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Table 2 Characteristics of included reviews

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
  1. Legend: cTnT Cardiac Troponin T, ANP Atrial Natriuretic Peptide, NT-BNP N-terminal Brain Natriuretic Peptide, ACR, anthacyclines, LVEF Left ventricular ejection fraction, HF Heart failure, 95 % CI 95 % Confidence Interval, RR Relative risk, OR, Odds ratio, HR Hazard ratio, RCT Randomised controlled trial.