Doxorubicin Cardiotoxicity: Growing Importance
Authors: Bülent Orhan, Charles L. Shapiro, Edith A. Perez
Journal: Journal of Clinical Oncology (1999)

Article Tools Correspondence Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1999.17.7.2293c Journal of Clinical Oncology - published online before print September 21, 2016 Doxorubicin Cardiotoxicity: Growing Importance Bülent OrhanxBülent OrhanSearch for articles by this author Charles L. ShapiroxCharles L. ShapiroSearch for articles by this author , x Search for articles by this author , x Search for articles by this author Edith A. PerezxEdith A. PerezSearch for articles by this author , , Show More Uludag University School of Medicine, Bursa, TurkeyThe Ohio State University, Columbus, OHClinical Investigation and Breast Cancer Program, Breast Committee, North Central Cancer Treatment Group, Mayo Clinic Jacksonville, Jacksonville, FL https://doi.org/10.1200/JCO.1999.17.7.2293c First Page Full Text PDF Figures and Tables © 1999 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical Oncology 071999 071999Reply 1: Twenty years ago, Von Hoff et al1 defined the risk factors for doxorubicin-induced congestive heart failure (CHF). In addition to the total cumulative dose of doxorubicin, older age and the schedule of administration were independent risk factors for doxorubicin-induced CHF. Higher bolus doses of doxorubicin were associated with an increased risk of CHF as opposed to prolonged infusions for 48 to 96 hours or weekly administration of lower doses.1,2 Dr Orhan suggests that clinicians revisit this data in view of the potential increased cardiotoxicity associated with adjuvant doxorubicin and breast radiation, and newer combinations of doxorubicin with paclitaxel and Herceptin that are also associated with cardiotoxicity.1,3,4 It is well established that continuous infusion of doxorubicin results in less cardiac toxicity. So why has this data not been incorporated into the design of adjuvant breast cancer trials over the past 20 years? I can think of several reasons. First, the incidence of doxorubicin-induced CHF in the adjuvant setting is low. The results in our study showed that total cumulative adjuvant doxorubicin doses of 450 mg/m2 administered by bolus infusion in combination with higher dose-volumes of breast (cardiac) radiation were associated with an increased risk of cardiac events.5 Fortunately, the higher doxorubicin doses and the higher radiation doses and field arrangements the breast cancer patients received in our study are not routinely used today. An equally if not more important result in our study was that the 225-mg/m2 total cumulative dose of adjuvant doxorubicin administered by bolus infusion with any dose-volume of breast (cardiac) radiation was not associated with any detectable increase in the risk of cardiac events. These results are consistent with what has been observed in large adjuvant trials in which the incidence of doxorubicin-related CHF was 1% or less when the total cumulative doxorubicin dose is limited to less than 300 mg/m2.6,7 In addition, the standard total cumulative doses of adjuvant doxorubicin is likely to remain at 240 mg/m2 because there is no evidence that total cumulative doses of 300 mg/m2 or 360 mg/m2 provide an incremental therapeutic benefit.8 Second, the emphasis has been, and continues to be, on the development of effective and safe outpatient adjuvant regimens. Orhan states that use of an ambulatory pump makes the delivery of infusional doxorubicin a practical option. However, dislodgment of the needle and skin extravastion may limit this approach. Third, the pharmaceutical industry has developed drugs to reduce doxorubicin-related cardiac toxicity, including dexrazoxane and liposomal-encapsulated doxorubicin. These can be given in the outpatient setting without altering the schedule of doxorubicin administration. As Orhan points out, new combinations of doxorubicin with paclitaxel or Herceptin have the potential to increase the cardiac risk, especially when these are administered concurrently. The short- and long-term risks of cardiac toxicity need to be further defined in ongoing studies, especially in view of the fact that we are diagnosing an increasing proportion of breast cancer patients with favorable prognoses and at the same time have lowered the threshold for administering doxorubicin-containing adjuvant chemotherapy. Reply 2: I agree with Orhan regarding the importance of these problems and that improvement methods to understand and amelioratethem are important for patient care. The risks associated with increasing cumulative dose and radiation to the heart are well established; the risks associated with the concurrent use of taxanes and now trastuzumab continue to be defined. Several important issues, including the potential interference with antitumor activity when “rescue” agents are used (including dexrazoxane or amifostine) and whether amifostine leads to clinically significant amelioration of cardiac toxicity, remain to be defined. Evaluation of cost effectiveness and, most importantly, the therapeutic ratio when using rescue agents must be performed before the widespread use of these combination therapies. With regard to the scheduling of doxorubicin, the studies documenting the potential improvement in the therapeutic ratio with continuous infusions or weekly therapies will ideally be validated with modern cardiac monitoring techniques, as the data available come from studies published more than 10 to 15 years ago. 1. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91::710,1979-717, Crossref, Medline, Google Scholar2. Shan K, Lincoff AM, Young JB: Anthracycline-induced cardiotoxicity. Ann Intern Med 125::47,1996-58, Crossref, Medline, Google Scholar3. Gianni L, Dombernowsky P, Sledge G, et al: Cardiac function following combination therapy with Taxol® (T) and doxorubicin (A) for advanced breast cancer (ABC). Proc Am Soc Clin Oncol 17:115a, 1998 (abstr 444) Google Scholar4. Hudis C, Seidman A, Paton V, et al: Characterization of cardiac dysfunction observed in the Herceptin™ (trastuzumab) clinical trials. Breast Cancer Res Treat 50::232,1998, Google Scholar5. Shapiro CL, Hardenbergh PH, Gelman R, et al: Cardiac effect of adjuvant doxorubicin and radiation therapy in breast cancer patients. J Clin Oncol 16::3493,1998-3501, Link, Google Scholar6. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8::1483,1990-1496, Link, Google Scholar7. Buzdar AU, Marcus C, Smith TL, et al: Early and delayed clinical cardiotoxicity of doxorubicin. Cancer 55::2761,1985-2765, Crossref, Medline, Google Scholar8. Henderson IC, Berry D, Demetri G, et al: Improved disease-free (dfs) and overall survival (OS) from the addition of sequential paclitaxel (T) but from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (PTS) with node-positive primary breast cancer (BC). Proc Am Soc Clin Oncol 17::390,1998, (abstr) Google Scholar