Department of Medical Oncology
Breast Diseases Centre
Anthracyclines are among the most effective drugs in the treatment of cancers, but their use is limited by their cardiotoxicity. This toxicity is cumulative and dose-dependent. Measurements of left ventricular ejection fraction (LVEF) and endomyocardial biopsies have revealed that subclinical cardiac abnormalities are evident from low doses of anthracyclines.(1)
The cardiac damage is irreversible and can result in congestive heart failure. Cardioprotective agents have been developed to prevent or reduce this toxicity.
Dexrazoxane, the most studied agent, exerts its cardioprotective effect through the chelation of iron, preventing the formation of anthracycline-iron complexes and the production of free radicals that lead to oxidative damage to cardiac tissue. The mode of action of dexrazoxane is not tumour-specific and cardioâ€‘protection has been shown in different tumour types, including children’s carcinomas.
A Cochrane review of cardioprotective interventions for cancer patients receiving anthracyclines was published in 2007.(2) Data were collected from five randomised trials published between 1992 and 1998, with a total of 975 patients.
Meta-analysis showed a benefit in favour of dexrazoxane use, with 10 cases of clinical heart ï¿½failure among 472 patients randomised to dexrazoxane and 59 among 503 patients randomised to the control group (RRâ€‰=â€‰0.18, 95% CI: 0.10-0.35, pâ€‰<â€‰0.00001). If subclinical heart failure was associated with clinical heart failure, the meta-analyses also showed a benefit in favour of dexrazoxane use (RRâ€‰=â€‰0.28, 95% CI: 0.18-0.42, pâ€‰<â€‰0.00001). No heterogeneity was detected among the studies.
The response rates in these studies were analysed and the meta-analyses showed a nonâ€‘significant lower response rate (RRâ€‰=â€‰0.88, 95% CI: 0.77-1.01, pâ€‰=â€‰0.06) among the patients treated with dexrazoxane. The methods used for evaluating the response rates are likely to have a large observer variation and response rate is not always correlated with survival.
In terms of progression-free survival, no difference was observed (HRâ€‰=â€‰1.13, 95% CI: 0.95-1.35), neither was it in terms of overall survival (HRâ€‰=â€‰1.07, 95% CI: 0.89-1.28).
Adverse effects were not pooled since none of the randomised clinical trials used the same definitions. However, the analysis performed concluded that there was no difference between the treated patients and the control arm.
The authors concluded that their meta-analysis clearly showed the efficacy of dexrazoxane in preventing heart damage in patients treated with anthracyclines and that, if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane.
We participated in a multicentre phase III study of the cardioprotective effect of dexrazoxane in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy.(3) A total of 164 patients were randomised to be treated with or without dexrazoxane. Compared with those receiving anthracycline alone, patients treated with dexrazoxane experienced significantly fewer cardiac events (39% versus 13%, pâ€‰<â€‰0.001) and a lower and less severe incidence of congestive heart failure (11% versus 1%, pâ€‰<â€‰0.005). Patients in the dexrazoxane group had a significantly longer ï¿½cardiac event-free survival time (median, not reached for dexr-zoxane, range 0.8-28+ months, versus 7.1 months, range 1.3-13.4+ months, for control, pâ€‰=â€‰0.004). Tumour response rate was unaffected by dexrazoxane treatment, with an overall response rate of 35% (95% CI: 25-46%) for the dexrazoxane group and 35% (95% CI: 25-47%) for the control group. There was also no statistically significant difference in progression-free survival or overall survival. The frequency of adverse events was similar in the two groups, with the possible exception of anaemia, which appeared to be more frequent in the dexrazoxane group and asthenia and mucosal inflammation in the control group. Neutropenia was the most common grade 3-4 toxicity and occurred in one-third of patients.
This study confirms the cardioprotective effect of dexrazoxane in a group of patients with existing subclinical myocardial damage following prior anthracycline exposure, resulting in a roughly threefold decline in the risk of developing a cardiac event, while the risk of developing heart failure fell by nearly 90%. This benefit is comparable to that described in the meta-analysis of studies where dexrazoxane was given from the first dose of anthracycline.
Other trials have been conducted with other molecules: N-actylcysteine, phenetylamines, coenzyme Q10 and a combination of vitamin E, vitamin C and N-acetylcysteine.(4-8) The methodoâ€‘logical quality of these studies was poor, so it is impossible to make firm conclusions about the efficacy of these cardioprotective interventions.
In conclusion, dexrazoxane is cardioprotective not only when given from the first dose of anthracycline but also in patients with metastatic disease who were at high risk of cardiotoxicity due to previous anthracycline treatment. Dexrazoxane can make optimal anthracycline therapy possible by facilitating completion of the full treatment schedule and retreatment with anthracyclines among patients who relapse. It could allow the use of higher doses of anthracyclines, which may boost survival in some cancers. Today many treatments combine anthracyclines and potentially other cardiotoxic drugs such as paclitaxel or herceptin.(9) Dexrazoxane could boost these treatments’ risk-to-benefit ratio.
- Ewer MS, Ali MK, Mackay B, et al. A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving adriamycin. J Clin Oncol 1984;2:112-7.
- Van Dalen EC, Caron HN, Dickinson HO, Kremer LCM. Cardioprotective interventions for cancer patients receiving anthracyclines (review). Cochrane Database Syst Rev 2007:1-24.
- Marty M, Espiï¿½ M, Llombart A, Monnier A, Rapoport BL, Stahalova V. Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol 2006;17:614-22.
- Kraft J, Grille W, Appelt M, et al. Effects of verapamil on anthracycline-induced cardiomyopathy: preliminary results of a prospective multicenter trial. Haematol Blood Transfus 1990;33:566-70.
- Milei J, Marantz A, Ale J, Vazquez A, Buceta JE. Prevention of adriamycin-induced cardiotoxicity by prenylamine: a pilot double blind study. Cancer Drug Deliv 1987;4:129-36.
- Myers C, Bonow R, Palmeri S, et al. A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin Oncol 1983;10:53-5.
- Wagdi P, Rouvinez G, Fluri M, et al. [Cardioprotection in chemo- and radiotherapy for malignant diseases: an echocardiographic pilot study]. Schweiz Rundsch Med Prax 1995;84:1220-3.
- Iarussi D, Auricchio U, Agretto A, et al. Protective effect of coenzyme Q10 on anthracyclines cardiotoxicity: control study in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma. Mol Aspects Med 1994;15 Suppl:s207-12.
- Gianni L, Capri G, Munzone E, Straneo M. Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose finding and sequence finding study. J Clin Oncol 1995;13:2688-99.