Clinical Status and Optimal Use of the Cardioprotectant, Dexrazoxane

Dr. Blum has written a comprehensive summary of the natural history, pathology, prevention, and management of anthracycline-induced cardiotoxicity. His excellent state-of-the-art review updates readers on most of the recent advances in this field.

Incidence of Anthracycline-Induced Cardiotoxicity

Although most physicians believe that anthracycline-induced cardiac damage is not a problem until a cumulative doxorubicin dose of 350 mg/m² is reached, recent information from the pediatric literature suggests that we probably should be concerned about this toxicity at much lower anthracycline doses. A study by Sorenson et al from England recently reported that children who received cumulative daunorubicin (Cerubidine) doses as low as 90 mg/m² had significant, measurable cardiac damage even 10 years after therapy.[1] This cardiac damage manifested as decreased left-ventricular fractional shortening and increased left-ventricular end-systolic stress.

Children seem to be exquisitely susceptible to anthracycline-induced cardiotoxicity. It is not unreasonable to state that cardiac damage occurs, to some extent, at all anthracycline dose levels in this patient population.

The elderly population also seems to be more vulnerable to the cardiotoxic effects of anthracyclines. Sonneveld et al conducted a prospective, controlled trial in which 100 lymphoma patients over 60 years old (age range, 60 to 86 years; median age, 70.5 years) were randomized to either CHOP (cyclophosphamide, doxorubicin HCl, Oncovin, and prednisone) or CNOP (cyclophosphamide, Novantrone, Oncovin, and prednisone) chemotherapy. Cardiac function was assessed by measuring left-ventricular ejection fraction (LVEF) after each of two cycles of treatment.[2] The median cumulative dose of doxorubicin given to these patients was 240 mg/m².

Cardiotoxicity (defined as a more than 15% decrease in LVEF) was observed in 47% of these patients. In 30% of patients, the decrease in LVEF was accompanied by clinical heart failure. This study clearly shows that standard-dose doxorubicin causes significant cardiac morbidity in older patients.

Early vs Delayed Dexrazoxane Administration

In most studies of cardioprotective agents, dexrazoxane (Zinecard) has been administered beginning with the first dose of doxorubicin. This practice was based on the premise that anthracycline-induced cardiac damage begins to occur with the first dose, and therefore, the best time to prevent cardiotoxicity would be at the inception of therapy. Because the FDA was concerned about the possibility that dexrazoxane might interfere with the antitumor activity of doxorubicin, in the United States, dexrazoxane was approved for use only after patients had already received a 300-mg/m² cumulative dose of doxorubicin. In Canada and Europe, dexrazoxane can be started at the initiation of doxorubicin-based chemotherapy; this obviates the need to administer a certain amount of doxorubicin without cardioprotection.

It appears that long-lasting, measurable cardiac damage can result from the administration of very small doses of anthracyclines. Thus, it seems reasonable to consider beginning cardioprotection early on, especially in vulnerable populations.

Lack of Long Term Epidemiologic Data

There is a lack of long-term epidemiologic follow-up of adults who have been treated with doxorubicin-containing chemotherapy. The two largest populations of such patients are: (1) women who have received FAC (fluorouracil, Adriamycin, and cyclophosphamide) chemotherapy as adjuvant treatment for breast carcinoma, over 60% to 70% of whom are expected to be alive at least 10 years after administration of chemotherapy; and (2) patients with non-Hodgkin’s lymphoma who have been treated with CHOP chemotherapy, 30% to 40% of whom would be expected to be alive at 10 years. It would be useful to conduct detailed epidemiologic studies in these populations using various cardiac assessment techniques (eg, two-dimensional echocardiograms, multiple-gated acquisition [MUGA] scans). Such studies may help us quantify the incidence of chronic cardiomyopathy in adults who have been exposed to doxorubicin.

Ongoing Clinical Trials

Clinical trials are currently being designed to study the effect of dexrazoxane in patients receiving intensive CHOP chemotherapy for aggressive lymphoma. Hopefully, these trials will confirm the cardioprotective efficacy of dexrazoxane and also will allow us to determine whether this drug interferes with the antilymphoma activity of doxorubicin. These trials, if positive, also will broaden the applicability of dexrazoxane to hematologic malignancies.

Other ongoing trials of dexrazoxane are being conducted by the Pediatric Oncology Group. One of these studies is randomizing children with Hodgkin’s lymphoma to ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine) with or without dexrazoxane. The goal of the study is to prevent both the doxorubicin-induced cardiotoxicity and the bleomycin-induced pulmonary toxicity caused by ABVD. In vitro data have suggested that dexrazoxane can minimize bleomycin-induced free radical formation,[3] and hence, may decrease the incidence of pulmonary toxicity seen with ABVD.

Conclusions

Anthracycline-induced cardiotoxicity is a significant, albeit relatively underrecognized, complication of chemotherapy. As larger numbers of individuals who have been exposed to anthracyclines stay in remission for prolonged periods, we will begin to see a higher incidence of chronic cardiac morbidity in this patient population. It is important to collect long-term epidemiologic data on both adults and children to assess the actual incidence of anthracycline-induced cardiotoxicity. Future trials also should allow us to answer more definitively the lingering question about the possible interference of dexrazoxane with the antitumor activity of anthracycline antibiotics.

References:

1. 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.

2. Sonneveld P, Hop W, Mulder AH, et al: Full-dose chemotherapy for non-Hodgkin’s lymphoma in the elderly: Dutch Hematology-Oncology in Adults Study Group. Semin Hematol 31(suppl 3): 9-12, 1994.

3. Herman EH, Hasinoff BB, Zhang J, et al: Morphologic and morphometric evaluation of the effect of ICRF-187 on bleomycin-induced pulmonary toxicity. Toxicology 98(1-3):163-175, 1995.