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© 2001 American Society for Clinical Oncology Congestive Heart Failure After Treatment for Wilms’ Tumor: A Report From the National Wilms’ Tumor Study GroupFrom the Department of Pediatrics, Roswell Park Cancer Institute, and the Department of Pediatrics, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY; the Department of Biostatistics, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, WA; and the Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA. Address reprint requests to Daniel M. Green, MD, Department of Pediatrics, Roswell Park Cancer Institute, Elm and Carlton Sts, Buffalo, NY 14263; email: daniel.green{at}roswellpark.org
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/m2; 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/m2 significantly reduces this risk.
THE PROGNOSIS FOR children with Wilms’ tumor has improved dramatically during the past three decades. Results of the National Wilms’ Tumor Studies (NWTS) demonstrated that abdominal radiation therapy was not necessary for patients with stage I and II favorable histology tumors1-3 when adjuvant chemotherapy with vincristine and dactinomycin was given postoperatively. The prognosis for children with stages III and IV favorable histology Wilms’ tumor treated with radiation therapy and the combination of vincristine and dactinomycin was not as good as that for children with stage I or II tumors.1 To improve the prognosis in these groups of children, a third drug, doxorubicin, was added to the two-drug combination. This modification resulted in a significant improvement in the relapse-free and overall survival percentages for children with stage III favorable histology tumors.2,3 Several reports documented the adverse effect of prior therapy with an anthracycline on the cardiac function of long-term survivors of childhood cancer.4-7 Although there have been reports of congestive heart failure many years after the completion of anthracycline therapy,8 including in adult survivors whose treatment for Wilms’ tumor included an anthracycline,9 the frequency of and risk factors for this outcome have not previously been examined in the cohort of children treated on the NWTS. The present investigation was conducted to determine the frequency of congestive heart failure following chemotherapy that included doxorubicin and to evaluate other possible risk factors for the occurrence of congestive heart failure.
NWTS-1, -2, -3, and -4 were multi-institutional randomized clinical trials of different treatment regimens for patients who were younger than 16 years old at diagnosis who were diagnosed with Wilms’ tumor. The grouping and staging of patients in the NWTS and the designation of patients as randomized or followed have been discussed elsewhere.2,3 The overall results of NWTS-1, -2, -3, and -4 have been reported elsewhere.1-3,10,11 Flow sheets, radiation therapy summaries, long-term follow-up physical examination forms, hospital and clinic notes, and autopsy protocols were reviewed for all randomized and followed patients. All cardiovascular system conditions, including hypertension, cardiomegaly, heart murmur, decreased ejection fraction, cardiomyopathy, congestive heart failure, and congenital cardiac malformations were abstracted and coded. The flow sheets of all patients diagnosed with a cardiovascular condition, with the exception of hypertension, innocent murmur, or mitral valve prolapse, were reviewed by one of us (D.M.G.) to determine whether the condition (eg, cardiomegaly) was a manifestation of congestive heart failure. Additional information was requested from the registering institution to confirm the diagnosis of all patients suspected of having had congestive heart failure. Congestive heart failure was considered to have occurred if the patient required treatment with digoxin and diuretics. Patients with cardiac enlargement of unknown etiology or with chamber enlargement or decreased ejection fraction in the absence of a past or present requirement for digoxin and diuretics were not evaluated as having congestive heart failure. Doxorubicin-treated patients with congestive heart failure caused by some other illness, such as chronic renal failure (four patients), pulmonary hypertension (one patient), and congenital cardiac malformation (one patient), were not included in this analysis. One additional doxorubicin-treated patient—a female treated with left abdominal irradiation who presented with a left ventricular thrombus, a cerebrovascular accident, and multiple systemic emboli without a documented history of congestive heart failure—was also excluded. Three patients with congestive heart failure from other causes (chronic renal failure, one patient; pulmonary hypertension, one patient; preterminal event in a patient with multiorgan failure, one patient) who were not treated with doxorubicin were excluded from the analysis. The total dose of doxorubicin (mg/m2) given during the course of therapy was calculated within consecutive 6-month intervals for patients who developed congestive heart failure and their matched controls. The right, left, and whole abdomen radiation doses; the whole lung radiation dose; and the dose given to smaller ("boost") fields was determined within consecutive 6-month intervals by review of flow sheets and radiation therapy summaries. The chemotherapy and radiation therapy doses were calculated within consecutive 6-month intervals to facilitate their use as time-dependent covariates in the statistical analysis (see below). Two cohorts were constructed. The first (Cohort 1) consisted of all patients in NWTS-1 through -4 who received doxorubicin as part of their initial therapy for Wilms’ tumor. The second (Cohort 2) consisted of all patients in NWTS-1 through -3 who did not receive doxorubicin for their initial therapy, but who received doxorubicin for treatment of relapse. NWTS-4 patients were not included in cohort 2 because abstraction and coding of retrieval therapy data for the relapsed patients in NWTS-4 is not complete. Only one congestive heart failure case was observed among these latter patients. A nested case-control design was used.12 For each congestive heart failure case, several controls were randomly sampled without replacement from the "risk set" of the case. The risk set of each case consisted of all subjects who were still being followed at the "failure time" (time from first administration of doxorubicin to congestive heart failure) of the case. Controls were matched by cohort, study, and time at risk from first administration of doxorubicin. Doses of doxorubicin and radiation for the controls were cumulated only to the time corresponding to the failure time of the matched case. Sixteen patients in NWTS-1 who received doxorubicin for their initial therapy as participants in a pilot study were combined with patients from NWTS-2 who received doxorubicin in Cohort 1. Four matched controls were selected for each case in Cohort 1, and four to six matched controls were selected for each case in Cohort 2. Controls were replaced by newly sampled controls when their records were not adequate for data abstraction. The case-control data file contained 172 subjects. One subject was selected as a control in three risk sets, and four subjects were selected as controls in two risk sets.
Relative risk (RR) measures of treatment effects on the risk of congestive heart failure and the corresponding baseline hazard were estimated from the case-control data by conditional logistic regression and the weighted Breslow estimate, respectively.12,13 Cumulative doses of doxorubicin and radiation were treated both as continuous and as categorical variables in two separate analyses. The cumulative dose of doxorubicin was categorized in three levels: 0 mg/m2 to 199 mg/m2, 200 mg/m2 to 299 mg/m2, and Cumulative rates of congestive heart failure were estimated from the cohort data by the Kaplan and Meier method.14 Death and loss to follow-up were treated as censoring events. The cumulative incidence curves were compared by the (stratified) log-rank test.
Thirty-five congestive heart failure cases were observed in NWTS-1 through -4 patients by the closing date of December 1998. Twenty-three episodes of congestive heart failure occurred among the 2,483 patients in Cohort 1. Twelve of the 227 patients in Cohort 2 developed congestive heart failure. Characteristics of patients who did and did not develop congestive heart failure in the two cohorts are listed in Table 1. Although most (93%) Cohort 1 patients received doxorubicin during the first 3 months after their cancer diagnosis, a few received doxorubicin after a "late change" in their initial regimen. The maximum time elapsed between Wilms’ tumor diagnosis and initial administration of doxorubicin was 33 months. Seven of 2,483 patients started to receive doxorubicin more than 9 months from diagnosis. Two of these patients relapsed and died, but none developed congestive heart failure. For patients in Cohort 2, doxorubicin may have been administered for the first or a subsequent relapse. Thus only 68% of patients in Cohort 2 received doxorubicin within 3 months of their first relapse. For Cohort 2 patients in the case-control sample, 50 (11 cases of congestive heart failure) initially received doxorubicin for a first relapse, 10 (1 case of congestive heart failure) for a second relapse, and two (zero cases of congestive heart failure) for a third or fourth relapse. Descriptive data regarding the 35 patients who developed congestive heart failure are listed in Table 2, and the percentage of patients followed at various times after treatment with doxorubicin is shown in Fig 1.
Cohort Study The cohort analysis assessed the effects of the covariates available for all subjects, such as sex and age at diagnosis. The cumulative risk of congestive heart failure was higher for Cohort 2 than for Cohort 1 (P < .001). One wave of congestive heart failure events occurred during the first 3 years after treatment with doxorubicin. A second wave in Cohort 1 occurred 8 to 12 years after treatment ( Fig 2). Patients in NWTS-1 and -2 had a higher risk of developing congestive heart failure than did patients in NWTS-3 or -4 in both Cohort 1 ( Fig 3, P = .02) and Cohort 2 ( Fig 4, P = .02).
Females had a higher risk of developing congestive heart failure than did males in both cohorts ( Figs 5 and 6). The effect of sex after stratification by cohort was statistically significant (P = .02).
Case-Control Study RRs of congestive heart failure estimated for treatment variables in both continuous and categorical form are shown in Tables 3 and 4, respectively. The risk for girls was estimated to be approximately four times that for boys with the same level of cumulative doxorubicin exposure and radiation to the lung and the left abdomen (P < .005). The risk was estimated to increase by a factor of 3.3 for each additional 100 mg/m2 of doxorubicin among patients of the same sex who received the same level of cumulative radiation to the lungs and abdomen (P < .001). The risk of congestive heart failure was estimated to increase by a factor of 1.6 for every 10 Gy of lung irradiation and by 1.8 for every 10 Gy of left abdominal irradiation. By contrast, there was no evidence that right abdominal radiation increased the risk (P = .71).
Results for the categorical variable analysis ( Table 4) were broadly similar. They demonstrated a clear trend of increasing risk with increasing doses of doxorubicin greater than 300 mg/m2 and with increasing lung radiation. Patients who received left or whole abdomen radiation had a higher risk of congestive heart failure than did patients who received either no radiation therapy or radiation therapy only to the right abdomen (RR 4.0; P = .01). Among nine bilateral tumor cases in the case-control study, four developed congestive heart failure. Five cases did not receive abdominal radiation, including two who developed congestive heart failure.
Results of the continuous variable analysis of doxorubicin are depicted graphically in Fig 7. The smoothed distribution of cumulative dose among the controls rises slowly until just before 300 mg/m2 and then falls abruptly. It has a median of 257 mg/m2. Eight controls, three of whom were sampled more than once, had cumulative doses in the range of 419 mg/m2 to 450 mg/m2. All but one were from Cohort 2 and from NWTS-1 or NWTS-2. The distribution of doxorubicin doses for the cases is skewed slightly to the right and has a median of 302 mg/m2. Also plotted in Fig 7 (right ordinate) is the estimated linear increase in log RR estimated from the multiple regression model listed in Table 3, with 300 mg/m2 selected as "baseline" (RR = 1). The 3.6 unit increase between 150 mg/m2 and 450 mg/m2 suggests that the risk of congestive heart failure increases more than 35-fold over this range. A change point model where the slopes were allowed to change at 300 mg/m2 suggested that the RR per 100 mg/m2 was 2.3 for doses less than 300 mg/m2 and 4.1 per 100 mg/m2 for doses greater than 300 mg/m2. However, there was no evidence to suggest the slopes truly differed (P = .52).
The present study was undertaken to evaluate the frequency of and risk factors for the occurrence of congestive heart failure following treatment for Wilms’ tumor. New cases occurred as long as 19.9 years after diagnosis, indicating that patients treated for Wilms’ tumor must be followed indefinitely by a physician who is familiar with the potential complications of anthracycline therapy. Two cohorts of doxorubicin-exposed patients were identified. One cohort included those patients whose initial chemotherapy regimen for Wilms’ tumor included doxorubicin. The other cohort included those patients whose initial chemotherapy regimen did not include doxorubicin but who received doxorubicin as a component of their treatment for relapsed Wilms’ tumor. The cumulative risk of congestive heart failure was 4.4% at 20 years after doxorubicin treatment for patients in Cohort 1 and 17.4% at 20 years for patients in Cohort 2. This difference was statistically significant. Cohort 1 included patients treated on NWTS-4 that included a randomization between two different cumulative dosages of doxorubicin—150 mg/m2 and 300 mg/m2. In addition, fewer patients entered on NWTS-4 received abdominal irradiation. Those who did receive such irradiation were treated with a lower dose than was employed in NWTS-1 and NWTS-2. Most recurrences of Wilms’ tumor are in the lung.15 As a result, the patients in Cohort 2 were more likely to have received treatment to a volume that included both lungs and the heart. Female sex was associated with a four-fold elevation in risk of congestive heart failure. This finding is consistent with earlier reports that demonstrated an increased risk of impaired cardiac function in anthracycline-treated female survivors of acute lymphoblastic leukemia or osteosarcoma.6 Silber et al reported a RR of 3.2 for a cardiac test abnormality in females compared with males,7 and Krischer et al reported a RR of 1.9 for the occurrence of clinical cardiotoxicity (congestive heart failure, sudden death, or abnormal measurements of cardiac function) in anthracycline-exposed females compared with males.17 Others found no effect of sex on the risk of impaired cardiac function in anthracycline-treated Wilms’ tumor survivors,16 acute lymphoblastic leukemia survivors,18 or survivors with various diagnoses.19 Several studies did not evaluate the effect of sex on cardiac function.20-23 The present finding of an increased risk of clinically diagnosed congestive heart failure in female patients after prolonged survival raises the possibility that the subclinical abnormalities reported in prior studies may progress to a clinically significant impairment of cardiac function. Doxorubicin pharmacokinetics have been shown to vary with sex in adults, with females demonstrating significantly lower doxorubicin clearance, even when corrected for (1) surface area,24 an effect that has been related to the relatively greater percentage of body fat in postpubertal females,25 (2) the low concentration of doxorubicin that is achieved in adipose tissue,26 and (3) the reduced systemic clearance of doxorubicin in obese subjects.27 The pharmacokinetics of doxorubicin in children are similar to those in adults.28 The trend is for doxorubicin clearance to be lower in females than in males, although this difference was not statistically significant (males, 1462 mL/m2 v females, 1,209 mL/m2; Mann-Whitney U test P = .167) (W.E. Evans, personal communication, April 2000).
Cumulative doxorubicin dose was the most important risk factor for the occurrence of congestive heart failure. This finding is consistent with several earlier studies that evaluated risk factors for abnormal left ventricular function following anthracycline treatment.6,16,17,22,29 Silber et al reported that the odds ratio for having a cardiac test abnormality was 5.2 for cumulative anthracycline doses of 400 mg/m2 compared with 100 mg/m2.7 Steinherz et al reported poor cardiac functioning at late testing in 11% (nine of 79 patients) of patients treated with less than 400 mg/m2 compared with 23% (22 of 96 patients) of those treated with 400 to 599 mg/m2, 47% of those treated with 600 mg/m2 to 799 mg/m2, and 100% of seven patients treated with greater than 800 mg/m2.5 Bu’Lock et al reported a shortening fraction of less than 35% in 48% (11 of 23 patients) of patients who received Radiation therapy to a volume that included the left ventricle was a significant risk factor for congestive heart failure. This occurred both as the result of whole lung irradiation and left hemiabdomen irradiation. Previous case reports suggested that there might be a relationship between mediastinal32 or abdominal irradiation33,34 and cardiac function after treatment with anthracyclines. Bu’Lock et al reported symptomatic cardiac disease in 23% (five of 22 patients) of patients who had received cardiac irradiation, compared with 3% (six of 204 patients) among the unirradiated patients.19 Steinherz et al reported that mediastinal irradiation, as a dichotomous variable, and mediastinal radiation dose were both significant predictors in univariate analyses of late cardiac dysfunction in anthracycline treated patients. Mediastinal irradiation, as a dichotomous variable, remained significant along with cumulative anthracycline dose and duration of follow-up in a linear regression analysis.5 Sorensen et al were unable to demonstrate such a relationship in their analysis of cardiac function in anthracycline-exposed Wilms’ tumor patients,16 and Krischer et al were unable to demonstrate an effect of radiation that involved the heart on the risk of cardiotoxicity.17 Radiation therapy of children and adolescents to fields that include the heart is associated with significant late morbidity and mortality. Pericarditis is the most frequently diagnosed complication, but a recent report has recorded the frequency of coronary artery disease, cardiomyopathy, and valvular disease in survivors of childhood or adolescent Hodgkin disease irradiated at Stanford University Medical Center.35 Women treated surgically followed by local irradiation for breast cancer had an increased risk for a significant cardiac event (symptomatic congestive heart failure or acute myocardial infarction) if they were randomized to treatment with 10 rather than five cycles of cyclophosphamide and doxorubicin combination chemotherapy, a randomization giving cumulative doxorubicin doses of 450 mg/m2 compared with 225 mg/m2. Although the radiation therapy doses and volumes varied in this study, a statistically significant effect of radiation therapy on the risk of a cardiac event could not be identified in the multivariate analysis after the effects of cumulative doxorubicin dose and age at treatment were entered into the model.36
The anthracycline treatment schedule differed on NWTS-1 (pilot study) and NWTS-2 compared with NWTS-3 and NWTS-4. In the first two studies, doxorubicin was administered as a single dose of 60 mg/m2, whereas on NWTS-3 (regimen DD-RT), and the standard regimen of NWTS-4 (regimen DD), doxorubicin was administered using a schedule of 20 mg/m2/d for 3 consecutive days. The test regimen in NWTS-4 (regimen DD-4A) used a dose of 45 mg/m2 every 6 weeks for the first two doses and then a dose of 30 mg/m2 every 6 weeks to a cumulative dose of 150 mg/m2 or 300 mg/m2, depending on the randomized duration of treatment. We identified a significant difference in the rate of congestive heart failure among patients treated on NWTS-1 and NWTS-2 compared with NWTS-3 or NWTS-4, with the rate being 6.6% at 20 years after treatment for those treated in NWTS-1 or NWTS-2 compared with 1.1% at 11 years for those treated on NWTS-3 and 0.6% at 7 years for those treated on NWTS-4. Krischer et al reported that the RR of clinical cardiotoxicity was 2.81 among those patients treated with
The elapsed time from treatment with doxorubicin to the onset of congestive heart failure is variable. Lipshultz et al demonstrated that left ventricular function worsened during the first 2 years after completion of treatment with doxorubicin. Left ventricular function then improved without becoming normal 2 to 6 years after the completion of therapy. Left ventricular function then progressively deteriorated during the period 7 to 14 years after the completion of therapy.38 The present series, which includes prolonged follow-up of a large cohort of doxorubicin exposed patients, included 15 patients who developed congestive heart failure The Kaplan-Meier estimates of the cumulative percentage of patients who developed congestive heart failure are dependent on the completeness of follow-up and may be over estimated if cases of congestive heart failure are selectively reported to the NWTSG Data and Statistical Center. A previous report by Breslow and his colleagues documented the completeness of follow-up of the NWTSG cohort.45 We have identified congestive heart failure as a significant morbidity in children treated with doxorubicin and thoracic or left abdominal irradiation for Wilms’ tumor. Female patients were at greater risk for congestive heart failure. Former patients should be told of their risk for subsequent events. Rigorous evaluation of the sensitivity and specificity of noninvasive methods for the assessment of cardiac function of doxorubicin treated patients needs to be performed. Exposed patients who anticipate the initiation of a vigorous program of physical activity or who are planning to get pregnant should be closely monitored by a cardiologist. We will continue to monitor the morbidity and mortality experience of this doxorubicin exposed cohort.
Supported in part by United States Public Health Service Grant CA-42326. Principal investigators at participating institutions also receive support from the National Cancer Institute. We thank the many pathologists, surgeons, pediatricians, radiation oncologists, and other health professionals of the Pediatric Oncology Group and Children’s Cancer Group who managed these children, without whom this study would have been impossible, and Diane Piacente for preparation of the manuscript.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
300 mg/m2. Cumulative lung radiation dose also was categorized in three levels: 0 Gy, 10 Gy to 19.99 Gy, and 
100 mg/m2 of anthracycline, compared with 40% (19 of 48 patients) of patients who received 101 mg/m2 to 200 mg/m2, 46% (22 of 48 patients) of those who received 201 mg/m2 to 300 mg/m2, 73% (36 of 49 patients) of those who received 301 mg/m2 to 400 mg/m2, 83% (38 of 46 patients) of those who received 401 mg/m2 to 500 mg/m2, and 83% (10 of 12 patients) of those who received 
