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© 2002 American Society for Clinical Oncology Doxorubicin Administration by Continuous Infusion Is Not Cardioprotective: The Dana-Farber 91-01 Acute Lymphoblastic Leukemia ProtocolByFrom the Divisions of Pediatric Cardiology and Pediatric Hematology/Oncology, Strong Children’s Hospital and University of Rochester Medical Center, James P. Wilmot Cancer Center, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY; Departments of Pediatric Oncology and Biostatistical Science, Dana-Farber Cancer Institute, Division of Hematology/Oncology and Department of Cardiology, Children’s Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA; Department of Biometry and Epidemiology, Medical University of South Carolina, Charleston, SC; Department of Pediatrics, McMaster University, Hamilton, Ontario, Hospital Ste Justine, Montreal, and Le Centre Hospitalier de L’Universite, Laval, Quebec, Canada; San Jorge Children’s Hospital, Puerto Rico; Maine Children’s Cancer Program, The Barbara Bush Children’s Hospital at Maine Medical Center, Portland, ME; and Department of Pediatrics, Oschsner Institutions, New Orleans, LA. Address reprint requests to Steven E. Lipshultz, MD, Division of Pediatric Cardiology, University of Rochester Medical Center, 601 Elmwood Ave, Box 631, Rochester, NY 14642; email: steve_lipshultz@ urmc.rochester.edu.
PURPOSE: Acute doxorubicin-induced cardiotoxicity can be prevented in adults by continuous infusion of the drug, but mechanisms of cardiotoxicity are different in children. We compared cardiac outcomes in children receiving bolus or continuous infusion of doxorubicin. PATIENTS AND METHODS: In a randomized study, children with high-risk acute lymphoblastic leukemia received doxorubicin 360 mg/m2 in 30-mg/m2 doses every 3 weeks either by bolus (within 1 hour, n = 57) or by continuous infusion (over 48 hours, n = 64). Echocardiograms obtained before doxorubicin and at longest follow-up times were centrally remeasured, and z scores of cardiac measurements were calculated based on a healthy population. RESULTS: The groups were similar in age, sex distribution, doxorubicin dose, and duration of follow-up. Before treatment, measures of left ventricular (LV) structure and function did not reveal dilated cardiomyopathy and were not statistically different between bolus and continuous-infusion groups. The follow-up echocardiograms demonstrated no significant difference between the two groups for any cardiac characteristic, but both groups showed significant abnormalities of LV structure and function compared with normal and with baseline. For example, the mean LV fractional shortening fell by approximately two SD in both groups between the two echocardiograms. LV contractility was depressed in both groups (for bolus patients, median z score = -0.70 SD, P = .006; for continuous-infusion patients, median z score = -0.765, P = .005). Dilated cardiomyopathy and inadequate LV hypertrophy were noted in both groups. Clinical cardiac manifestations and event-free survival did not differ. CONCLUSION: Continuous doxorubicin infusion over 48 hours for childhood leukemia did not offer a cardioprotective advantage over bolus infusion. Both regimens were associated with progressive subclinical cardiotoxicity. Other cardioprotective strategies should be explored.
MODIFYING THE DOSAGE of doxorubicin to lower the peak dose delivered may prevent doxorubicin-induced cardiomyopathy. For adults, continuous infusions are less cardiotoxic than bolus infusions, when effects are assessed during or shortly after therapy.1-5 Such continuous infusions allow the cumulative doxorubicin dose to be increased by a factor of at least two and do not attenuate the oncologic effect of the drug.1-5 However, children treated with doxorubicin can develop late cardiotoxicity by mechanisms that differ from those that lead to acute cardiotoxicity in adults.6,7 Dosage studies on adults, therefore, may not be generalizable to children. The objective of this study was to compare continuous versus bolus infusion of doxorubicin in children to determine whether either offers a clear cardioprotective advantage without loss of event-free survival.
Two hundred forty children with high-risk acute lymphoblastic leukemia (ALL) were enrolled on Dana-Farber Cancer Institute (DFCI) childhood ALL protocol 91-01 between 1991 and 1996. This protocol included more intense postremission therapy than previous protocols, dexamethasone was substituted for prednisone, and intensified asparaginase administration was prolonged from 20 to 30 weeks.8 For this study, we prospectively collected data from high-risk patients who had been randomly assigned to receive continuous (over 48 hours) or bolus (over 1 hour) infusions of doxorubicin (30 mg/m2 every 3 weeks). The patients underwent serial echocardiographic evaluations as part of an analysis of cardiac toxicity resulting from doxorubicin therapy. Patients were studied at 10 institutions: 67 at DFCI, Boston, MA; 29 at University of Rochester Medical Center and Children’s Hospital at Strong, Rochester, NY; 13 at Maine Children’s Cancer Program, Portland, ME; 13 at University of Massachusetts Medical Center, Worcester, MA; 57 at Hospital Ste Justine, Montreal, Quebec; five at Centre Hospitalier L’Universite-Laval, Sainte-Foy, Quebec; eight at Mount Sinai Hospital, New York, NY; 21 at McMaster University Medical Center, Hamilton, Ontario; 12 at Ochsner Clinic, New Orleans, LA; and 15 at San Jorge Children’s Hospital, Santurce, Puerto Rico. All studies were approved by the institutional review board at each clinical center, and informed consent was obtained from patients or their families. For this analysis, we included only patients who had at least one follow-up echocardiogram of left ventricular (LV) structure and function obtained before April 1, 1997. Patients still receiving doxorubicin therapy or whose doxorubicin dose was reduced for cardiac reasons during the treatment course and before the last follow-up echocardiogram were excluded. Eligible patients who died, relapsed, or discontinued treatment before their last follow-up echocardiogram were also excluded. No patient died of primary cardiac disease. Potentially eligible patients were identified by the central protocol coordinator between May 1995 and December 1997. Each of the consortium centers was informed beginning in August 1996 about follow-up echocardiographic data that should be submitted to the central technician for remeasurement. Sample echocardiographic strip chart recordings were provided to assist the institutions in determining what information would be most useful for the technician during remeasurement. Institutions that failed to send requested materials, as well as those that sent inadequate data, were recontacted until sufficient data were submitted, reasons for unsubmitted data were provided, or the period of data collection ended. Some centers called patients back for a follow-up echocardiogram specifically for this analysis. According to the protocol, all children underwent protocol-directed echocardiographic testing at predetermined intervals regardless of their clinical status. The two-dimensional echocardiographic and Doppler studies resulted in measurement of left ventricular (LV) dimensions, thickness, fractional shortening (FS), and calculation of LV mass from the M-mode measurements by the method of Devereux et al.6,7 At DFCI, patients had stress-velocity analysis of LV contractility,6,7 measurement of afterload as meridional end-systolic LV wall stress, and measurement of peak systolic wall stress. Heart rate and blood pressures were measured at the time of echocardiography. To ensure uniformity of echocardiographic measurements, all echocardiograms were remeasured at a central location by one technician, and a random sample of 10% was spot-checked by one echocardiographer (S.D.C.) for quality assurance. Both the technician and echocardiographer were unaware of the treatment status of the patients during remeasurement. Discrepant measurements of tracings were redone or discarded from the data set, depending on the quality of the tracing. Z scores of LV measurements were based on measurements collected from a healthy population.6,7 A z score of 0 is at the healthy population mean, whereas a z score of 2 represents two SDs above the normal mean.
Statistical Methods Only 45 of the 64 subjects who received bolus doxorubicin and 44 of the 57 who received continuous infusions were assessed at baseline. We selected the posttreatment measurements of patients who had pretreatment measurements and found that the median z scores of this group were similar to those of the entire group. Thus, we consider the subjects who did have pretreatment measurements to be a random sample of all subjects, and we expect no bias from using their data to estimate predoxorubicin echocardiographic parameters. The similarity also suggested that the pretreatment and posttreatment differences from our entire patient data set are an unbiased estimate of the true differences in the population. With approximately 60 patients in each treatment group, for the main variables LV FS, end-diastolic dimension, end-systolic dimension, wall thickness, and mass, this study had 80% power to detect a 0.5 SD difference between post median z scores using a Wilcoxon rank-sum test at a 5% level of significance. For the other variables in which there were approximately 30 patients per treatment group, this study had 80% power to detect a one SD difference between post median z scores in the two treatment arms using a Wilcoxon rank-sum test at a 5% level of significance. Finally, when testing for equal pre-post differences between the two treatment groups, with approximately 35 patients per treatment arm, this study had 80% power to detect a one SD difference between median prepost differences across the two treatment groups using a Wilcoxon rank-sum test at a 5% level of significance. We think that anything less than a one SD difference (and particularly 0.5 SD difference for the main comparisons) is not clinically important, so that our study has sufficient power to find clinically meaningful differences. For example, a 0.5 SD difference in LV FS z score represents only approximately a 1.3 percentage point change in the raw FS measurement.
Study Population By December 1996, information on 240 patients with high-risk ALL enrolled onto DFCI protocol 91-01 had been submitted to the data coordinating center. Of those patients, five were not included in the analysis because of relapse before the latest postdoxorubicin follow-up echocardiogram. Six patients were not included because of noncardiac death before the latest follow-up echocardiogram. Forty-six patients at one center received dose reductions before the last follow-up echocardiogram and were not included in the analysis; the dose reduction was ordered for 36 patients because of a low neutrophil count, for eight patients because of noncardiac treatment sequelae, and for only two patients because of cardiac sequelae. Five patients were still receiving doxorubicin treatment at the time of data collection and therefore could not be included. One patient could not be included in the analysis because of premature discontinuation of doxorubicin treatment. Of the remaining 177 high-risk patients, echocardiographic data for 32 patients were not submitted for central remeasurement because either the patients did not receive a follow-up echocardiogram or the requested data were unavailable for remeasurement. Therefore, 145 patients were identified as eligible for this study. The echocardiographic data for 24 of these patients were of too low quality to be centrally remeasured and analyzed. The remaining 121 (83%) of the 145 eligible patients had a postdoxorubicin echocardiographic evaluation 0 to 4.7 years from ALL diagnosis (median of 1.5 years) that could be adequately remeasured centrally and were included as the study sample. The 24 eligible patients with inadequate echocardiographic data did not differ in baseline characteristics from the rest of the study sample. No patient in this study had clinically evident cardiac disease before, during, or after chemotherapy. Of the 121 evaluated patients, 64 had received continuous infusion and 57 had received bolus infusion.
Patient Characteristics
Echocardiography Before Doxorubicin Echocardiography was performed a median of 2.1 days before treatment in the bolus group and 2.8 days before treatment in the continuous-infusion group (P = .32). Table 2 shows that there were no significant differences between the groups at baseline. Both groups had abnormalities of LV structure and function, specifically increased FS and mass compared with healthy external controls. We have consistently found this in our prior studies in newly diagnosed children6,7 and speculate that it relates to an enhanced adrenergic state, increased preload, and tachycardia. We have also reported that this difference persists in long-term survivors of childhood ALL who received standard-risk, low cumulative dose doxorubicin therapy.9
Echocardiography After Doxorubicin After doxorubicin treatment, there were still no differences between the two groups (Table 3). This was true for the entire group of patients, who were tested for the five standard echocardiographic measurements, as well as for the subgroup of patients treated at DFCI, where additional echocardiographic characteristics were measured. Both the bolus and the continuous-infusion patients showed significant abnormalities of LV structure and function compared with healthy subjects.
Supporting the concept that dilated cardiomyopathy early after doxorubicin therapy is a common doxorubicin effect,6,7 it is not surprising that depressed LV function was seen in both groups of patients on the study. The median LV FS fell significantly (P < .001) by approximately two SD in both groups (Table 4). For a patient at the median age of 5.3 years who undergoes an average follow-up of 18 months, a two-SD fall would represent a change in the percent FS value of approximately -5.5%. Left ventricular contractility, a sensitive load-independent measure of the health of cardiomyocytes, was significantly depressed in both groups (Table 3). The median LV systolic dimension z score increased significantly in both groups (Table 4), and the left ventricle was significantly dilated in systole in both groups (Table 3).
Another late cardiac effect we found in children treated with doxorubicin was inadequate LV hypertrophy.6,7 Both groups in our study experienced decreases in median LV wall thickness of approximately 0.3 SD during the study period (Table 4); wall thickness was significantly below normal in both groups (Table 3). Similarly, the median LV mass z score fell significantly (P < .001) by approximately 0.7 SD in bolus patients and 0.5 SD in continuous-infusion patients over the study period (Table 4) and was significantly below normal in both groups (Table 3). Left ventricular peak systolic wall stress, a mediator of LV hypertrophy that is elevated when hypertrophy is inadequate,10 was significantly elevated in both groups (Table 3).
Treatment Effects
Nonechocardiographic Comparisons
At the doses evaluated, 48-hour continuous doxorubicin infusion for childhood ALL offered no advantage over bolus infusion in terms of avoiding dilated cardiomyopathy or inadequate LV hypertrophy 1.5 years after ALL diagnosis. Both continuous and bolus infusions were associated with progressive subclinical cardiotoxicity. This was true even though our protocol used lower dose rates and lower cumulative doses than some adult protocols.1-5 Because continuous infusion did not offer cardioprotection, it should not be continued in this population if the reason for its use is cardioprotection. Prior studies examining the cardioprotective effects of continuous doxorubicin were limited to assessment during therapy and did not report data on cardiac status after therapy was completed.1-5,11-19 Some prior studies reported only clinically apparent cardiotoxicity and did not include subclinical markers of LV structure and function.1-5,11-19 However, these markers are important because hearts with asymptomatic LV dysfunction are at risk for progressive functional deterioration.6,7 We have previously reported that a subgroup of doxorubicin-treated DFCI 91-01 ALL patients (whether treated with bolus or continuous infusion) had elevated serum cardiac troponin T, suggesting active cardiomyocyte injury.20 In addition, in vitro studies have shown that the survival of cells treated with doxorubicin depends on the duration of exposure as well as the peak drug concentration.21,22 These facts, in combination with the findings of this study, suggest the possibility that in the continuous-infusion regimen, the benefit accrued by the lower peak dose is offset by damage caused by the more prolonged exposure. In other words, the entire area under the curve may be important to late toxicity, not just the height of the peak serum level. In addition to the standard echocardiographic measurements of left ventricular dimensions and wall thickness and the standard function measurement of percent FS, we obtained indices that provide sensitive measures of afterload and contractility. Afterload was assessed as the end-systolic wall stress, and contractility was assessed as the heart rate and afterload-adjusted velocity of fiber shortening.6,7 These indices have been described in detail in other publications6,7 and have proved valuable in the assessment of doxorubicin cardiomyopathy.6,7 This additional information allows one to ascertain whether the observed changes in percent FS are secondary to intrinsic contractile dysfunction or to altered ventricular loading conditions. Our prior data in patients with doxorubicin cardiomyopathy6,7 indicate that contractile dysfunction and afterload excess may well represent fundamentally different forms of injury. It is entirely possible that interventions aimed at cardioprotection, such as continuous-infusion regimens, could have differential effects on these two forms of injury, a difference that would be obscured if only FS were measured. In fact, posttreatment afterload and contractility were indistinguishable in the two groups (Table 3), supporting the interpretation that this mode of administration had no measurable impact on either the magnitude or type of cardiac injury. Although not formally evaluated in this study, continuous infusion seemed to be associated with more hospitalizations, costs, and complications such as mucositis and thromboembolic events. The effects of increased hospitalization on the patient’s quality of life and psychologic well-being are important to consider. Our study had limitations. Whether differences will emerge with longer follow-up remains unknown. However, both groups showed dilated cardiomyopathy and inadequate LV hypertrophy at intermediate follow-up. We have found that LV abnormalities rarely resolve beyond 2 years after therapy,6,7 suggesting that resolution is unlikely for our study patients. We also do not know if the frequency of progressive dysfunction will vary between the two groups. Finally, it is not clear whether our results can be generalized to adults treated for other malignancies or to adults treated with higher doxorubicin dose rates, higher cumulative doxorubicin doses, or longer infusion durations. In summary, 48-hour continuous infusion of doxorubicin was not cardioprotective for children with ALL. Other cardioprotective strategies should be explored.
Supported in part by grant nos. CA 68484, CA 55576, and CA 06516 from the National Institutes of Health, Bethesda, MD.
1. Legha SS, Benjamin RS, Mackay B, et al: Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 96: 133-139, 1982 2. Weiss AJ, Metter GE, Fletcher WS, et al: Studies on Adriamycin using a weekly regimen demonstrating its clinical effectiveness and lack of cardiac toxicity. Cancer Treat Rep 60: 813-822, 1976[Medline] 3. Chlebowski RT, Paroly WS, Pugh RP, et al: Adriamycin given as a weekly schedule without a loading course: Clinically effective with reduced incidence of cardiotoxicity. Cancer Treat Rep 64: 47-51, 1980[Medline] 4. Hortobagyi GN, Frye D, Budzar AU, et al: Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 63: 37-45, 1989[CrossRef][Medline] 5. Shapira J, Gotfried M, Lishner M, et al: Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen: A prospective randomized evaluation. Cancer 65: 870-873, 1990[CrossRef][Medline] 6. 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[Abstract]
7.
Lipshultz SE, Lipsitz S, Goorin AM, 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
8.
Silverman LB, Gelber RD, Kimball Dalton V, et al: Improved outcome for children with acute lymphoblastic leukemia: Results of Dana-Farber Consortium Protocol 91-01. Blood 97: 1211-1218, 2001 9. Nysom K, Holm K, Lipsitz SR, et al: The relation between cumulative anthracycline dose and late cardiotoxicity in survivors of childhood leukemia. J Clin Oncol 16: 545-550, 1998[Abstract] 10. Lipshultz SE, Orav EJ, Sanders SP, et al: Abnormalities of cardiac structure and function in HIV-infected children treated with zidovudine. N Engl J Med 327: 1260-1265, 1992[Abstract] 11. Ewer MS, Jaffe N, Ried H, et al: Doxorubicin cardiotoxicity in children: Comparison of a consecutive divided daily dose administration schedule with a single dose (rapid) infusion administration. Med Pediatr Oncol 31: 512-515, 1998[CrossRef][Medline]
12.
Zalupski M, Metch B, Balcerzak S, et al: Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: A Southwestern Oncology Group study. J Natl Cancer Inst 83: 926-932, 1991 13. Torti FM, Bristow MR, Howes AE, et al: Reduced cardiotoxicity of doxorubicin delivered on a weekly schedule: Assessment by endomyocardial biopsy. Ann Intern Med 99: 745-749, 1983 14. Valdivieso M, Burgess MA, Ewer MS, et al: Increased therapeutic index of weekly doxorubicin in the therapy of non-small-cell lung cancer: A prospective, randomized study. J Clin Oncol 2: 207-214, 1984[Abstract] 15. Legha SS, Benjamin RS, Mackey B, et al: Adriamycin therapy by continuous intravenous infusion in patients with metastatic breast cancer. Cancer 49: 1762-1766, 1982[CrossRef][Medline] 16. Casper ES, Gaynor JJ, Hajdu SI, et al: A prospective randomized trial of adjuvant chemotherapy with bolus versus continuous infusion of doxorubicin in patients with high-grade extremity soft tissue sarcoma and an analysis of prognostic factors. Cancer 68: 1221-1229, 1991[CrossRef][Medline] 17. Steinherz PG, Redner A, Steinherz L, et al: Development of a new intensive therapy for acute lymphoblastic leukemia in children at increased risk of early relapse. Cancer 72: 3120-3130, 1993[CrossRef][Medline] 18. Bielack SS, Ertmann R, Winkler K, et al: Doxorubicin: Effect of different schedules on toxicity and anti-tumor efficacy. Eur J Cancer Clin Oncol 25: 8733-8882, 1989 19. Bielack SS, Fuchs N, Bieling P, et al: Effect of doxorubicin (DOX) schedule on tumor response and survival in osteosarcoma (OS): Results of sequential trials Coss 86 A-C. SIOP XXVI abstracts. Med Pediatr Oncol 23: 176, 1994 (abstr)
20.
Lipshultz SE, Rifai N, Sallan SE, et al: Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 96: 2641-2648, 1997 21. Eichholtz-Wirth H: Dependence of the cytostatic effect of Adriamycin on drug concentration and exposure time in vivo. Br J Cancer 41: 886-891, 1980[Medline]
22.
Haskell CM, Sullivan A: Comparative survival in tissue culture of normal and neoplastic human cells exposed to Adriamycin. Cancer Res 34: 2991-2994, 1974. Submitted April 3, 2001; accepted December 4, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
