From: The prevention, detection and management of cancer treatment-induced cardiotoxicity: a meta-review
Author (Year) | PICO | Characteristics of included studies | Intervention details | Summary of findings | Meta-analysis | AMSTAR score |
---|---|---|---|---|---|---|
 |  |  | Detection |  |  |  |
Bryant et al. (2007) [36] | P: Children receiving anthracyclines | • One controlled trial and 6 cohort studies | • cTnT | • C-TnT can be used to assess cardioprotection using dexrazoxane | n | 7 |
I: Cardiac markers | • Published from 1983 to 2005 | • echocardiography | • ANP and BNP are elevated in children who received anthracyclines | |||
C: Healthy control group | • Length of follow-up in the studies was not reported | • ANP, BNP | • NT-pro-BNP levels higher in children receiving anthracyclines and had cardiac dysfunction compared to those without | |||
O: Cardiac damagePublish | • Serum lipid peroxide | |||||
• Serum carnitine | ||||||
• NT-pro-BNP | ||||||
Prevention of anthracycline-induced cardiotoxicity | ||||||
Van Dalen et al. (2010) [30] | P: Cancer patients | • 8 controlled trials | • Doxorubicin vs epirubicin | • No difference in rate of clinical heart failure between epirubicin and doxorubicin (RR = 0.36; 95 % CI = 0.12–1.11) | y | 11 |
I: Anthracycline derivative | • Published from 1984 to 2004 | • Doxorubicin vs liposomal-encapsulated doxorubicin | • Lower rate of clinical heart failure (RR = 0.20, 95 % CI 0.05 to 0.75) and subclinical heart failure (RR = 0.38, 95 % CI 0.24 to 0.59) associated with liposomal-encapsulated doxorubicin compared with doxorubicin. | |||
C: Another anthracycline with the same infusion duration and peak dose. Other chemotherapy and radiotherapy involving the heart region must have been the same as the intervention group. | • Median length of follow-up ranged from 21 to 41 months | • Epirubicin vs liposomal-encapsulated doxorubicin | • No significant difference in the occurrence of clinical and subclinical heart failure between epirubicin and liposomal-encapsulated doxorubicin (RR = 1.13, 95 % CI 0.46 to 2.77, p = 0.80). | |||
O: Anthracycline-induced heart failure, subclinical cardiac dysfunction, abnormalities in cardiac function, tumor response, patient survival, other toxicities, quality of life. | ||||||
Van Dalen et al. (2009) [31] | P: Cancer patients who received anthracycline chemotherapy | • 11 controlled trials | • Infusion duration | • In meta-analysis of 5 studies with 557 patients, a lower rate of clinical heart failure was observed with an infusion duration of 6 h or longer as compared to a shorter infusion duration (RR = 0.27; 95 % CI = 0.09 to 0.81) | y | 11 |
I: Dosage schedule (different peak dose or infusion duration) | • Published from 1989–2008 | • Peak doses (maximal dose received in one week) | • No significant difference in the occurrence of heart failure for different peak doses of anthracyline chemotherapy | |||
C: Same anthracycline derivative with the same dose. Other chemotherapy and radiotherapy involving the heart region must have been the same as the intervention group. | • Length of follow-up ranged from 7 days to median of 9 years. | |||||
O: heart failure, subclinical cardiac dysfunction, abnormalities in cardiac function, tumor response, patient survival, other toxicities, quality of life. | ||||||
Van Dalen et al. (2011) [29] | P: Cancer patients | • 18 controlled trials | • N-acetylcysteine | Only dexrazoxane showed a statistically significant cardioprotective effect (Heart failure RR = 0.29; 95 % CI = 0.20–0.41) | y | 11 |
I: Anthracycline with a cardioprotective agent | • 1983–2009 | • Phenethylamines | ||||
C: Anthracycline with or without a placebo | • Length of follow-up was not available for most of the included studies | • Coenzyme Q10 | ||||
O: Anthracycline-induced heart failure, subclinical cardiac dysfunction, abnormalities in cardiac function, tumor response, patient survival, other toxicities, quality of life. | • In those that reported length of follow-up, it ranged from 6 months up to 5.2 years. | • Combination of vitamin E, vitamin C and Nacetylcysteine | ||||
• Dexrazoxane | ||||||
• Amifostine | ||||||
• Carvedilol | ||||||
• L-carnitine | ||||||
Itchaki et al. 2013 [33] | P: advanced follicular lymphoma | • 8 RCT conducted between 1974 and 2011. | • ACR regardless of additional agents, with or without radiotherapy. | • No advantage to ACR in overall survival (HR = 0.99; 95 % CI = 0.77–1.29) | y | 11 |
I: anthacyclines (ACR) | • Length of follow-up ranged from 3 to 5 years in most trials. | • Non-ACR, as a single agent or multiple agents, regardless of dose. | • ACR not significantly better than non-ACR in complete response (RR 1.05;95 % CI 0.94–1.18) | |||
C: non ACR regardless of dose | • ACR superior to non-ACR in disease control (HR = 0.65; 95 %CI = 0.52–0.81) | |||||
O: overall survival, Progression free survival, Complete response, overall response rate, remission duration, relapse, disease control, Quality of life, adverse events. | Increased risk for cardiotoxicity associated with ACR (RR = 4.55; 95 % CI = 0.92–22.49) | |||||
Smith et al. (2010) [32] | P: child and adult patients with Breast or ovarian cancer, sarcoma, non-Hodgkin's or Hodgkin's lymphoma, myeloma | • 55 RCT |  | Clinical cardiotoxicity (congestive heart failure) | y | 9 |
I: anthracycline agent in liposomal or non-liposomal formulation or another non-anthracycline containing chemotherapy regimen | • Studies published between 1985 and 2007 | Anthracyclines: doxorubicin, epirubicin, duanorubicin, idarubicin. | • Authors reported that outcomes occurred early and while participants were receiving treatment except in one study where it was not clear when cardiotoxicity occurred. | |||
C: anthracycline agent | • Length of follow-up not summarised | • Anthracycline vs no anthracycline (OR 5.43; 95 % CI = 2.34–12.62) | ||||
O: Clinical cardiotoxicity (diagnosis of chronic heart failure) | • Bolus versus continuous infusion (OR = 4.13; 95 % CI = 1.75–9.72) | |||||
Subclinical cardiotoxicity (Reduction in left ventricular ejection fraction or abnormality in cardiac function determined using a diagnostic test) | • Liposomal doxorubicin vs doxorubicin (OR = 0.18; 95 % CI = 0.08–0.38) | |||||
• Epirubicin vs doxorubicin OR = 0.39 (95 % CI = 0.2–0.78) | ||||||
• Anthracycline vs mitoxantrone OR = 2.88 (95 % CI = 1.29–6.44) | ||||||
• Dexrazoxane vs no dexrazoxane OR = 0.21 (95 % CI = 0.13–0.33) | ||||||
• Anthracycline was associated with increased risk of sub-clinical cardiotoxicity (OR = 6.25; 95 % CI = 2.58–15.13). | ||||||
• Rate of cardiac deaths in 4 studies was significantly higher in the anthracycline groups (OR = 4.94; 95 % CI = 1.23–19.87, p = 0.025). | ||||||
Dietary supplementation | ||||||
Roffe et al. (2004) [34] | P: Cancer patients | • 6 controlled trials | Dose ranged from 30 mg per day to 240 mg per day | • Significant differences between groups observed in various ECG measures. | n | 7 |
I: Coenzyme Q10 | (1 placebo-controlled, double-blinded study, 5 open label) | • Effect on heart failure or subclinical cardiac dysfunction was not reported in the trials | ||||
C: Any comparison | • Published between 1982 and 1996 | |||||
O: All outcomes considered | • Length of follow-up was not reported | |||||
Prevention of cardiotoxicity associated with prostate cancer treatment | ||||||
Shelley et al. (2008) [27] | P: Hormone-refractory prostate cancer | • 47 RCT published between 1977 and 2005 | Drug categories included: | • Severe cardiovascular toxicity was more common with Estramustine versus Best Supportive Care or Hormones. | n | 10 |
I: Chemotherapy | • Length of follow up was not reported | • estramustine, | • Similar rates of cardiotoxicity with estramustine alone and medroxyprogesterone acetate plus epirubicin. | |||
C: Any comparison | • 5-fluorouracil | • Cardiotoxicity was less common with epirubicin (11 %) than doxorubicin (48 %). | ||||
O: Overall survival, Disease-specific survival, PSA response, time to progression, pain response, toxicity, quality of life. | • cyclophosphamide | • Doxorubicin combined with diethlystilbestrol was more cardiotoxic than doxorubicin (7 % vs 1 %). | ||||
• doxorubicin | ||||||
• mitoxantrone | ||||||
• docetaxel | ||||||
Prevention in children | ||||||
Bryant et al. (2007) [35] | P: Children receiving anthracyclines | • 4 controlled trials published between 1994 and 2004 | • Infusion versus rapid bolus infusion | • No cost-effectiveness data were identified in the systematic review | n | 7 |
I: Any cardioprotection intervention | • Length of follow-up ranged from 25 to 56 months | • Coenzyme Q10 | • There were conflicting results in trials of rapid or continuous infusion of anthracycline chemotherapy | |||
C: Any comparison | • Dexrazoxane | • Coenzyme Q10 was examined in one small trial (n = 20). | ||||
O: Mortality, heart failure, arrhythmia, measures of cardiac function and cost-effectiveness | • Mean reduction in percentage left ventricular fraction shortening was lower in the group that received coenzyme Q10. | |||||
• Dexrazoxane was examined in a trial with 105 participants. | ||||||
• Fewer patients who received dexrazoxane had elevations in troponin (21 % vs 50 %; p < 0.001) | ||||||
Sieswerda et al. 2011 [37] | P: children with cancer | • 15 observational studies published between 1998 and 2007 | • Different liposomal anthracyclines looked at Liposomal daunorubicin, pegylated liposomal doxorubicin, liposomal doxorubicin. | No evidence from controlled trials was identified. | n | 7 |
I: liposomal anthracyclines | • (9 prospective cohort studies, 2 retrospective cohort studies, three case reports, one unclear design) | Impossible to know whether there are differences in outcomes | ||||
C: Any comparison | • Duration of follow up was reported in 10 studies (ranged from 1 to 58 months) | |||||
O: cardiotoxicity, tumour response, adverse events | ||||||
Van dalen et al. 2012 [28] | P: children with cancer | • 8 RCT published from 1975 to 2009 | 1153 treatment, 1121 control. | • Rate of cardiac death was similar between treatment groups in meta-analysis of two trials (RR = 0.41; 95 % CI = 0.04–3.89) | y | 11 |
I: anthracyclines | • Length of follow-up was not mentioned in the majority of trials | Culmulative duanorubicin treatment protocol 90–350 mg/m2. | • No significant difference in HF between treatment groups in one trial (RR = 0.33; 95 % CI = 0.01–8.02) | |||
C: non anthracycline | Peak dose of anthracycline in one week = 25–90 mg/m2. doxorubicin treatment protocol was 300–420 mg/m2. | |||||
O: survival | Peak dose doxorubicin in 1 week 25–60 mg/m2 | |||||
Tumour response cardiotoxicity | ||||||
Prevention of cardiotoxicity associated with breast cancer treatment | ||||||
Valachis et al. (2013) [24] | P: Breast cancer | • 6 controlled trials that were all published in 2012. | Anti-HER2 monotherapy (lapatinib or trastuzumab or pertuzumab) | • Pooled OR for CHF in patients with breast cancer receiving dual anti-HER2 therapy versus anti-HER2 monotherapy was 0.58 (95 % CI: 0.26–1.27, p-value = 0.17) | y | 8 |
I: anti-HER2 monotherapy | • Length of follow-up was not reported. | • Pooled OR of LVEF decline with dual anti-HER2 therapy versus anti-HER2 monotherapy was 0.88 (95 % CI: 0.53–1.48, p-value = 0.64) | ||||
C: anti-HER2 combination therapy | • Comparable cardiac toxicity between these two therapies | |||||
O: LVEF decline less than 50 % or more than 10 % from baseline, National Cancer Institute Common Toxicity Criteria Chronic heart failure grade 3 or more. | ||||||
Viani et al. 2007 | P: HER-2-positive early breast cancer | • 5 RCT published in 2005 and 2006 | Doxorubicin and cyclophosphamide (AC) + paclitaxel (P). | • Meta-analysis of 5 trials of adjuvant trastuzumab revealed a significant reduction in mortality (p < 0.00001), recurrence (p < 0.00001), metastases (p < 0.00001) and second tumours (p =0.007) compared with no trastuzumab | y | 10 |
I: adjuvant trastuzumab | • Length of follow-up ranged from 9 to 60 months after randomisation | Docetaxel or vinorelbine + fluorouracil, epirubicin and cyclophosphanide. | • Increased cardiotoxicity including symptomatic cardiac dysfunction and asymptomatic decrease in LVEF with trastuzumab compared to no trastuzumab | |||
C: any comparison | Doxo, cyclo + trastuz. | • The likelihood of cardiac toxicity was 2.45 times higher for trastuzumab compared with no trastuzumab (statistically significant heterogeneity) | ||||
O: mortality, recurrance, metastases, second tumour no breast cancer rate | Docetaxel, carboplatin + trastuz. | |||||
Cardiac toxicity and brain metastases | AC + docetaxel. | |||||
Qin et al. 2011 [21] | P: node negative breast cancer | • 19 RCT published from 2003 to 2010 | Taxane treatment vs non taxane treatment | • Disease free survival: taxane treatment HR 0.82, 95 % CI 0.76–0.88 | y | 10 |
I: adjuvant taxane | • Median length of follow-up ranged from 35 to 102 months | • Overall Survival: HR 0.85, 95 % CI 0.78–0.92 favoured taxane | ||||
C: chemo without taxane | • increased toxicity for neutropenia (OR = 2.28, 95 % CI 1.25–4.16), fatigue (OR = 2.10, 95 % CI 1.37–3.22), diarrhea (OR = 2.16, 95 % CI 1.32–3.53), stomatitis (OR 1.68, 95 % CI 1.04–2.71), oedema (OR 6.61, 95 % CI 2.14–20.49). | |||||
O: disease free survival, overall survival, drug related toxicityof taxane | • In pooled analysis of results from 7 trials, there was no statistically significant difference in the rate of cardiotoxicty between chemotherapy regimens with or without taxanes (OR 0.95; 95 % CI = 0.67–1.36) | |||||
• taxane treatment showed significant reduction in death and recurrence | ||||||
Lord et al. 2008 [26] | P: metastatic breast cancer | • 34 RCT published between 1974 and 2004 | • Comparison between anthracyclines and non-antitumour antibiotic regimens. | • 23 trials with 4777 patients that compared anthracycline with non-antitumour antibiotic regimens reported on cardiotoxicity. | y | 10 |
I: anti-tumour antibiotics | • Length of follow-up was not reported in most trials | • Comparison between mitoxantrone and non-anti-tumour antibiotic regimen | • Patients who received anthracyclines were more likely to develop cardiotoxicity OR = 5.17 (95 % CI = 3.16–8.48) | |||
C: chemo regimens without anti tumour antibiotics | • Estimated length of follow-up from survival curves ranged from 2 to 102 months. | • Overall survival was reported in 23 studies of anthracyclines. No statistically significant difference in overall survival was observed between the regimens (HR 0.97, 95 % CI 0.91–1.04) | ||||
O: overall survival, time to progression, response, quality of life, toxicity | • The rate of cardiotoxicty was not reported in the mitoxantrone comparison. | |||||
Ferguson et al. 2007 [22] | P: breast cancer | • 12 RCT published from 2002 to 2006 | Any taxane contain regime vs regimen without taxane | • No difference in the risk of developing cardiotoxicity between taxane containing and non-taxane containing regimens (OR 0.90, 95 %CI 0.53 to 1.55) in meta-analysis of 6 studies involving 11557 patients. | y | 11 |
I: chemotherapy with taxane | • Length of follow-up was 43 to 69 months. | |||||
C: chemotherapy without taxane | ||||||
O: overall survival, disease free survival, toxicity, quality of life, cost effectiveness | ||||||
Duarte et al. 2012 [25] | P: breast cancer | • 4 RCT published between 2003 and 2009 | Combinations Taxane and anthracycline; anthracycline; combined neo-adjuvant and adjuvant chemo; adjuvant vs non-adjuvant therapy; granulocyte colony-stimulation factor; adjuvant tamoxifan prescribed for 5 years | • Disease free survival: dose dense therapy significant improvement (HR = 0.83; 95 % CI = 0.73–0.95) | y | 9 |
I: conventional chemotherapy | • Length of follow-up ranged from 23 to 125 months | • Dose dense chemotherapy not capable of improving overall survival (HR = 0.86; 95 % CI 0.73–1.01). | ||||
C: aggressive adjuvant chemo | • Women who received a dose-dense chemotherapy regimen were not more likely to develop cardiotoxicity (OR = 0.5; 95 % CI = 0.05–5.54). | |||||
O: overall survival, disease free survival, incidence of Common Toxicity Criteria Scale grades 3,4,5 | ||||||
Management | ||||||
Sieswerda et al. 2011 [38] | P: children with cancer | 2 RCT published in 2004 and 2008 | • Enalapril Vs placebo | • 203 patients in total | n | 11 |
I: anthracycline induced cardiotoxicity medical interventions | • Phosphecreatine vs control treatment (vitamin C, adenosine tri-phosphate, vitamin E, oral co-enzyme Q10) | Enalapril trial | ||||
C: placebo, other medical interventions, no treatment | • Median follow-up was 2.8 years | |||||
O: overall survival, mortality due to HF, development of HF, adverse events and tolerability | • One intervention participant developed clinically significant decline in cardiac performance compared with 6 control participants (RR = 0.16, 95 % CI 0.02–1.29). | |||||
• Higher occurrence of dizziness or hypotension (RR 7.17, 95 % CI 1.71 to 30.17) associated with enalapril | ||||||
• Higher occurrence of fatigue associated with enalapril (p = 0.013). | ||||||
Phosphocreatine trial | ||||||
• Length of follow-up estimated to be 15 days | ||||||
• No deaths in both groups | ||||||
• No adverse events reported | ||||||
• no definitive conclusions can be drawn due to small sample size |