after diagnosis among patients treated initially with doxorubicin and 17.4% at 20 years after diagnosis among those treated with doxorubicin for their first or subsequent relapse of Wilms' tumor. The relative risk (RR) of congestive heart failure was increased in females (RR = 4.5; P =.004) and by cumulative doxorubicin dose (RR = 3.3/100 mg/m(2); P <.001), lung irradiation (RR = 1.6/10 Gy; P =.037), and left abdominal irradiation (RR = 1.8/10 Gy; P =.013). CONCLUSION: We conclude that congestive heart failure is a risk of treatment with doxorubicin for Wilms' tumor. Additional follow-up of those children treated on NWTS-4 will be necessary to determine if the decrease in dose to 150 mg/m(2) significantly reduces this risk.

Long-term renal function in patients with irradiated bilateral Wilms tumor. National Wilms' Tumor Study Group.

The treatment of bilateral Wilms tumor (BWT) involves a multidisciplinary approach including surgery, chemotherapy, and radiation therapy. The long-term renal function in patients receiving all three treatment modalities has not been evaluated. Long-term renal function was evaluated in 81 children with synchronous BWT who received radiation therapy as part of their treatment. Renal function was assessed by measuring blood urea nitrogen (BUN) and serum creatinine (Cr). The normal range for the BUN was defined as 10-24 mg/dl, and the Cr was considered normal at levels of <1.5 mg/dl. Moderate elevations were defined as a BUN of 25-50 mg/dl and/or a Cr of 1.6-2.5 mg/dl and marked elevations as a BUN of >50 mg/dl and/or a Cr of >2.5 mg/dl. BUN and Cr levels were measured prior to treatment and at the following intervals: 6 months after treatment, 1 year after treatment, 2 years after treatment, and at last follow-up. Any elevation during the posttreatment follow-up period was considered abnormal. A total of 28 children (34.6%) had elevated BUN and/or Cr levels, and 18 had moderate and 10 had marked renal insufficiency. No dose-response relationship was established when comparing the radiation doses of those with elevated values to those with normal values. The renal complication rate was moderate, and other factors including surgery, extent and nature of chemotherapy, and recurrent tumor must also be taken into account. The elevations present in several children could be attributed to tumor recurrence and in one case to gentamicin toxicity. The management of children with BWT should consider all of these risks, and attempts to preserve renal parenchyma are warranted.

Diastolic hypertension in Wilms' tumor survivors: a late effect of treatment? A report from the National Wilms' Tumor Study Group.

Following treatment by the National Wilms' Tumor Study Group (NWTS) 2,243 children with Stages I-IV Wilms' tumor, have remained relapse-free for 5 or more years. Of these, 1,528 children had at least one blood pressure measurement recorded during follow-up. Using standards developed by the Second Task Force on Blood Pressure Control in Children, it appears that 5 or more years following diagnosis the general distribution of blood pressures for NWTS survivors may be above that for the national population, especially at the younger ages.

Therapy and outcome in 51 children with mesoblastic nephroma: a report of the National Wilms' Tumor Study.

Mesoblastic nephroma is a distinctive pathologic renal tumor with unique clinical, therapeutic, and prognostic patterns. This report reviews 51 patients (2.8% of 1905 patients submitted to NWTS with renal tumors) with this diagnosis from the NWTS contrasting this disease entity with Wilms' tumor. There were 33 males and 18 females, predominantly term babies born after uncomplicated pregnancies. The mean age at tumor excision was 3.44 +/- 0.6 mo (one child 9 yr). A palpable mass was the predominant presentation in 48 patients and in addition hematuria (9), hypertension (2), vomiting (3), and jaundice (1) were noteworthy. Diagnostic studies included IVP (49 positive, 2 negative) and ultrasound (15 positive, 1 negative). Adequate operative excision was achieved in 43 of 51 patients while 8 children had local extension and 10 had tumor spillage. Operation alone (23), predominantly since 1978, surgery plus chemotherapy (24), prior to 1978, and surgery, chemotherapy, and radiation therapy (4), prior to 1976, were the modes of therapy. The follow-up ranges from 4 mo to 11.5 yr. Survival was excellent; 50 patients survive (98%), only 1 dying of sepsis. These data suggest that mesoblastic nephroma contrasts with Wilms' tumor in that it occurs in a younger age group, has a benign biologic behavior, and a more favorable outcome. Aggressive multimodal treatment though utilized in the early years of the study is not essential to achieve this outcome.

Diffuse interstitial pneumonitis after pulmonary irradiation for metastatic Wilms' tumor. A report from the National Wilms' Tumor Study.

To evaluate the frequency, etiology, and outcome of diffuse interstitial pneumonitis after treatment of children with Stage IV (favorable histologic type) Wilms' tumor using whole-lung and abdominal radiation therapy, and combination chemotherapy, all cases reported in such patients entered on National Wilms' Tumor Study 3 were reviewed. Diffuse interstitial pneumonitis was reported in 13.0% of patients. The etiology was varicella, one patient; Pneumocystis carinii, three patients; and unknown, 15 patients. The time elapsed after the completion of whole-lung irradiation did not distinguish those patients with pneumonitis due to P. carinii from those with pneumonitis of unknown etiology. All three children with pneumonitis due to P. carinii survived the episode, whereas only four of 15 (27%) patients with pneumonitis of unknown etiology survived the episode. Management of Wilms' tumor patients who develop diffuse interstitial pneumonitis after whole-lung irradiation should include a diagnostic procedure known to be sensitive for the diagnosis of P. carinii infection.

Severe hepatic toxicity after treatment with single-dose dactinomycin and vincristine. A report of the National Wilms' Tumor Study.

Dactinomycin is an antitumor antibiotic with known activity against many pediatric solid tumors. Administration of dactinomycin using a single-dose schedule was incorporated into the design of the National Wilms' Tumor Study 4 (NWTS-4). This was done to determine whether laboratory and preliminary clinical data, suggesting that such a schedule was associated with increased antitumor effect and/or decreased normal tissue toxicity, could be validated in a large clinical trial. Five patients treated with regimens EE-4 or K-4, regimens that included single-dose dactinomycin and no abdominal irradiation, experienced severe hepatic toxicity. The clinical courses of these patients suggested that multiple factors, including the administration of other hepatotoxic agents, contributed to the toxicity observed. The study has been modified by decreasing the dose of dactinomycin from 60 micrograms/kg to 45 micrograms/kg. Further evaluation of other potential contributing factors, such as the use of halogenated hydrocarbon inhalational anesthetic agents, is needed.

Retrospective validation of a new staging system for Wilms' tumor.

Prognostic significance has been ascribed to certain clinicopathological features of the Wilms' tumor. Examples are size, vascular invasion, histologic characteristics, tumor rupture, and lymph nodal involvement. Several of these were arranged into a grouping system, and used in a cooperative clinical trial, the first National Wilms' Tumor Study (NWTS). Detailed clinicopathologic information was accumulated for each patient entered in the study, and these data were analyzed with respect to their prognostic import. Factors found to be of significance were rearranged into a proposed staging system, believed more likely to be predictive of outcome for patients with tumor spread beyond the kidney confines, but without distant metastases (Groups II and III). The postulated discriminatory superiority was tested using Group II and III patients entered in the second NWTS. The same children were reassigned retrospectively to Stages II and III, and the outcomes compared. Statistically significant differences were noted between Stages II and III, but not for Groups II and III. These results encourage the use of the new staging system in the third NWTS.

Late effects of treatment for Wilms' tumor. A report from the National Wilms' Tumor Study Group.

The National Wilms' Tumor Study (NWTS) was initiated in 1969. One of its objectives was to modulate treatments according to risk factors to minimize the number and severity of treatment-related short-term and long-term iatrogenic complications. The NWTS has therefore incorporated a Long Term Follow-up Study (LTFS) within its framework to monitor late effects. The LTFS is confined to relapse-free survivors alive 5 years or longer after initial surgery, and data are collected using specifically designed forms. A total of 787 patients registered on NWTS-1 or NWTS-2 (1969 to 1979) were eligible, of whom 680 (86%) were available for analysis regarding musculoskeletal, cardiovascular, and neuropsychologic status, and the presence of benign and malignant tumors. Patients with early-stage disease who were treated with radiation had scoliosis reported, along with other musculoskeletal abnormalities (32 versus 2), nearly seven times as often as did the members of the cohort population who did not undergo radiation (35 of 57 versus 5 of 53, respectively). The difference in cardiovascular problems recorded in survivors who did and did not receive Adriamycin (Adria Laboratories, Columbus, OH) (2.4 versus 1.1 per 100-person years at risk) had borderline statistical significance (P = 0.06). No excess in neuropsychologic events was reported for those given the neurotoxin vincristine. When considering patients with disease of all stages, all 5 second malignant tumors occurred in the 623 patients who underwent radiation (RT patients); benign tumors were also more frequent in RT patients than in those patients who did not undergo radiation (41 of 486 or 8% versus 4 of 194 or 2%). Continuing study of this unique body of patients is needed, especially for those given Adriamycin, because of the known long interval needed for latent cardiomyopathy to become clinically manifest in some patients.

Screening of children with hemihypertrophy, aniridia, and Beckwith-Wiedemann syndrome in patients with Wilms tumor: a report from the National Wilms Tumor Study.

To evaluate the usefulness of regular radiographic screening to detect an asymptomatic intraabdominal tumor in patients with an increased risk of developing Wilms tumor, we reviewed the files of patients with hemihypertrophy, aniridia, or Beckwith-Wiedemann syndrome who were registered on the National Wilms Tumor Studies. Screening was employed infrequently in the management of children with hemihypertrophy, with only 25% (6/24) of those whose hemihypertrophy was identified more than 30 days prior to the diagnosis of Wilms tumor undergoing such examinations. Most patients with aniridia were evaluated regularly for the occurrence of Wilms tumor. There were more stage 1 tumors identified in patients whose tumor was detected only through radiographic evaluation. The role of routine radiographic screening needs to be carefully evaluated in a homogeneous group of patients such as those with aniridia using a prospective study design to determine if such screening improves the survival rate of children with this rapidly growing, but readily treatable form of childhood cancer.

Accuracy of current imaging modalities in the diagnosis of synchronous bilateral Wilms' tumor. A report from the National Wilms Tumor Study Group.

BACKGROUND: Five percent of patients with Wilms' tumor will present with bilateral disease. Recent reports suggest that preoperative imaging studies can exclude contralateral disease reliably, obviating the need for formal surgical exploration of the contralateral kidney. This study was undertaken to determine the accuracy of preoperative imaging in diagnosing bilateral Wilms' tumor. METHODS: The charts of 122 patients with synchronous bilateral Wilms' tumor enrolled in National Wilms Tumor Study-4 were reviewed. With the exception of one child, all had an abdominal computed tomography (CT), ultrasound, or magnetic resonance imaging performed. RESULTS: There were nine patients (7%) in whom the diagnosis of bilaterality was missed by the preoperative imaging studies. All but one of the missed lesions were small, five less than 1 cm and three 1-3 cm. The accuracy of each imaging modality was correlated with tumor size. Computed tomography was more sensitive in detecting bilaterality than ultrasound. However, there was not a single study that was able to detect more than 50% of lesions less than 1 cm in greatest dimension. CONCLUSIONS: This review indicates that even with current advances in imaging technology, synchronous bilateral Wilms' tumor will go unrecognized in 7% of patients if formal exploration of the contralateral kidney is omitted. Although this represents a small percentage of all patients presenting with Wilms' tumor, preoperative diagnosis of bilaterality is essential if parenchymal-sparing procedures are to be performed. Until a more reliable indicator of bilateral disease is found, exploration of the contralateral kidney continues to be recommended.

Hepatocellular carcinoma as second malignant neoplasms in successfully treated Wilms' tumor patients. A National Wilms' Tumor Study report.

Although rare, second malignant neoplasms (SMN) after treatment for Wilms' tumor are deadly. A recent National Wilms' Tumor Study (NWTS) report identified 15 patients with second malignancies discovered over 14,381 person-years of observation. This report described four patients with secondary hepatocellular carcinoma in greater detail. These patients were strikingly similar in that all had right-sided tumors and each one had received right upper-quadrant irradiation. All patients died shortly after diagnosis of the SMN.

Results of two radiation therapy randomizations in the third National Wilms' Tumor Study.

In the third National Wilms' Tumor Study (NWTS-3), patients with Stage II favorable histologic type (FH) or Stage III FH Wilms' tumor were randomized according to a factorial design for both radiation therapy (RT) and chemotherapy to be given after nephrectomy. Patients with Stage II FH disease were randomized between 2000 cGy and no postoperative RT; patients with Stage III FH disease were randomized between 2000 and 1000 cGy. No significant differences in survival were noticed. Although there were no significant differences in the rate of intraabdominal relapses, those patients with Stage III disease who received 1000 cGy and dactinomycin and vincristine (seven patients) experienced a relapse in the abdomen more frequently than those who received 2000 cGy and dactinomycin and vincristine (three patients), 1000 cGy and dactinomycin, vincristine, and doxorubicin (three patients), or 2000 cGy and dactinomycin, vincristine, and doxorubicin (two patients). This would suggest that doxorubicin might be a good substitute for the second 1000 cGy of RT. Boost doses of RT, although allowed, were rarely given and no assessment of the value of supplemental RT can be made. The dismal prognosis of abdominal relapse after RT is confirmed and delay of initiation of treatment beyond 10 days after surgery was a significant adverse factor as in NWTS-1 and NWTS-2.

Prognostic implications of hepatic adhesion, invasion, and metastases at diagnosis of Wilms' tumor. The National Wilms' Tumor Study Group.

In the Third National Wilms' Tumor Study, (NWTS-3), 190 patients with Favorable Histology (FH) Wilms' tumor (WT) were identified as having tumor adherent to, directly invading, or metastatic to the liver at diagnosis. Analyses of the 3-year relapse-free survival and survival of these patients show that adhesion to the liver surface, direct invasion of the liver, and liver metastases have no additional detrimental effect on prognosis stage-for-stage. The authors conclude that hepatic involvement, when present at the time of diagnosis, should not be regarded as different from other patterns of the disease. Treatment policies should follow those appropriate for stage.

Intracardiac extension of Wilms' tumor. A report of the National Wilms' Tumor Study.

Extension of Wilms' tumor through the inferior vena cava into the heart presents a formidable clinical challenge. Excision of such a tumor without provoking emobilization may require cardiopulmonary bypass (CPB). The completeness of excision and the likelihood of tumor embolization during operation guide subsequent radiation therapy (RT) and chemotherapy. To help define these issues, the clinical records of 15 patients enrolled in three National Wilms' Tumor Studies (NWTS) who had intracardiac tumor extension (ICE) were reviewed. The median age at diagnosis was 4 years. One patient had clear cell sarcoma (CCS); the remainder had favorable histologic findings (FH). The clinicopathologic stage was stage II in one patient, stage III in eight patients, and stage IV in six patients. ICE was detected before operation in six patients, during operation in five patients, and after operation in five patients. CPB was used in 10 patients. Eleven patients (73%) had operative complications, with major intraoperative hemorrhage occurring most often (six patients). Complications occurred less often when ICE was recognized before operation (three of six patients) than when it was not (eight of nine patients). Embolization occurred in only two patients. There were no operative deaths. The patient with CCS died. Eleven of 14 patients with FH survived, with an actuarial event-free, 2-year survival rate of 86%. There were no patients in the first NWTS. Of the six patients in the second NWTS (NWTS-2), four died (67%). All nine patients in the third NWTS (NWTS-3) survived, but follow-up was shorter (median 4 years 9 months vs. 2 years 7 months). No particular surgical procedure was associated with an increased death rate. This review suggests Wilms' tumor with ICE presents a formidable surgical undertaking but has a relatively good prognosis. Embolization is an uncommon event in ICE (two patients, 13.3%), allowing a planned operative approach. Echocardiography and ultrasonography provide accurate preoperative diagnosis. And ICE should be suspected in patients with extensive vena cava thrombosis or who have hypotension or heart failure during examination or surgery.