Initial Use in Patients With Metastatic Breast Cancer 1999 Recommendation: It is recommended that dexrazoxane not routinely be used for patients with metastatic breast cancer receiving initial doxorubicin-based chemotherapy.
Delayed Use in Patients With Metastatic Breast Cancer Who Have Received >300 mg/m2 of Doxorubicin 1999 Recommendation: It is suggested that the use of dexrazoxane be considered for patients with metastatic breast cancer who have received more than 300 mg/m2 of doxorubicin in the metastatic setting and who may benefit from continued doxorubicin-containing therapy.
Management of patients who received more than 300 mg/m2 in the adjuvant setting and are now initiating doxorubicin-based chemotherapy in the metastatic setting should be individualized, with consideration given to the potential for dexrazoxane to decrease response rates, and to the risk of cardiac toxicity, and because these patients were not included in the clinical trials of dexrazoxane.
2002 Update: A meta-analysis5 of seven randomized, controlled trials, two of which were placebo-controlled, addressed the question of the efficacy of dexrazoxane in terms of decreasing the risk of clinical cardiotoxicity. Pooled results from the six studies that had been reported fully in the published literature indicated that the dexrazoxane use was associated with decreased risk of clinical cardiotoxicity (odds ratio, 0.21; 95% confidence interval, 0.09 to 0.5; P = .00037). One study6 assessed the costs of using dexrazoxane in combination with doxorubicin-based chemotherapy for patients with metastatic breast cancer. Using data from two previously reported,4,7 randomized, placebo-controlled trials to build a Markov model, the authors estimated the cost-per-cardiac event prevented by using dexrazoxane. The model demonstrated that use of dexrazoxane costs approximately $5,600.00 per cardiac event prevented.
2002 Recommendation: No change.
3. Use in Patients Receiving Adjuvant Chemotherapy for Breast Cancer 1999 Recommendation: The use of dexrazoxane in the adjuvant setting is not suggested outside of a clinical trial.
2002 Update: There are no reported randomized, controlled studies of dexrazoxane in the adjuvant chemotherapy setting for breast cancer. In the absence of high-quality, randomized, controlled trial data demonstrating efficacy of dexrazoxane and confirming lack of tumor protection, the use of dexrazoxane in the adjuvant setting should only be used in the clinical trial setting.
2002 Recommendation: No change.
1. Use in Adult Patients With Other Malignancies 1999 Recommendation: The use of dexrazoxane can be considered in adult patients who have received more than 300 mg/m2 of doxorubicin-based therapy. Caution should be exercised in the use of dexrazoxane in settings in which doxorubicin-based therapy has been shown to improve survival.
2002 Update: There are no new peer-reviewed, published, randomized, controlled trials addressing the efficacy of dexrazoxane for preventing cardiac toxicity in adult patients receiving doxorubicin-based therapy for malignancies other than breast cancer. A randomized trial of 155 patients (105 assessable) with small-cell lung cancer treated with cyclophosphamide, doxorubicin, and vincristine with or without dexrazoxane was reported in abstract and showed that the total number of cardiotoxicity events (both clinical congestive heart failure and subclinical decrease in left ventricular ejection fraction [LVEF]) was lower among the patients treated with dexrazoxane compared with those who received cyclophosphamide, doxorubicin, and vincristine alone (12% v 29%, P = .029).8 These data are similar to results of the two small randomized trials9,10 including sarcoma patients that were considered in the formulation of the 1999 guideline.
2002 Recommendation: No change.
2. Use in Pediatric Malignancies 1999 Recommendation: There is insufficient evidence to make a recommendation for the use of dexrazoxane in the treatment of pediatric malignancies.
2002 Update: Although several small studies (some with placebo control, others with historical controls) suggest that the use of dexrazoxane may decrease the risk of cardiac toxicity associated with anthracycline treatment in pediatric malignancies, data remain insufficient to make a specific recommendation regarding current use. The Pediatric Oncology Group is conducting an important study (POG-9426) of doxorubicin, bleomycin, vincristine, and etoposide with or without dexrazoxane, followed by low-dose involved-field radiotherapy, for children with newly diagnosed Hodgkins disease.
Other Anthracycline Doses and Schedules
1. Use in Patients Receiving Other Anthracyclines or Other Anthracycline Dose Schedules 1999 Recommendation: The current data regarding the use of dexrazoxane in patients receiving epirubicin-based therapy are insufficient to make a recommendation.
2002 Update: Since the publication of the 1999 guideline, epirubicin has received FDA approval for use in the treatment of breast cancer. Previous studies had demonstrated that the risk of cardiac toxicity from epirubicin may be lower than the risk with doxorubicin.11 However, at cumulative doses exceeding 1,000 mg/m2, cardiac toxicity may be observed in 16% to 35% of patients.12,13 A randomized trial of three different dosing regimens for treatment of metastatic breast cancer (fluorouracil 500 mg/m2 + epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 given every 3 weeks for 11 cycles [FEC 75] v fluorouracil 500 mg/m2 + epirubicin 100 mg/m2 + cyclophosphamide 500 mg/m2 given every 3 weeks for four cycles [FEC 100] followed by four additional cycles with the epirubicin reduced to 50 mg/m2 v FEC 100 for four cycles, with restart of treatment at time of progression of disease) showed that response duration and time to progression were superior with the longer-duration epirubicin-based regimens but that there was no difference in overall survival among the three treatment approaches in 417 chemotherapy-naive patients.14 Twelve patients had a decrease in LVEF: 11 in the two long-duration FEC arms, and one in the shorter-duration FEC arm. The median cumulative dose of epirubicin received by the 11 patients with a decline in LVEF was 600 mg/m2 (range, 451 to 817 mg/m2).
In an additional study,15 105 patients with metastatic breast cancer were treated with epirubicin 90 mg/m2 + paclitaxel 135 to 225 mg/m2 or epirubicin 90 mg/m2 + paclitaxel 175 mg/m2 + gemcitabine 1,000 mg/m2 on days 1 and 4. Nine patients developed congestive heart failure: four after cumulative epirubicin dose 1,080 mg/m2, two after 720 mg/m2, one after 630 mg/m2, and two after 540 mg/m2. All episodes of clinical congestive heart failure occurred 3 to 6 months after completion of epirubicin-based therapy. The cumulative risk of congestive heart failure was estimated to be 7.7% at a cumulative dose of 720 mg/m2 and 48.7% at a cumulative dose of 1,080 mg/m2. In a study reporting the results of the subset of patients with metastatic breast cancer who had not received prior anthracycline therapy and were treated with epirubicin 120 mg/m2, with or without dexrazoxane, as first-line therapy (note that these data do not represent a separate clinical trial; they are a subset analysis of the patients who received high-dose epirubicin in the previously reported trial), cardiotoxicity (defined as clinical congestive heart failure or ejection fraction decline to < 45% or > 20% from baseline) occurred in 19% after a median cumulative epirubicin dose of 720 mg/m2 (range, 120 to 1,440 mg/m2). Eighteen of the cardiac events occurred among the women treated with epirubicin alone, and six events occurred among those treated with epirubicin plus dexrazoxane.16
There are no new published randomized, controlled trials assessing the efficacy of dexrazoxane in decreasing the risk of epirubicin-associated cardiotoxicity. The results of the two previously published randomized controlled trials were detailed in the 1999 guideline. In the larger of these, 162 patients with advanced breast cancer were treated with cyclophosphamide, epirubicin 60 mg/m2, and fluorouracil (CEF) with or without dexrazoxane, or if the patient had never received anthracycline-based therapy, she received epirubicin 120 mg/m2 with or without dexrazoxane. Subclinical cardiotoxicity was less frequent among patients who received dexrazoxane (23% no dexrazoxane v 7.3% dexrazoxane). The cumulative probability of clinical or laboratory evidence of cardiotoxicity was significantly lower with dexrazoxane (odds ratio, 0.29; 95% confidence interval, 0.09 to 0.78). Response rates were similar (46.2% v 47.6%). All cardiotoxicity events were among those patients who received epirubicin 120 mg/m2.17 Although these studies support the conclusion that dexrazoxane decreases cardiotoxicity among patients treated with epirubicin, definitive trials large enough to confirm that treatment efficacy is equivalent have not been reported. There are no randomized trials comparing initial dexrazoxane use versus delayed use with epirubicin, although it is notable that no cardiotoxicity events occurred among the patients who had received prior anthracycline therapy and then were treated with cyclophosphamide, epirubicin 60 mg/m2, and fluorouracil.
There are no new randomized, controlled trials addressing the ability of dexrazoxane to decrease cardiotoxicity of other potentially cardiotoxic agents, such as mitoxantrone, daunorubicin, and liposomal doxorubicin.
2002 Recommendation: On the basis of the available data and extrapolations from the experience with doxorubicin plus dexrazoxane, the use of dexrazoxane may be considered for patients responding to anthracycline-based chemotherapy for advanced breast cancer and for whom continued epirubicin therapy is clinically indicated. Data for using dexrazoxane with epirubicin for treatment of other cancers are limited. Data are insufficient to make a recommendation regarding the use of dexrazoxane with other potentially cardiotoxic agents.
2. Use in Patients Receiving High-Dose Anthracycline Therapy 1999 Recommendation: There is insufficient evidence on which to base a recommendation for the use of dexrazoxane in patients receiving high-dose anthracycline therapy.
2002 Update: There are no new randomized, controlled trials addressing the efficacy of dexrazoxane in decreasing the risk of cardiotoxicity associated with high-dose anthracycline therapy. In the previously detailed trial,17 67 patients received epirubicin 120 mg/m2, and 68 received epirubicin plus dexrazoxane. All cardiotoxicity events occurred among the group of patients who received high-dose epirubicin at 120 mg/m2, with 18 events among those treated with epirubicin along and six events among those treated with epirubicin plus dexrazoxane. In this small subgroup of patients without prior anthracycline exposure who received high-dose epirubicin, dexrazoxane decreased the risk of cardiotoxicity. While response rates were similar, the study was underpowered to detect a moderate difference in response rates. Similarly in the randomized, controlled trial of epirubicin 160 mg/m2 with or without dexrazoxane for patients with metastatic breast cancer or soft tissue sarcoma, dexrazoxane was used with initial therapy, and dexrazoxane decreased the risk of cardiotoxicity.10
2002 Recommendation: Since data for superior outcomes with high-dose as compared with standard-dose epirubicin treatment for metastatic breast cancer are lacking, and since there are no new data from randomized trials confirming that efficacy of high-dose epirubicin is preserved when given with dexrazoxane, the panel considered the current data for high-dose epirubicin plus dexrazoxane insufficient to make a recommendation.
Patients With Cardiac Risks
1. Use in Patients With Cardiac Risk Factors 1999 Recommendation: There is insufficient evidence on which to base a recommendation for the use of dexrazoxane in patients with cardiac risk factors or underlying cardiac disease.
2002 Update: The role of pre-existing cardiac risk factors and the frequency of congestive heart failure among 105 patients with metastatic breast cancer receiving epirubicin/paclitaxel-based chemotherapy was investigated in a prospective study.15 In this study, age over 50 years, a history of prior chest wall radiotherapy, hypertension, and diabetes were considered cardiac risk factors. The cumulative probability of developing congestive heart failure was similar among patients with and patients without cardiac risk factors, up to a cumulative epirubicin dose of 990 mg/m2 (10% and 12%, respectively). Although no significant difference was found in the incidence of congestive heart failure between patients with and patients without cardiac risk factors, after adjusting for cumulative epirubicin dose, the study had limited power to detect such a difference because of the small number of events.
2002 Recommendation: No change.
1. Termination of Anthracycline Therapy for Patients Receiving Dexrazoxane 1999 Recommendation: Patients receiving dexrazoxane should continue to undergo cardiac monitoring. After cumulative doxorubicin doses of 400 mg/m2, cardiac monitoring should be frequent. The panel suggests repeating the monitoring study after 500 mg/m2 and subsequently after every 50 mg/m2 of doxorubicin. The panel suggests that the termination of dexrazoxane/doxorubicin therapy be strongly considered in patients who develop a decline in LVEF to below institutional normal limits or who develop clinical congestive heart failure.
2002 Recommendation: No change.
2. Dose of Dexrazoxane 1999 Recommendation: It is suggested that patients who are being treated with dexrazoxane receive dexrazoxane at a ratio of 10:1 with the doxorubicin dose, given by slow IV push or short IV infusion, 15 to 30 minutes before doxorubicin administration.
2002 Update: The randomized, controlled trials evaluating the cardioprotective effect of dexrazoxane used a dexrazoxane to doxorubicin ratio of 10:1, whereas the ratio of dexrazoxane to epirubicin ranged from 10:117 to 6.25:1.10 In a phase I trial,18 the maximum-tolerated doses of dexrazoxane and epirubicin were 1,200 mg/m2 and 135 mg/m2, respectively. Administration of dexrazoxane doses of 900 mg/m2 and 1,200 mg/m2 increased the clearance of epirubicin and decreased the area under the curve. The study was not designed to determine the optimal dexrazoxane to epirubicin ratio for cardioprotection, but it raises the possibility of a pharmacologic interaction between these agents.
2002 Recommendation: It is suggested that patients who are being treated with dexrazoxane receive dexrazoxane at a ratio of 10:1 with the doxorubicin dose, given by slow IV push or short IV infusion, 15 to 30 minutes before doxorubicin or epirubicin administration. A ratio of 10:1 with the epirubicin dose may be reasonable. However, it should be noted that the optimal dose ratio has not been determined.