Background
Methods
Information sources and search strategy
Study selection
Inclusion criteria
| • Study type: Systematic review of original research (as per the PRISMA statement. A systematic review was defined as a review with a clearly formulated question that used systematic and explicit methods to identify, select and critically appraise relevant research and to collect and analyse data from the studies that were included in the review. As such, the review had to describe a detailed search of the literature for relevant studies and synthesis of results) |
• Publication: Full peer-reviewed publication | |
• Population: Patients with cancer | |
• Intervention: Any intervention applied to prevent, diagnose or manage cancer treatment-induced cardiotoxicity. | |
• Comparison: Any comparison. | |
• Outcome: Cardiotoxicity, as defined by the authors of the original systematic review. Could be clinical diagnosis of heart failure, heart failure graded by a standardized reporting system, subclinical heart failure (identified by myocardial biopsy, non-invasive imaging techniques or biomarkers) or adverse cardiac events (myocardial infarction, arrhythmia). | |
Exclusion criteria
| • Systematic reviews focused on identifying the incidence of cardiotoxicity associated with particular cancer treatment regimens. |
• Poor quality (Literature search was not comprehensive, quality of included studies was not appraised, total AMSTAR score <7) |
Data extraction
Quality appraisal
Data synthesis
Results
Systematic review characteristics
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 |