Table 2 Characteristics of included reviews

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

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).

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

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

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

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

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