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Journal of Clinical Oncology, Vol 24, No 6 (February 20), 2006: pp. 925-928 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.5956 Anthracyclines Cause Endothelial Injury in Pediatric Cancer Patients: A Pilot StudyFrom the Department of Pediatrics, Lucile Salter Packard Children's Hospital, Stanford University, Stanford, CA Address reprint requests to David Rosenthal, MD, Department of Pediatric Cardiology, Stanford University, 750 Welch Rd, #305, Stanford, CA 94304; e-mail: david.rosenthal{at}stanford.edu
PURPOSE: The vascular endothelium plays a central role in the regulation of arterial vasomotor tone, releasing nitric oxide for vasodilation. Endothelial-dependent vasodilation can be assessed in vivo, using high resolution ultrasound to measure changes in diameter of the brachial artery. Animal studies have demonstrated that anthracyclines can damage the endothelium and impair the vasodilatory response of arteries; however, there are no comparable data in humans. This is a pilot study assessing endothelial toxicity from anthracyclines in pediatric cancer patients. PATIENTS AND METHODS: Fourteen control patients and 14 cancer patients (4 to 21 years) were studied. Cancer patients had completed chemotherapy containing no less than 300 mg/m2 of anthracyclines 2 to 60 months before study. Brachial artery diameters were measured at rest and 1 minute after blood pressure cuff occlusion. Brachial artery reactivity (BAR) was calculated as percent change between baseline and after cuff deflation measurements. Results were compared using unpaired, two-tailed t-test. RESULTS: Baseline characteristics, including age, percentage of females, blood pressure, and resting vessel diameters were similar between the two groups. BAR in the controls averaged 6.7% with a standard deviation (SD) of 3.3%, while BAR in patients receiving anthracyclines averaged 3.8% with an SD of 3.4%, demonstrating a significant decrease (P < .05) in vasomotor reactivity in the treated group. CONCLUSION: These results suggest that anthracyclines cause impaired endothelial function, an important and newly recognized toxicity. Since endothelial dysfunction is an early event in atherogenesis, there may be important clinical implications from these findings. Further study is required to confirm these preliminary results in a larger cohort.
The vascular endothelium secretes factors that regulate arterial vasomotor tone, platelet aggregation, and leukocyte interactions, which are crucial for proper arterial function. One important role of the endothelium is to synthesize nitric oxide from L-arginine resulting in vasodilation. Endothelial dysfunction, in which vasodilatory function is diminished, has been implicated as an early event in atherosclerosis and other cardiovascular disease.1,2 Brachial artery reactivity (BAR), or flow-mediated vasodilation, is a noninvasive test of endothelial function, in which blood flow to the brachial artery is occluded and then released to stimulate the endothelial-dependent vasodilatory response. Flow-mediated dilation has been used to demonstrate impaired endothelial function in patients with coarctation repair,3 active or passive smoke exposure,4,5 coronary artery disease,6 and hypercholesterolemia.7 Doxorubicin and daunorubicin are anthracycline antibiotics that are active against many important tumors and are used to treat a variety of cancers, including Hodgkin's lymphoma, myeloma, sarcomas, and breast cancer. Repetitive or long-term administration of anthracyclines is limited in part because of the adverse side effect of cardiotoxicity. There is a risk of both early and late cardiomyopathy after anthracycline therapy.8-10 Recent investigations in organ culture and in rabbit models have shown that doxorubicin may also have injurious effects on the vascular endothelium, inducing apoptosis of endothelial cells and leading to endothelial dysfunction.11-13 However, the effect of anthracyclines on endothelial function in humans has not been investigated. In this study, BAR in patients who have completed cancer chemotherapy with doxorubicin or daunorubicin was compared with normal controls to determine whether exposure to anthracyclines is associated with endothelial dysfunction.
Patients Fourteen anthracycline-treated patients (nine male, five female) were enrolled on this study. Age ranged from 7 to 21 years with median age 15.5 years. The characteristics of the patients are presented in Table 1. Study patients had cancer diagnoses of T-cell acute lymphocytic leukemia, Ewing sarcoma, osteosarcoma, primitive neuroectodermal tumor, acute myelogenous leukemia, abdominal sarcoma, or lymphoma. Patients were otherwise in good health with no other major medical illnesses or conditions known to influence BAR, including previous cardiovascular surgery, diabetes, hypertension, or smoking exposure. Cardiovascular status, as assessed by echocardiogram within 12 months of study, showed mean fractional shortening of 32% with a standard deviation (SD) of 4%.
Patients had completed cancer chemotherapy containing no less than 300 mg/m2 of doxorubicin or its equivalent, daunorubicin (mean, 350 mg/m2; SD, 31.0 mg/m2), a value chosen as a threshold for common chemotherapy protocol design because of an increased incidence and severity of late cardiotoxicity at cumulative doses greater than 300 mg/m2.14,15 The mean time between the last anthracycline dose and the date of study was 19.8 months with an SD of 18.7 months. The cancer diagnoses and cumulative doses of the specific anthracycline are presented in Table 2. Additional chemotherapeutic agents administered to the patients as part of their primary therapy ranged from antimetabolites, alkylating agents, and plant alkaloids to more targeted drugs such as asparaginase, imatinib, megestrol, tretinoin, and arsenic trioxide. None of these drugs have been shown to influence BAR. Seven patients received radiation therapy in addition to chemotherapeutics. The specific sites of radiation therapy are presented in Table 2. There was one patient in whom the radiation field included the brachial artery during total body radiation for a bone marrow transplant.
The control group consisted of 14 patients with age range 4 to 20 years (median age 9.5 years; P = not significant [NS] as compared with study subjects). There were an equal percentage of females (36%) in the control and study patient groups. No attempts to match patient controls to study population on the basis of race were made, as there have been no previous studies showing differences in vascular reactivity between races except between blacks and whites.16 No African American patients were recruited in this study. Baseline characteristics of the patient controls are presented in Table 1. All patient controls were in good overall health and free of major medical illnesses and denied any history of hypertension, diabetes, heart surgery, smoking exposure, or other conditions known to influence BAR. A subset of the patient controls has been previously reported.17 Informed consent was obtained from all patients, and the study protocol design was approved by the Human Subjects Committee for Medical Research at Stanford University.
Data Acquisition by Two-Dimensional Ultrasonography Off-line measurement of brachial artery diameter was performed with the reviewer blinded to the identity of the patient and the stage of the experiment. A single observer (C.C.), with experience in BAR methods, made all measurements. Vessel diameters were measured from anterior to posterior interfaces between the media and adventitia at the onset of the electrocardiographic R wave, as previously described.7 Three cardiac cycles were measured and averaged at baseline as well as at 1 minute after cuff deflation. BAR was calculated as percent change between baseline and 1 minute after cuff deflation measurements.
Statistical Analysis
Baseline characteristics of the patients and patient controls groups are presented in Table 1. The two groups had similar heights and weights. Vessel diameters at baseline were not different between patient controls (mean, 0.32 cm; SD, 0.07 cm) and anthracycline-treated patients (mean, 0.34 cm; SD, 0.04 cm; P = NS). Pressures used for occlusion averaged a mean of 143.1 mmHg with an SD of 15.9 mmHg in patient controls and a mean of 135.5 mmHg with an SD of 5.7 mmHg in study patients (P = NS). BAR was expressed as percent change from baseline. Control patients had an average BAR of 6.7% with an SD of 3.3%. In the anthracycline-treated patients, average BAR was only 3.8% with an SD of 3.4%. This difference was statistically significant (P = .03; Fig 1). No relationship between the time elapsed since treatment with anthracyclines and BAR was found (P = NS; r2 = 0.10). These data are depicted in Figure 2.
Repetitive or long-term administration of anthracyclines in patients has long been known to cause cardiac muscle injury, which limits the potential application of the anthracyclines to treat various cancers.8-10 Because of the cardiotoxicity, long-term follow-up of patients exposed to anthracyclines has been recommended.19 However, it has recently become evident that anthracyclines may also be injurious to the vascular endothelium, causing endothelial dysfunction. A marked decrease in endothelial-dependent relaxation after treatment with doxorubicin for 5 days has been shown in organ culture.11 Similar results have been demonstrated in vivo with impaired endothelial-dependent vasodilatory response to acetylcholine or adenosine in a doxorubicin-induced cardiomyopathy rabbit model.13 The data in this study in humans show that BAR, an established measure of endothelial vasodilatory function,17,18 is decreased in patients who have received at least 300 mg/m2 of anthracyclines as compared with patient controls, even at a mean duration of 19.8 months with an SD of 18.7 months after completion of therapy. These findings provide evidence that anthracyclines cause important vascular injury, which is reflected by endothelial dysfunction. This represents an important, newly recognized toxicity of the anthracyclines in humans. The relationship between endothelial dysfunction and the presence of coronary atherosclerotic lesions has been well-studied.20-23 Impaired endothelial-dependent vasodilation has also been observed in patients with risk factors for the development of atherosclerosis without clinically evident disease.24 Although superficial systemic arteries were assessed in our study, vasodilator changes in the brachial artery correlate well with coronary endothelial function.25 Systemic endothelial dysfunction is also closely related to the extent of coronary artery disease evident in coronary arteriography.26 Our results show that endothelial dysfunction caused by anthracycline administration is sustained for months to years, suggesting that it may be clinically relevant and play an important role in the progression of coronary disease. While the exact mechanism by which anthracyclines cause endothelial dysfunction is still unknown, it has been shown that doxorubicin causes apoptosis of vascular endothelial cells both in vitro and in vivo.11,12 This apoptosis damages the vessels, causing excoriation, thrombosis, and denudation of the endothelium in rabbit arteries.12,27 Increased apoptosis has also been associated with reduced endothelial cell density and decreased vasodilator responses to acetylcholine in old monkey arteries with no evidence of atherosclerosis.28 Thus, there appears to be a relationship between apoptosis and endothelial dysfunction in some models of vessel injury. This mechanism may be applicable to the anthracyclines as well, although, our study does not address that question. Our data in humans support and suggest that anthracyclines cause impairment of endothelial-dependent arterial vasodilation. The magnitude of decrease in BAR is similar to what has been observed in other studies of endothelial injury.3-6 One potential limitation of the study is that the influence on endothelial function of other chemotherapeutic agents used in conjunction with anthracyclines is unknown. Radiation therapy could also possibly have an effect, as it has been demonstrated in breast cancer patients to attenuate endothelial function in the axillary artery directly in the field of external beam radiation.29 The influence of radiation therapy is unlikely to affect the results of our study, however, since radiation was employed at sites distant from the artery where endothelial function was measured. Although further studies in a larger cohort that corroborate these results are required, our data have potential implications for long-term follow-up of patients exposed to anthracyclines, as well as for future protocol design.
The authors indicated no potential conflicts of interest.
Presented at the International Society of Paediatric Oncology 37th Congress, Vancouver, Canada, September 21-24, 2005 and the Heart Failure Society of America 9th Annual Scientific Meeting, Boca Raton, FL, September 18-21, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Ross R: The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature 362:801-809, 1993[CrossRef][Medline] 2. Ross R: Atherosclerosis: An inflammatory disease. N Engl J Med 340:115-126, 1999 3. Gardiner HM, Celermajer DS, Sorensen KE, et al: Arterial reactivity is significantly impaired in normotensive young adults after successful repair of aortic coarctation in childhood. Circulation 89:1745-1750, 1994 4. Kool MJF, Hoeks APG, Struijker Boudeir HAJ, et al: Short- and long-term effects of smoking on arterial wall properties in habitual smokers. J Am Coll Cardiol 22:1881-1886, 1993[Abstract] 5. Celermajer DS, Adams MR, Clarkson P, et al: Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N Engl J Med 334:150-154, 1996 6. Lieberman EH, Gerhard MD, Uehata A, et al: Flow-induced vasodilation of the human brachial artery is impaired in patients < 40 years of age with coronary artery disease. Am J Cardiol 78:1210-1214, 1996[CrossRef][Medline] 7. Celermajer DS, Sorensen KE, Gooch VM, et al: Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340:1111-1115, 1992[CrossRef][Medline] 8. Bristow MR, Thompson PD, Martin RP, et al: Early anthracycline cardiotoxicity. Am J Med 65:823-832, 1978[CrossRef][Medline] 9. 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] 10. Bristow MR, Billingham ME, Mason JW, et al: Clinical spectrum of anthracycline cardiotoxicity. Cancer Treat Rep 62:873-879, 1978[Medline] 11. Murata T, Yamawaki H, Yoshimoto R, et al: Chronic effect of doxorubicin on vascular endothelium assessed by organ culture study. Life Sci 69:2685-2695, 2001[CrossRef][Medline] 12. Wu S, Ko Y, Teng M, et al: Adriamycin-induced cardiomyocyte and endothelial cell apoptosis: In vitro and in vivo studies. J Mol Cell Cardiol 34:1595-1607, 2002[CrossRef][Medline] 13. Kaye DM, Jennings G, Angus JA: Evidence for impaired endothelium dependent vasodilation in experimental left ventricular dysfunction. Clin Exp Pharmacol Physiol 21:701-719, 1994[Medline] 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. 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[Abstract] 16. Perregaux D, Chaudhuri A, Rao S, et al: Brachial vascular reactivity in blacks. Hypertension 36:866-871, 2000 17. Rosenthal DN, Chin C: Brachial artery reactivity: A modified technique with applicability to children. J Am Soc Echocardiogr 12:850-852, 1999[Medline] 18. Sorensen KE, Celermajer DS, Spiegelhalter DJ, et al: Non-invasive measurement of human endothelium-dependent arterial responses: Accuracy and reproducibility. Br Heart J 74:247-253, 1995 19. The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. http://www.survivorshipguidelines.org 20. Cox DA, Vita JA, Treasure CB, et al: Atherosclerosis impairs flow-mediated dilation of coronary arteries in humans. Circulation 80:458-465, 1989 21. Zeiher AM, Drexler H, Wollschlager H, et al: Modulation of coronary vasomotor tone in humans: Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 83:391-401, 1991 22. Ludmer Pl, Selwyn AP, Shook TL, et al: Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 315:1046-1051, 1986[Abstract] 23. Fish RD, Navel EG, Selwyn AP, et al: Responses of coronary arteries of cardiac transplant patients to acetylcholine. J Clin Invest 81:21-31, 1988[Medline] 24. Vita JA, Treasure CB, Nabel EG, et al: Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation 81:491-497, 1990 25. Anderson TJ, Uehata A, Gerhard MD, et al: Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 26:1235-1241, 1999 26. Neunteufl T, Katzenschlager R, Hassan A, et al: Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis 129:111-118, 1997[CrossRef][Medline] 27. Durand E, Scoazec A, Lafont A, et al: In vivo induction of endothelial apoptosis leads to vessel thrombosis and endothelial denudation. Circulation 109:2503-2506, 2004 28. Asai K, Kudej RK, Shen Y, et al: Peripheral vascular endothelial dysfunction and apoptosis in old monkeys. Arterioscler Thromb Vasc Biol 20:1493-1499, 2000 29. Beckman JA, Thakore A, Kalinowski B, et al: Radiation therapy impairs endothelium-dependent vasodilation in humans. J Am Coll Cardiol 37:761-765, 2001 Submitted August 29, 2005; accepted November 14, 2005.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
