Our analyses demonstrate that anthracyclines increased the risk of clinical cardiotoxicity by 5.43 fold, subclinical cardiotoxicity by 6.25 fold, any cardiotoxicity by 2.27 fold and the risk of cardiac death by 4.94 fold compared with non-anthracycline regimens. For clinical cardiotoxicity, the risk was 4.13 fold higher with bolus administration compared to continuous infusion, and was 61% lower with epirubicin compared to doxorubicin. The risk was also 22% lower with liposomal doxorubicin, which allows a more favourable tumour to normal tissue concentration ratio. Risk was also 79% lower with the use of the cardioprotective agent dexrazoxane, which is an iron chelating agent and is thought to decrease the cardiotoxic effect of doxorubicin through preventing free radical formation [79
]. These data however do not allow us to comment on the absolute risks of early or late cardiac events after anthracyclines from this heterogeneous group of patients.
Despite an extensive literature search only 55 out of the 292 papers for which full text articles were obtained were eligible for this review. This reflects the focus of most oncology research on cause specific outcomes in relation to cancer, and only acute outcomes in relation to toxicity. The majority of the 55 included papers were on women with advanced breast cancer. As many of the risk factors for breast cancer are common to cardiovascular disease, the fact that breast cancer is numerically the largest group in this review may bias the results towards overestimating the cardiac risks, unless other competing co-morbidities are fully controlled for. Many patients with breast cancer had received prior chemotherapy, and only some patients with sarcoma, lymphoma and paediatric malignancy were treatment naïve. Within the breast cancer population, some patients had cardiac risk factors, of particular concern; the impact of left sided chest wall radiotherapy could not be assessed.
The quality of the papers in terms of determining cardiac outcome was variable and confounded by sample sizes which are inadequate to accurately estimate rare outcomes such as cardiotoxicity. Further limitations included the fact that they were reported only in subsets of participants in some studies, lack of common definitions for cardiac outcomes, and lack of common monitoring either in terms of modality to assess cardiac outcome or in terms of timing and duration of monitoring. This highlights the limitations of CTC reporting from a cardiology perspective.
A previous systematic review of RCTs and cohort studies in patients aged less than 18 years at cancer diagnosis has also addressed anthracycline cardiotoxicity [13
]. Only four RCTs were identified, and the same methodological problems were encountered as in our review. Bryant and colleagues found dexrazoxane was noted to offset toxicity, but there was no benefit to longer infusion times in patients receiving moderate doses of anthracyclines.
A large observational study of cardiac complication rates of women aged 66 to 80 years old receiving adjuvant anthracyclines using the Surveillance, Epidemiology and End Results (SEER) database has been conducted [80
]. A total of 43,338 women were identified, of whom 4,712 received adjuvant anthracyclines, and 3,012 women non-anthracycline containing regimens. For women aged 66 - 70 years at diagnosis, at 10 years post treatment, 29% of women who had no chemotherapy had been diagnosed with CHF, compared with 32.5% and 38.4% for women who received non-anthracycline and anthracycline based chemotherapy, respectively. The rates were significantly higher for anthracycline regimens compared with non-anthracycline chemotherapy -adjusted hazard ratio (HR) 1.26 (95% CI: 1.12, 1.42). For women aged 71 - 80 years at diagnosis the risk of CHF was not statistically significant between the three groups, although the cumulative rates of CHF were higher than in younger women in all three groups.
The similar rates of CHF in each group may be due to selection bias in the groups treated with adjuvant chemotherapy in this older age group, or reflect a less aggressive approach in those who did receive such treatment. The type of anthracycline used was not reported, but a previous report on a sub-set of the same data suggests that doxorubicin was used almost exclusively [81
]. The results from our review suggest that these results cannot be extrapolated to regimens where epirubicin was used, or to younger women as the SEER data include a sub-set of older patients who are at higher risk solely due to their age [82
]. However, the data do potentially reflect clinical practice more closely, in contrast with outcomes for the highly selected patients generally included in clinical trials.
Recommendations are that the cumulative dose of anthracycline should not exceed 600 mg/m2 for doxorubicin and 900 mg/m2 for epirubicin. Our data indicate a lower risk with continuous infusions compared with bolus dosing, but in practice this would neither allow dose escalation nor be a practical strategy to minimize cardiotoxicity in 'at risk' groups.
Other significant predictors of anthracycline associated cardiac toxicity include: pre-existing cardiovascular disease such as coronary artery disease, hypertension, peripheral vascular disease, and emphysema, diabetes, ethnicity, age [6
]. Treatment related factors are higher cumulative doses of anthracycline, associated mediastinal radiation therapy and combination chemotherapy (trastuzumab, cyclophoshphamide, etoposide, melphalan, paclitaxel, mitoxantrone, idarubicin) [6
]. Longer duration of survival is also a risk factor for cardiac toxicity, emphasising the importance of monitoring for long term effects in the growing population of cancer survivors [84
]. This is borne out by paediatric studies indicating continuous deterioration of cardiac function for up to 15 - 30 years after treatment [4
This systemic review and previous published studies have highlighted the potential cardiac sequelae of anthracyclines. As survival and indeed cure rates have increased, increased focus on lifetime risk of cancer and its treatment with strategies to limit short- and long-term toxicity without compromising efficacy is required. This is especially important in the paediatric, adolescent and young adult population where there is a long life expectancy. This requires the clinical assessment and investigation of pre-treatment cardiac risk with monitoring and proactive treatment of the cardiac effects of cancer treatment to become an essential component, not only of clinical trials, where cardiotoxicity may be an important secondary endpoint, but also of routine practice. This will require widespread agreement on cardiac monitoring techniques, and schedules with clear and appropriate cardiac endpoints in order to advance knowledge, and provide optimal cardiology care of oncology patients. Changes are necessary in trial protocols and in clinical practice. In particular:
• The CTC require revision to align them with modern cardiology evidence and practice.
• Cardiac function should be measured, and risk factors for cardiac dysfunction addressed prior to cancer treatment with cardiac toxic medication such as anthracyclines.
• Markers of cardiac damage and repeat measurements of cardiac function should be undertaken at intervals appropriate to the regimen prescribed.
• Cardiac follow-up should be continued long enough to accurately define the risk of long-term toxicity. Primary care colleagues should be alerted to the risks of cardiotoxicity in their patients, and if identified encouraged to inform the oncologist. This should be complimented by regular audit. Only then will it be possible to accurately define the competing life-time risks of cancer and its treatment which is essential to determine the optimal regimen for an individual patient, especially when given in the adjuvant setting.
Currently, cardiac monitoring primarily comprises measurement of LVEF with imaging techniques which have inherent limitations of inter-observer and inter-institution variation and of the late manifestation of ventricular dysfunction in the development of cardiac toxicity. The role of markers of cardiac damage or wall stress, such as cardiac troponins and natriuretic peptides, in predicting late cardiac effects and guiding treatment is being actively investigated in prospective research.