Anthracycline-Induced Clinical Heart Failure in a Cohort of 607 Children: Long-Term Follow-Up Study

By L.C.M. Kremer, E.C. van Dalen, M. Offringa, J. Ottenkamp, and P.A. Vote
Purpose: To determine the early and late cumulative incidence of anthracycline-induced clinical heart failure (A-CHF) after anthracycline therapy in childhood and to identify associated risk factors. Patients and Methods: The cumulative incidence of A-CHF and the risk factors of A-CHF were assessed in a cohort of 607 children who had been treated with anthracyclines between 1976 and 1996. For 96% of the cohort, we obtained the clinical status up to at least January 1997. The mean follow-up time was 6.3 years. Results: The cumulative incidence of A-CHF was 2.8%, after a mean follow-up time of 6.3 years and a mean cumulative dose of anthracyclines of 301 mg/m2. A cumulative dose of anthracycline higher than 300 mg/m2 was associated with an increased risk of A-CHF (relative risk, 11.8; 95% condence interval, 1.6 to
59.5) compared with a cumulative dose lower than 300 mg/m2. The estimated risk of A-CHF increased with time after the start of anthracycline chemotherapy to 2% after 2 years and 5% after 15 years. Conclusion: Up to 5% of patients will develop A-CHF 15 years after treatment, and patients treated with a cumulative dose of anthracyclines higher than 300 mg/m2 are at highest risk for A-CHF. This is thus a considerable and serious problem among these young patients. The ndings reinforce the need for strategies for early detection of patients at risk for A-CHF and for the evaluation of other chemotherapeutic possibilities or cardioprotective agents in relation to the survival. J Clin Oncol 19:191-196. 2001 by American Society of Clinical Oncology.

NTHRACYCLINES HAVE gained widespread use in the treatment of childhood leukemia and solid tumors. Clinically, the most important side effect of anthracycline chemotherapy is a dose-dependent cardiotoxicity.1 Heart damage after anthracycline chemotherapy can be divided into early and late cardiotoxicity. By denition, early cardiotoxicity refers to cardiotoxicity that develops during chemotherapy or in the rst year after its completion; whereas late cardiotoxicity occurs at least 1 year after completion of therapy.2 Cardiotoxicity can become manifest in patients as subclinical heart failure and as clinical heart failure. Several studies have evaluated the incidence and risk of early clinical cardiotoxicity and late subclinical cardiotoxicity.3-15 The risk for both types of cardiotoxicity increases with a higher cumulative dose of anthracyclines, female sex, younger age at the start of chemotherapy, type of tumor, black race, presence of trisomy 21, radiation therapy involving the heart, and exposure to cyclophosphamide, ifosfamide, or amsacrine.3-15 Only a few studies have evaluated the incidence of late anthracycline-induced clinical heart failure (A-CHF) in long-term survivors.10-18 However, these studies have serious limitations in that the study populations were small, only subgroups were described, and most studies had a short follow-up period. Because children should have a long life expectancy after a successful antineoplastic treatment, it is important to evaluate the frequency and consequences of late A-CHF. In this study, we evaluated the cumulative incidence of early and late A-CHF and related risk factors in

a large cohort of children treated with anthracyclines between 1976 and 1996.
PATIENTS AND METHODS

Patients
Since 1966, all children who are treated for childhood cancer in the Emma Kinder Ziekenhuis/Academic Medical Center are registered at the Hospital Tumor Registry. This registry maintains data on diagnosis, treatment, last known medical status, and follow-up of all admitted patients and served as the basis for the selection of patients in the current study. We included only those patients who received their rst treatment with anthracyclines after 1976, because the chemotherapeutic treatment was not specied in the early years of the registration. According to the computer database of the Hospital Tumor Registry, 609 children had been treated in the Emma Kinder Ziekenhuis/ Academic Medical Center with anthracycline chemotherapy between 1976 and 1996.

Treatment and Follow-Up Data

Data of 567 of 609 children were collected directly from the medical records by one of the authors (E.C.vD.). For 40 patients whose medical

From the Departments of Pediatric Oncology, Pediatric Cardiology, and General Pediatrics, Academic Medical Center, Emma Kinder Ziekenhuis, University of Amsterdam, Amsterdam, the Netherlands. Submitted March 21, 2000;accepted August 2, 2000. Address reprint requests to L.C.M. Kremer, MD, Department of Pediatrics, Emma Kinder Ziekenhuis, Academic Medical Center, University of Amsterdam, G8-259, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; email L.C.Kremer@AMC.UVA.NL. 2001 by American Society of Clinical Oncology. 0732-183X/01/1901-191

Journal of Clinical Oncology, Vol 19, No 1 (January 1), 2001: pp 191-196

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records were missing, we obtained information by means of the registry charts kept by the Hospital Tumor Registry. No data were available for two children. Therefore, the study population consisted of 607 patients. For each patient, the following information was recorded: (1) date of birth, (2) sex, (3) type of malignant lesion and tumor status, (4) chemotherapeutic protocol, including the cumulative doses of administered anthracyclines (doxorubicin, daunorubicin, idarubicin, and/or epirubicin), cyclophosphamide, and ifosfamide, (5) date of start of anthracycline treatment, (6) concurrent radiotherapy involving the heart, including left abdominal irradiation, (7) last follow-up date, (8) date and cause of death, (9) signs and symptoms of clinical heart failure and, if that was the case, etiology, treatment, and clinical outcome. Attempts were made to establish the clinical status of patients lost to follow-up by sending a questionnaire to their general practitioners. We nally succeeded in obtaining information on the clinical status up to at least January 1997 (or date of death) for 580 patients (96% of the cohort).

KREMER ET AL

RESULTS

Patients The clinical characteristics of the study population are listed in Table 1. The mean age at the time of diagnosis was
Table 1. Clinical Characteristics of 607 Children Treated With Anthracyclines
Children With A-CHF (n 17) No. %

Characteristic

No. of Patients (N 607)

Denition of Clinical Cardiotoxicity

A case of A-CHF was dened as congestive heart failure not attributable to other known causes, such as direct medical effects of the tumor, septic shock, or renal failure. We dened congestive heart failure as the presence of the following clinical signs and symptoms: dyspnea, pulmonary edema, peripheral edema, and/or exercise intolerance that were treated with anticongestive therapy. A pediatric cardiologist (J.O.) conrmed the diagnosis in patients with cardiac events that may or may not have met this denition of clinical cardiotoxicity. The clinical outcome of A-CHF was either death, alive with anticongestive treatment, or clinical recovery without current requirement for anticongestive therapy, but anticongestive treatment previously. Depending on the time of onset, the A-CHF was classied as early A-CHF, ie, during anthracycline chemotherapy or within the rst year after the end of treatment, or as late A-CHF, ie, CHF more than 1 year after the completion of anthracycline chemotherapy.

Statistical Analysis
The main outcome event was dened as the occurrence of A-CHF. Event-free survival was dened as the time from the start of rst administration of anthracycline until the development of A-CHF, or until the latest follow-up evaluation, or until death. The risk factors for A-CHF were a high cumulative dose of anthracyclines ( 300 mg/m2), treatment with ifosfamide or with cyclophosphamide, irradiation involving the heart, female sex, and age at diagnosis younger than 4 years. The risk factors for A-CHF were rst compared with the log-rank test. The relative risk for each risk factor was estimated by the Cox regression model.19 Statistical signicance (P .05) was determined with a two-sided test. Multivariate analysis was performed with a stepwise Cox regression model. The P value of the coefcient of the risk factor had to be less than .10 for the risk factor to remain in the model. The cumulative risk of A-CHF was estimated as a function of the follow-up time from the start of anthracycline treatment and of the cumulative anthracycline dose by the Kaplan-Meier method.20 Survival curves were constructed and the condence intervals (CIs) were calculated. Analyses were performed using the statistical software SPSS for Windows 8.0 (release 1997; SPSS, Inc, Chicago, IL).

Sex Male Female Age at rst dose of anthracyclines 2 years 2-4 years 5-9 years 10-14 years 14 years Diagnosis Leukemia ALL AML Lymphoma Hodgkins disease Non-Hodgkins disease Solid tumors Osteosarcoma Ewings sarcoma Rhabdomyosarcoma Wilms tumor Hepatoblastoma Other Cumulative dose of anthracyclines 150 mg/m2 150-300 mg/m2 300-450 mg/m2 450-600 mg/m2 600 mg/m2 Unknown Ifosfamide None Any Unknown Cyclophosphamide None Any Unknown Irradiation involving the heart None Any Unknown Period of diagnosis 1976-1980 1981-1985 1986-1990 1991-1995

345 262 43 113 174 194 83

9 8 1 2 5 6 3

2.6 3.1 2.3 1.8 2.9 3.1 3.6

123 55 52 130 87 53 26 40 10 31 70 208 183 108 20 18 454 138 15 286 307 14 501 102 4 18 156 208 225

1 3 0 4 4 3 2 0 0 0 0 1 5 7 3 1 10 4 3 8 7 2 13 4 0 1 4 10 2

0.8 5.5 0 3.1 4.6 5.7 7.7 0 0 0 0 0.5 2.7 6.5 15.0 5.6 2.2 2.9 0.2 2.8 2.3 0.1 2.6 3.9 0 5.6 2.6 4.8 0.9

Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia.

EARLY AND LATE ANTHRACYCLINE CARDIOTOXICITY

Table 2.
Patient No.

193

Characteristics, Treatment, and Follow-Up of 17 Patients With A-CHF

Total Dose of Anthracycline* (mg/m2) Outcome of A-CHF

Sex

Diagnosis

Age at Diagnosis (years)

Radiation Therapy

Ifosfamide

Cyclophosphamide

Time to A-CHF

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

M F M F M F M M M F F F F M F M M

Rhabdomyosarcoma Lymphoma Lymphoma Leukemia Osteosarcoma Osteosarcoma Osteosarcoma Osteosarcoma Lymphoma Ewings sarcoma Leukemia Leukemia Lymphoma Leukemia Ewings sarcoma Ewings sarcoma Rhabdomyosarcoma

5.5 3.5 7.0 12.1 10.6 10.5 15.9 9.8 6.4 14.5 3.1 10.3 9.9 12.1 15.2 15.4 1.3

600 ? 300 300 375 225 450 450 700 360 570 520 450 810 480 480 300

N N N Y N N N N N Y Y N Y N N N N

Y ? N N Y N ? Y N Y N N N N N ? N

N ? Y N N N N N Y N Y Y Y Y N ? Y

During A During A During A During A During A During A 0.1 0.2 0.1 0.4 0.4 0.1 0.2 1.4 13.3 6.7 20.2

T T T T No T T Death No T Death T T No T No T Death No T T Death

Abbreviations: A, anthracycline; N, no; Y, yes; T, anticongestive treatment; No T, no anticongestive treatment at the time of last follow-up but anticongestive treatment previously; ?, data missing. *At time of A-CHF diagnosis. During anthracycline therapy or in years after the end of anthracycline therapy. Died from tumor progression or from medical conditions related to tumor treatment.

9.1 years (range, 0.1 to 17.9 years). The mean cumulative dose of anthracyclines was 301 mg/m2 (range, 14 to 960 mg/m2): 37 children received only daunorubicin, 352 children received only doxorubicin, 95 children received only epirubicin, and 118 children received a combination of doxorubicin, daunorubicin, and epirubicin. The exact cumulative dose of the different anthracyclines of 13 patients and the exact chemotherapeutic combinations and doses for ve patients are unknown. In addition to anthracyclines, 307 children were treated with cyclophosphamide, and 138 children were treated with ifosfamide. The mean follow-up time after the rst dose of anthracycline treatment for the whole group was 6.3 years (range, 0.01 to 21.7 years). The mean age of the patients at the end of the follow-up was 15.4 years (range, 0.3 to 37.6 years). For patients alive at the most recent follow-up date, 64.3% of the cohort, the mean follow-up period was 8.6 years (range, 0.23 to 21.7 years). For 23.4% of the patients, the follow-up was longer than 10 years, and for 7.6%, it was longer than 15 years. At last contact, 217 patients (35.7%) had died. Four patients died of A-CHF (Table 2). Incidence and Outcome of A-CHF The cumulative incidence of A-CHF at a mean follow-up time of 6.3 years was 2.8% (17 patients). The risk of developing A-CHF as a function of the follow-up time based on Kaplan-Meier estimates is shown in Fig 1. The risk

of A-CHF after 2 years was 2% (95% CI, 0.8% to 3.2%); after 5 years, it was 2.8% (95% CI, 1.3% to 4.3%); after 10 years, it was 3.3% (95% CI, 1.6% to 5.0%); and after 15 years, it was 4.8% (95% CI, 1.8% to 8.3%). Thirteen cases (2.1%) of A-CHF occurred during or within the rst year of therapy. The median time between the rst dose of anthracycline and A-CHF was 3.6 years. The characteristics of the patients with A-CHF are listed in

Fig 1. Kaplan-Meier plot of the estimated risk of A-CHF as a function of the follow-up time (in years) after the start of anthracycline therapy.

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Table 3. Cumulative Doses of Chemotherapy for Patients With and Without A-CHF
Cumulative Dose (mg/m2) Anthracyclines (n 589)* Mean Range Mean Cyclophosphamide (n 307) Range Mean Ifosfamide (n 138)

KREMER ET AL

Range

Without A-CHF With A-CHF Mean difference 95% CI P

296 461 164.2 91-237 .001

14-960 225-810

6,027 8,246 2,219 1,353 to 5,790 .22

60-21,000 1,120-18,200

28,309 36,750 8,441 17,856 to 34,740 .53

1,800-126,000 12,000-63,000

*Number of patients.

Table 2. The mean age of the patients with A-CHF at the time of anthracycline chemotherapy was 9.6 years (range, 1.3 to 15.9 years). The mean cumulative dose of anthracycline at the onset of A-CHF was 461 mg/m2 (range, 225 to 803 mg/m2). Seven children were also treated with cyclophosphamide, and four children were also treated with ifosfamide. Of these children, the differences in the chemotherapy doses between patients with and without A-CHF are listed in Table 3. Four patients (0.7% of the study group) died from A-CHF within 0 to 5.5 years after the onset of symptoms. One patient with A-CHF was still being treated with anticongestive treatment, whereas the other ve were not. Of the ve patients, one patient developed A-CHF during pregnancy. Follow-up echocardiographic studies of this last patient are not known. The left ventricular shortening fraction, measured by echocardiography, of the other four patients was 28%, 32%, 37%, and 42% at 7, 8.5, 6, and 7.5 years, respectively, after the start of A-CHF. Risk Factors for A-CHF Univariate analyses of the risk factors for the occurrence of A-CHF showed a statistically signicant increase in the risk of A-CHF associated with a cumulative dose of anthracyclines higher than 300 mg/m2. The results of univariate analysis of the different risk factors are listed in Table 4. The other possible risk factors for A-CHF (ie, treatment with ifosfamide or with cyclophosphamide, radiTable 4.
Risk Factor* No. of Patients

ation therapy involving the heart, female sex, and age at diagnosis younger than 4 years) were not associated with an increased risk. In multivariate Cox analysis, a cumulative dose of anthracyclines higher than 300 mg/m2 was the only independent risk factor. The risk of A-CHF as a function of the cumulative anthracycline dose is shown in Fig 2. The risk of A-CHF at 300 mg/m2 was 1.1% (95% CI, 0.1% to 2.5%); at 450 mg/m2, it was 4.5% (95% CI, 1.5% to 7.5%); and at 600 mg/m2, it was 17.8% (95% CI, 5.5% to 30.1%).
DISCUSSION

Our study is the rst to investigate the incidence of both early and late A-CHF in a large cohort of children treated with anthracyclines with such a long and complete followup. We estimated the cumulative incidence and risk and possible risk factors for A-CHF in a cohort patients treated with anthracycline therapy for childhood malignancy. In this study, a marked number of patients was found to have developed A-CHF at a young age. The cumulative incidence of early cardiotoxicity of 2.1% in this study is in agreement with the cumulative incidence of 1.6% mentioned before in two large cohort studies of children by von Hoff et al3 and Krischer et al.12 Two other cohort studies of more than 200 children showed cumulative incidences of 2.8% and 4.0%.4,6 The cumulative incidence of late A-CHF was 0.7% in our study with a mean follow-up

Relative Risks for A-CHF (univariate analyses)

No. With A-CHF Relative Risk* 95% CI

Female sex Age at diagnosis 2 years Dose anthracyclines 300 mg/m2 Additional treatment with Ifosfamide Cyclophosphamide Radiotherapy Total *Relative risk based on Cox model.

262 43 311 138 307 102 607

8 1 15 4 7 4 17

1.18 0.85 11.8 1.80 0.70 1.75

0.45-3.06 0.11-6.31 1.56-89.48 0.54-5.99 0.25-1.94 0.56-5.43

.74 .85 .02 .34 .49 .34

EARLY AND LATE ANTHRACYCLINE CARDIOTOXICITY

195
Only Swain et al21 mentioned that A-CHF begins at a cumulative dose of 300 mg/m2 in adults. In the present study, 12 out of 17 patients with A-CHF were treated with a cumulative dose of anthracyclines lower than 550 mg/m2. The fact that A-CHF may occur in children at doses as low as 300 mg/m2 reinforces the need to re-evaluate the safe maximum cumulative dose of 450 to 550 mg/m2 of anthracyclines in children and the desirability of treating children who will receive a cumulative dose of anthracyclines of more than 300 mg/m2 with cardioprotective agents or other treatment possibilities. In contrast with other studies, which evaluated the risk factors related to subclinical cardiotoxicity or early A-CHF, we could not identify other risk factors for the development of A-CHF.3-15 A limitation of the present study is the lack of information on the course of action when subclinical heart damage was diagnosed by echocardiography during treatment. Echocardiography has been used in our hospital since 1985. It is our policy to stop or adjust treatment with anthracyclines if there is large decrease in the left ventricular shortening fraction or a left ventricular shortening fraction 28%. It is not clear whether this policy will diminish the frequency of early and late A-CHF. Lipshultz et al22 stated that the adjustment of the dose in asymptomatic patients may potentially harm patients if the efcacy of their anticancer therapy is reduced. It is possible that we underestimate the real incidence of A-CHF. In this study, we used a very strict denition of A-CHF, ie, cardiac heart failure not attributable, as far as we know, to other known causes. Furthermore, not all the patients had had a check-up by a specialist in the hospital; for 96 patients, information was obtained from the general practitioner. The risk of A-CHF 15 years after the start of anthracycline treatment was estimated to be approximately 5% in this study. It is unclear what the frequency of late A-CHF will be later on, when aging of the heart becomes important. That the percentage of subclinical cardiac abnormalities increases with longer follow-up times suggests a further increase in the incidence of late A-CHF with time. This reinforces the need for sufciently long complete follow-up studies, strategies for early detection of patients at risk for A-CHF, and the evaluation of other chemotherapeutic possibilities or cardioprotective agents in relation to the survival.

Fig 2. Kaplan-Meier plot of the estimated risk of A-CHF as a function of the cumulative dose of anthracyclines.

time of 6.3 years and a mean cumulative dose of 300.9 mg/m2. Dearth et al13 and Krischer et al12 described cumulative incidences of late A-CHF of 0.9% and 0.1%, respectively, in a cohort of patients. However, the completeness and the length of follow-up were not mentioned. Other studies described an incidence of late A-CHF between 1.7% and 11%.10,11,14-18 A subgroup of patients was investigated in these studies, so selection bias could have caused this broad variation in frequency of A-CHF. In the present study, the rate of occurrence of A-CHF was highest in the rst 2 years, ie, 0% to 2%, and 2% to 5% in the next 12 years. It is possible that the clinical condition of patients during chemotherapy, when they often suffer from anemia, acidosis, cachexia, fever, or overhydration from intravenous uid, lowers the threshold for clinical heart failure. It is known that A-CHF is a dose-dependent phenomenon. The cumulative risk of A-CHF at 550 mg/m2 of 10% in our study is higher than the 7% found by von Hoff et al3 in a study of both children and adults. The higher susceptibility of children with regard to adults and the longer follow-up of our study can explain these differences. A cumulative dose of anthracyclines higher than 300 mg/m2 was the only signicant risk factor for A-CHF. In fact, A-CHF occurred in only one patient treated with a lower dose. The threshold of a cumulative dose of 300 mg/m2 as a risk factor for A-CHF, used in this analysis, is low in comparison with that used in other studies, which used a value of 550 mg/m2.12

REFERENCES
1. Lefrak EA, Pitha J, Rosenheim S, et al: A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 32:302-314, 1973 2. Shan K, Lincoff AM, Young JB: Anthracycline induced cardiotoxicity. Ann Intern Med 125:47-58, 1996

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3. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710717, 1979 4. Goorin AM, Borow KM, Goldman A, et al: Congestive heart failure due to adriamycin cardiotoxicity: Its natural history in children. Cancer 47:2810-2816, 1981 5. Sorensen K, Levitt G, Sebag-Monteore D, et al: Cardiac function in Wilms tumor survivors. J Clin Oncol 13:1546-1556, 1995 6. Sallan SE, Clavell LA: Cardiac effects of anthracyclines used in the treatment of childhood acute lymphoblastic leukemia: A 10-year experience. Semin Oncol 11:19-21, 1984 7. Lipshultz SE, Colan SD, Gelber RD, et al: Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 324:808-815, 1991 8. Nysom K, Holm K, Lipsitz SR, et al: Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J Clin Oncol 16:545-550, 1998 9. Silber JH, Jakacki RI, Larsen RL, et al: Increased risk of cardiac dysfunction after anthracyclines in girls. Med Pediatr Oncol 21:477-479, 1993 10. Lipshultz SE, Lipsitz SR, Mone SM, et al: Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 332:1738-1743, 1995 11. Steinherz LJ, Steinherz PG, Tan CTC, et al: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266:1672-1677, 1991 12. Krischer JP, Epstein S, Cuthbertson DD, et al: Clinical cardiotoxicity following anthracycline treatment for childhood cancer: The Pediatric Oncology Group experience. J Clin Oncol 15:1544-1552, 1997

KREMER ET AL 13. Dearth J, Osborn R, Wilson E, et al: Anthracycline-induced cardiomyopathy in children: A report of six cases. Med Pediatr Oncol 12:54-58, 1984 14. Sorensen K, Levitt G, Bull C, et al: Anthracycline dose in childhood acute lymphoblastic leukemia: Issues of early survival versus late cardiotoxicity. J Clin Oncol 15:61-68, 1997 15. BuLock FA, Mott MG, Oakhill A, et al: Left ventricular diastolic function after anthracycline chemotherapy in childhood: Relation with systolic function, symptoms, and pathophysiology. Br Heart J 73:340-350, 1995 16. Steinherz LJ, Steinherz PG, Tan C: Cardiac failure and dysrhythmias 6-19 years after anthracycline therapy: A series of 15 patients. Med Pediatr Oncol 24:352-361, 1995 17. Gilladoga AC, Manuel C, Tan CTC, et al: The cardiotoxicity of adriamycin and daunomycin in children. Cancer 37:1070-1078, 1976 18. Evans AE, Norkoll P, Evans I, et al: Late effects of treatment for Wilms tumor: A report from the national Wilms tumor study group. Cancer 67:331-336, 1991 19. Cox DR: Regression models and life-tables. J R Stat Soc 34:187-220, 1972 20. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 21. Swain SM, Whaley FS, Gerber MC, et al: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15:1318-1332, 1997 22. Lipshultz SE, Sanders SP, Goorin AM, et al: Monitoring for anthracycline cardiotoxicity. Pediatrics 93:433-437, 1994

ERRATA
In the January 1, 2001, issue of the Journal of Clinical Oncology, an article by Kremer et al, entitled AnthracyclineInduced Clinical Heart Failure in a Cohort of 607 Children: Long-Term Follow-Up Study (J Clin Oncol 19:191-196, 2001), contained an error. The legends of Fig 1 and Fig 2 on pages 193 and 195 were interchanged.

In the March 15, 2001, issue of the Journal of Clinical Oncology, an article by Pisters et al, entitled Phase I Trial of Oral Green Tea Extract in Adult Patients With Solid Tumors (J Clin Oncol 19:1830-1838, 2001), contained an error. The dose levels given in Fig 1-3 should be g/m2, not mg/m2.

In the March 15, 2001, issue, the ASCO Special Article by Bast et al, entitled 2000 Update of Recommendations for the Use of Tumor Markers in Breast and Colorectal Cancer: Clinical Practice Guidelines of the American Society of Clinical Oncology (J Clin Oncol 19:1865-1878, 2001), contained an error. The rst authors name in reference 49 on page 1876 should be Starr A instead of Alexander S.

In the May 1, 2001, issue of the Journal of Clinical Oncology, the Rapid Publication by Kirkwood et al, entitled High-Dose Interferon Alfa-2b Signicantly Prolongs Relapse-Free and Overall Survival Compared With the GM2-KLH/ QS-21 Vaccine in Patients With Resected Stage IIB-III Melanoma: Results of Intergroup Trial E1694/S9512/C509801 (J Clin Oncol 19:2370-2380, 2001), contained an error. In the Results section of the abstract, the survival hazard ratio (OS HR) for the eligible population should read 2.17, not 2.71.

In the May 15, 2001, issue of the Journal of Clinical Oncology, an article by Kemeny et al, entitled Phase I Study of Hepatic Arterial Infusion of Floxuridine and Dexamethasone With Systemic Irinotecan for Unresectable Hepatic Metastases From Colorectal Cancer (J Clin Oncol 19:2687-2695, 2001), contained an error. Some of the partial responses in Table 5 were in the wrong column. The correct Table 5 is shown below.
Table 5.
Dose Arm Irinotecan (mg/m2) FUDR (mg/kg/d) No. of Assessable Patients CR

Response of Noncryosurgery Patients

Response PR SD Baseline Increased CEA CEA 50% Decrease Normalized CEA

Noncryosurgery Phase I

MTD Totals (%)

60 80 100 100 100 125 100

0.12 0.12 0.12 0.14 0.16 0.14 0.16

3 3 6 4 7 8 7 38

0 1 0 3 0 5 2 1 0 5 1 5 0 5 28 (74)*

1 0 1 1 1 2 2 8 (21)

3 2 6 3 7 8 7 36 (95)

1 2 5 2 4 7 6 27 (75)

0 2 2 1 1 4 2 12 (33)

Abbreviations: CR, complete response; SD, stable disease. *A partial response was seen in 13 of 16 patients who had received prior irinotecan.

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