Cardiotoxicity from cytotoxics in the 21st century

Br J Cardiol 2009;16:60–2 Leave a comment
Click any image to enlarge

In this issue, Pfeffer et al. discuss the impact of anthracycline-related cardiotoxicity and strategies for its treatment and prevention (see pages 85–9). Anthracyclines are not the only widely used class of cytotoxics with the potential to cause cardiotoxicity, but they are the most studied and the effects are well described. The antimetabolites 5-fluorouracil (5FU) and capecitabine, an oral pro-drug of 5FU, can cause an acute and chronic cardiotoxicity1,2 while vinorelbine, a vinca alkaloid, can cause angina.3 Paclitaxel, a taxane, has been shown to augment the cardiac side effects of doxorubicin, an anthracycline.4,5 The potential for cardiotoxicity is therefore, a major consideration when determining appropriate treatment for patients.

Angina - BJC Learning programme
For healthcare professionals only

Cardiotoxicity and adjuvant anthracycline in early breast cancer

Anthracycline-based polychemotherapy regimens for early-stage breast cancer have demonstrated a superior disease-free and overall survival in comparison to non-anthracycline based regimens.6 The increasing usage and efficacy of adjuvant chemotherapy is a significant factor contributing to the fall in mortality from breast cancer.6-9 However, the rising numbers of patients treated with anthracyclines in the adjuvant setting could mean that many women have sustained subclinical cardiac damage that is not yet clinically apparent. A recent analysis has attempted to define the extent of cardiac sequelae following adjuvant treatment for breast cancer.10 This study reported, reassuringly, that over 13 years of follow-up, exposure to doxorubicin did not increase the likelihood of adverse cardiac effects (arrhythmia, congestive heart failure, angina) and while 9% of patients were recorded to have experienced arrhythmia, none had experienced heart failure or angina within a year of being assessed at eight and 13 years. However, this was a small sample with only 180 of 1,176 potential patients participating. In addition, the dataset to 13 years consisted of only 17 subjects, therefore, the frequency of cardiac damage may have been underestimated. The possible presence of subclinical cardiotoxicity has important implications for the choice of treatment in those who develop metastatic disease. The risk of re-challenge with an anthracycline or exposing the patient to another class of drugs, such as the taxanes, may result in clinical cardiotoxicity.

Trastuzumab-related cardiotoxicity

Trastuzumab is a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) that increases survival in early11,12 and metastatic13 breast cancer when given in combination with, or sequentially following, chemotherapy. Trastuzumab-associated cardiotoxicity presents a particular problem as it can occur with monotherapy, but importantly, there is an additive risk when administered with anthracyclines or in patients previously exposed to anthracycline, such as those treated adjuvantly for breast cancer. Consequently, the number of patients potentially at risk is significant. Suter et al.14 analysed cardiovascular adverse events in patients treated with trastuzumab monotherapy within the Herceptin Adjuvant (HERA) trial and found that the incidence of trastuzumab discontinuation due to cardiac disorders was 4.3% and that most cardiac dysfunction was reversible within six months of stopping treatment. In the Slamon15 study the incidence was much higher at 20% and one of the reasons may have been the difference in left ventricular ejection fraction (LVEF) entry criteria between the two trials: the HERA trial required a LVEF of at least 55% while the Slamon trial accepted a value of 50%. Given that the cardiotoxicity from trastuzumab is probably reversible, the question of how much monitoring and how to deal with decreasing function in an asymptomatic patient have become everyday clinical issues.

Cumulative cardiotoxicity is likely to be an increasingly common clinical problem due to the rise in use of anthracycline-containing adjuvant chemotherapy regimens and now long-term treatment with antibodies such as trastuzumab in adjuvant patients (up to one year at present) or indeed long-term treatment in metastatic patients (several years in some cases).

Strategies for management of cytotoxic cardiotoxicity

As Pfeffer et al. point out, the observed clinical course of cytotoxic-related cardiotoxicity can be acute, chronic or late, varying according to individual drugs. The authors discuss options for the prevention and management of acute onset adverse cardiac sequelae including dose reduction, anthracycline analogues and use of cardioprotectants such as dexrazoxane. However, there are drawbacks to these options.

In the first instance, adjustments to adjuvant chemotherapy regimens, such as switching to a taxane as in sequential combinations (ACT16 and FECT17), using a less cardiotoxic anthracycline regimen (e.g. FEC 100 x 6,18 FEC 60 x 8,19 and shorter courses of anthracycline AC x 420) may help to reduce the anthracycline risk.

Unfortunately, evidence shows that dose reduction of chemotherapy given adjuvantly decreases long-term survival and decreases response rates in metastatic disease.21-23 In reality, the clinical decision balances the likelihood of long-term morbidity and mortality from possible cardiotoxicity against potentially reduced efficacy due to attenuated dose.

The question of efficacy is also relevant when switching to an alternative drug. Several phase III clinical trials in metastatic breast cancer have shown at least equivalent efficacy when substituting doxorubicin with either a pegylated or non-pegylated liposomal analogue.24-28 The data are less convincing for the substitution of epirubicin with a liposomal analogue.27-29 There are no data to recommend this option in the adjuvant setting although, if clinically necessary, the dosing schedule applied in metastatic breast cancer can be used as a guide. In addition, although the risk of cardiac side effects is decreased, there are other acute toxicities such as hand–foot syndrome and stomatitis, which can be unpleasant in the short term.30

There is evidence to support the use of dexrazoxane to reduce the incidence of anthracycline-related cardiotoxicity31,32 but one study showed a lower response rate with dexrazoxane, although overall survival was not reduced.32 In addition, the mechanism of this effect is unknown, myelosuppression is often enhanced in patients receiving a combination of dexrazoxane and anthracycline, it is expensive and there are no current data on the interaction with trastuzumab. More recently, troponin I used as a biochemical marker in the acute setting to risk-stratify patients in conjunction with assessment of LVEF, has shown promise in the early detection of subclinical cardiac damage. Initial results suggest that persistently elevated troponin I levels have predictive value for those at risk of long-term adverse cardiac outcome secondary to anthracycline treatment.33 While biochemical markers are a useful adjunct to assessment of LVEF they are not yet sufficiently sensitive to replace echocardiography in determining cardiac risk.

Strategies for prevention of cytotoxic cardiotoxicity

Cardinale et al.34 used troponin positivity as a biomarker to initiate treatment with an angiotensin-converting enzyme (ACE) inhibitor as a cardioprotectant irrespective of LVEF with promising results showing that LVEF was preserved in the group of patients receiving enalapril. ACE inhibitors and beta blockers (e.g. carvedilol) are sometimes used for asymptomatic patients with a drop in LVEF and those who have developed symptomatic chronic cardiotoxicity, although there are inherent risks, such as renal failure, with these drugs and no good prospective data exist.35,36 A third generation beta blocker, nebivolol, was cardioprotective against anthracycline-induced cardiotoxicity using the model of isolated perfused rat heart.37 There is no clear evidence that this approach specifically for anthracycline-mediated cardiac damage is more or less effective than the treatment of other causes of heart failure. Further evaluation in randomised clinical trials is needed. Patients with a good prognosis from their cancer who develop chronic cardiac dysfunction can be considered for heart transplantation.

An alternative aspect of prevention is targeting anthracycline exposure more effectively to patients most likely to derive benefit and tolerate it well. For example, the recent meta-analysis by Gennari et al.8 found that in HER2-negative disease (n=3,818 patients), anthracyclines did not improve disease-free (hazard ratio [HR]=1.00; 95% confidence interval [CI]=0.90 to 1.11; p=0.75) or overall (HR=1.03; 95% CI=0.92 to 1.16; p=0.60) survival.

Furthermore, evidence is now available from two clinical trials suggesting that the use of an anthracycline-based regimen can be replaced in most situations by an equally effective non-anthracycline based regimen in breast cancer. The classic AC regimen (doxorubicin and cyclophosphamide) had less favourable disease-free survival in the adjuvant setting than a combination of docetaxel and cyclophosphamide (TC) although there was no significant difference in overall survival at five years.38 Robert et al.39 showed that TCH (docetaxel, carboplatin and trastuzumab) was equivalent to the anthracycline regimen AC, and neoadjuvant carboplatin and paclitaxel, with or without herceptin, also looks promising.40,41 It now appears that if we have concerns about potential cardiotoxicity then we can tailor treatment to patients needs by using TC or TCH.

Monitoring patients at risk of cytotoxic cardiotoxicity

Monitoring for cardiotoxicity in clinical practice is somewhat empirical but the guidelines followed in the HERA trial, 12-lead electrocardiogram (ECG) and assessment of LVEF by echocardiography or multi-gated acquisition (MUGA) scanning at baseline and 3, 6, 12, 18, 24, 30, 36 and 60 months of trastuzumab treatment, are now widely applied. No clear consensus yet exists on whether serial echocardiography or MUGA scans are preferable, and the duration of monitoring is also debated, although in practice it is not lifelong. As trastuzumab-related cardiotoxicity is reversible, it is likely intensive, prolonged monitoring is unnecessary for periods of greater than six months. The use of biomarkers is likely to improve monitoring and risk-stratification of patients.


A comprehensive evidence-base is vital for advising patients receiving anthracycline or trastuzumab appropriately and to manage their risks more effectively. For example, should patients exercise or not during treatment or after treatment, what should the advice be if they are found to have a reduced LVEF and how intensive can this exercise be without putting them at risk? What are the guidelines for the duration of treatment with ACE inhibitors or beta blockers? Does subclinical cardiac damage contribute to the fatigue of chemotherapy? Could reduction in levels of oestrogen and progesterone as a result of chemotherapy be contributing to observed cardiotoxicity?

A greater understanding of mechanism and optimal management (both preventive and treatment) is still required in patients with cancer receiving cardiotoxic drugs with emphasis on research investigating the use of ACE inhibitors, quality of life and health economics.

Conflict of interest

RK: none declared. MO’B has participated in clincal trials for liposomal doxorubicin (Caelynx®) and received speaker’s and advisory board honoraria from Schering Plough.


  1. Ng M, Cunningham D, Norman AR. The frequency and pattern of cardiotoxicity observed with capecitabine used in conjunction with oxaliplatin in patients treated for advanced colorectal cancer (CRC). Eur J Cancer 2005;41:1542–6.
  2. Alter P, Herzum M, Soufi M, Schaefer JR, Maisch B. Cardiotoxicity of 5-fluorouracil. Cardiovasc Hematol Agents Med Chem 2006;4:1–5.
  3. Kirschner J, Kolb M, Müller J, Jacobi I. Adverse cardiovascular effects of vinorelbine in non-small-cell bronchial carcinoma. Pneumologie 2000;54:54–7.
  4. Salvatorelli E, Menna P, Cascegna S et al. Paclitaxel and docetaxel stimulation of doxorubicinol formation in the human heart: implications for cardiotoxicity of doxorubicin-taxane chemotherapies. J Pharmacol Exp Ther 2006;318:424–33.
  5. Minotti G, Saponiero A, Licata S et al. Paclitaxel and docetaxel enhance the metabolism of doxorubicin to toxic species in human myocardium. Clin Cancer Res 2001;7:1511–15.
  6. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687–717.
  7. Clarke M, Coates AS, Darby SC et al. Early Breast Cancer Trialists’ Collaborative Group. Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: patient-level meta-analysis of randomised trials. Lancet 2008;371:29–40.
  8. Gennari A, Sormani MP, Pronzato P et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 2008;100:14–20.
  9. De Laurentiis M, Cancello G, D’Agostino D et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 2008;26:44–53.
  10. Ganz PA, Hussey MA, Moinpour CM et al. Late cardiac effects of adjuvant chemotherapy in breast cancer survivors treated on southwest oncology group protocol S8897. J Clin Oncol2008;26:1223–30.
  11. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med2005;353:1659–72.
  12. Smith I, Procter M, Gelber RD et al. HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet2007;369:29–36.
  13. Eiermann W; International Herceptin Study Group. Trastuzumab combined with chemotherapy for the treatment of HER2-positive metastatic breast cancer: pivotal trial data. Ann Oncol2001;12(suppl 1):S57–S62.
  14. Suter TM, Procter M, van Veldhuisen DJ et al. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol 2007;25:3859–65.
  15. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–92.
  16. Henderson IC, Berry DA, Demetri GD et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003;21:976–83.
  17. Roché H, Fumoleau P, Spielmann M et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol2006;24:5664–71.
  18. Coombes RC, Bliss JM, Wils J et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. The International Collaborative Cancer Group. J Clin Oncol 1996;14:35–45.
  19. Levine MN, Pritchard KI, Bramwell VH et al.; National Cancer Institute of Canada Clinical Trials Group. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol 2005;23:5166–70.
  20. 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 1990;8:1483–96.
  21. Tannock IF, Boyd NF, DeBoer G et al. A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol 1988;6:1377–87.
  22. Brufman G, Colajori E, Ghilezan N et al. Doubling epirubicin dose intensity (100 mg/m2 versus 50 mg/m2) in the FEC regimen significantly increases response rates. An international randomised phase III study in metastatic breast cancer. The Epirubicin High Dose (HEPI 010) Study Group. Ann Oncol 1997;8:155–62.
  23. Bonneterre J, Roché H, Kerbrat P et al. Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol 2005;23:2686–93.
  24. O‘Brien ME, Wigler N, Inbar M et al. CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004;15:440–9.
  25. Keller AM, Mennel RG, Georgoulias VA et al. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol 2004;22:3893–901.
  26. Chan S, Davidson N, Juozaityte E et al. Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer. Ann Oncol 2004;15:1527–34.
  27. van Dalen EC, Michiels EM, Caron HN, Kremer LC. Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev 2006;4:CD005006.
  28. Batist G, Harris L, Azarnia N, Lee LW, Daza-Ramirez P. Improved anti-tumor response rate with decreased cardiotoxicity of non-pegylated liposomal doxorubicin compared with conventional doxorubicin in first-line treatment of metastatic breast cancer in patients who had received prior adjuvant doxorubicin: results of a retrospective analysis. Anticancer Drugs 2006;17:587–95.
  29. Ewer MS, Martin FJ, Henderson C et al. Cardiac safety of liposomal anthracyclines. Semin Oncol 2004;31(suppl 13):161–81.
  30. O’Brien ME. Single-agent treatment with pegylated liposomal doxorubicin for metastatic breast cancer. Anticancer Drugs 2008;19:1–7.
  31. Venturini M, Michelotti A, Del Mastro L et al. Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 1996;14:3112–20.
  32. Swain SM, Whaley FS, Gerber MC et al. Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy.J Clin Oncol 1997;15:1333–40.
  33. 33. Adamcova M, Sterba M, Simunek T et al. Troponin as a marker of myocardiac damage in drug-induced cardiotoxicity. Expert Opin Drug Saf 2005;4:457–72.
  34. Cardinale D, Colombo A, Sandri MT et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation2006;114:2474–81.
  35. Wouters KA, Kremer LC, Miller TL, Herman EH, Lipshultz SE. Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol2005;131:561–78.
  36. Carreira RS, Monteiro P, Gon Alves LM, Providência LA. Carvedilol: just another beta-blocker or a powerful cardioprotector? Cardiovasc Hematol Disord Drug Targets 2006;6:257–66.
  37. de Nigris F, Rienzo M, Schiano C et al. Prominent cardioprotective effects of third generation beta blocker nebivolol against anthracycline-induced cardiotoxicity using the model of isolated perfused rat heart. Eur J Cancer 2008;44:334–40.
  38. Jones SE, Savin MA, Holmes FA et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 2006;24:5381–7. Erratum in: J Clin Oncol 2007;25:1819.
  39. Robert NJ, Eiermann W, Pienkowski T et al on behalf of the BCIRG 006 Investigators. BCIRG 006: docetaxel and trastuzumab-based regimens improve DFS and OS over AC-T in node positive and high risk node negative HER2 positive early breast cancer patients: quality of life (QOL) at 36 months follow-up. J Clin Oncol 2007; ASCO Annual Meeting Proceedings 2007;25:18S.
  40. Ries M, Fenton MA, Dizon DS et al.; Brown University Oncology Group. Neoadjuvant q4week carboplatin and weekly paclitaxel + trastuzumab in resectable and locally advanced breast cancer: A Brown University Oncology Group (BrUOG) study. J Clin Oncol 2005; ASCO Annual Meeting Proceedings 2005;23:16S.
  41. Sikov WM, Fenton MA, Strenger R et al.; Brown University Oncology Group. Preliminary recurrence and survival analysis of patients (pts) receiving neoadjuvant q4week carboplatin and weekly paclitaxel + weekly trastuzumab in resectable and locally advanced breast cancer: update of BrUOG BR-95. San Antonio Breast Cancer Symposium, 2007.