Table 1.
Studies evaluating the use of biomarkers to predict chemotherapy-induced cardiac toxicity.
| Troponin-I | ||
|---|---|---|
| Papers demonstrating correlation between increase in biomarker and cardiotoxicity |
||
| Cardinale et al. [83] | 50 patients received EPI–CYC, 41 received taxotere–EPI–CYC, 48 received Ifosfamide–CARB–ETO 16 received taxotere–Ifosfamide–CARB–ETO, 49 received CYC. |
All patients with decrease in LVEF of greater than 30% had TnI elevation greater than 0.5 ng/mL |
| Cardinale et al. [78] | 51 patients received EPI–CYC (EC), 85 received taxotere–EPI–CYC (TEC), 43 patients who had previously been treated with anthracyclines received Ifosfamide–CARB–ETO (ICE) while 32 other patients previously treated with anthracyclines received taxotere– ifosfamide–CARB–ETO (TICE). All subsequently received radiotherapy. |
The percentage of patients with TnI positivity was 53% in EC, 31% in TEC, 28% in ICE and 16% in TICE. A strong correlation was found between the magnitude of TnI rise and reduction in EF. |
| Cardinale et al. [68] | 703 patients enrolled in a number of different regimens including: EPI–CYC; taxotere–EPI–CYC; ifosfamide–CARB–ETO; taxotere– isofamide–CARB–ETO; carmustine–ETO–cytarabine–melphalan; ETO–solumedrol–cytarabine–platinum; mitoxantrone; melphalan; idarubicin; sequential; CYC. |
Correlation between elevated TnI and reduction in ejection fraction was even more likely in individuals with elevated Tn’s at multiple time points during and after chemotherapy. |
| Cardinale et al. [100] | 251 patients received TZT with or without other chemotherapy (197 had prior exposure to anthracyclines). |
TnI identifies patients at risk for developing cardiotoxicity (including decrease in LVEF) who are unlikely to recover following completion of therapy. |
| Drafts et al. [85] | 37 patients received DOX and 16 received daunorubicin. | TnI trended upward with therapy. 26% showed positivity by the end of 6 months, BNP fell during therapy. |
| Ky et al. [77] | 78 patients received DOX–CYC every 3 weeks for 4 cycles, followed by PAC–TZT weekly for 12 weeks, followed by TZT every 3 weeks totaling a full year of therapy. |
Increases in TnI and MPO levels were associated with the development of cardiac dysfunction. |
| Lee et al. [70] | 67 patients received DOX, 15 received daunorubicin, 1 received EPI, 1 received idarubicin, 1 received DOX and EPI, 1 received DOX and idarubicin. |
TnI and BNP concentrations correlated with anthracycline cumulative dose and LVEF. Heart failure was more common if BNP levels reached 100 pg/mL at least once. |
| Lipshultz et al. [107] | 100 patients received DOX, 105 received DOX and dexrazoxane. | TnI and NT-proBNP levels during the first 90 days of treatment predicted the development of cardiac dysfunction 4 years later. |
| Morris et al. [124] | 95 patients initially received DOX–CYC (DC) followed by PAC–TZT– lapatinib for 3 months with continuation of TZT–lapatinib for 1 year. |
TnI rise preceded maximal decline in LV function, CRP did not correlate with cardiotoxicity. |
| Sandri et al. [84] | 79 patients received TEC, 49 received CYC–MTX–ETO–idarubicin (SEQ), 26 received TICE, 17 received ICE, 8 received EC. |
52 (32%) of patients with a positive TnI had a decrease in LVEF. No LV dysfunction was noted in the group with negative TnI. |
| Sawaya et al. [81] | 39 patients received DOX–taxanes, 4 received EPI–taxanes; 10 received anthracycline containing chemotherapy prior to enrollment. |
TnI elevation at 3 months was predictive of the development of LV dysfunction at 6 months. |
| Sawaya et al. [69] | 82 patients received DOX or EPI for 3 months followed by weekly PAC–TZT for 3 months followed by 9 more months of TZT. |
TnI and peak systolic myocardial strain predicted cardiotoxicity, no significant associations were observed for LVEF, NT-proBNP or ST-2, and the development of heart failure. |
| Specchia et al. [73] | Anthracycline containing chemotherapy with median doses of daunorubicin 300 mg/m2, idarubicin 51 mg/m2, and mitoxantrone 47 mg/m2 |
Echocardiography findings showed transient decrease in EF correlated with increased TnI levels |
| Papers failing to demonstrate correlation between increase in biomarker and cardiotoxicity |
||
| Grover et al. [92] | 46 patients received three to six 21 day cycles of EPI, DOX, and/or TZT with or without taxanes. |
TnI and CRP increased with therapy but did not correlate with subsequent LV dysfunction. |
| Soker et al. [95] | 31 patients received DOX based therapy. | NT-proBNP levels were significantly more elevated in patients with LV dysfunction, cTnI remained undetectable throughout the study. |
| Zver et al. [21] | 30 patients received VCR–EPI–dexamethasone followed by CYC– melphalan followed by autologous hematopoietic stem cell transplantation. |
Increased levels of BNP and ET-1 were associated with worsening LV diastolic dysfunction. TnI remained within the normal range. |
| Troponin-T | ||
| Papers demonstrating correlation between increase in biomarker and cardiotoxicity |
||
| Auner et al. [18] | 2 patients received DOX, 28 received pegylated liposomal DOX, 3 received daunorubicin, 43 received idarubicin, 58 received Mitoxantrone. |
Patients with positive TnT levels correlated with greater decrease in LVEF. |
| Geiger et al. [104] | 40 patients received DOX, 6 received mitoxantrone–daunorubicin, 2 received mitoxantrone, 1 received liposomal DOX, 1 received liposomal DOX. |
NT-proBNP levels increased more in patients who subsequently developed reduced EF, TnT levels increased following chemotherapy and were also associated with reduced EF. |
| Kilickap et al. [74] | 29 patients received DOX, 5 received idarubicin, 4 received daunorubicin, 3 received EPI. |
Positive TnT levels were associated with LV diastolic dysfunction in younger patients. |
| Mavinkurve-Groothuis et al. [71] | 60 patients received 120 mg/m2 of anthracyclines and were then stratified to low (n = 20), moderate (n = 30) or high risk (n = 10) based on response with moderate risk receiving an additional 180 mg/m2 of anthracycline and high risk receiving either an additional 120 mg/m2 anthracycline +18 mg/m2 idarubicin +52.5 mg/m2 mitoxantrone or consideration of bone marrow transplantation. |
TnT elevations predicted some LV dysfunction, NT-proBNP was not predictive of cardiac toxicity. |
| Mornos et al. [80] | 100 patients received anthracycline containing therapy. | Changes in TnT levels predicted the development of cardiac toxicity while changes in NT-proBNP did not show significant predictive value. |
| Troponin-I | ||
| Papers failing to demonstrate correlation between increase in biomarker and cardiotoxicity |
||
| Kremer et al. [94] | 20 patients received DOX, 4 received daunorubicin, 9 received EPI, 5 received mitoxantrone. |
Measurement of TnT within the first 24 h of chemotherapy did not predict subsequent development of cardiac toxicity. |
| Dodos et al. [91] | 100 patients received anthracycline containing chemotherapy, 53 received DOX, 29 received EPI, 15 received daunorubicin, 2 received mitoxantrone, and 1 received idarubicin. |
TnT and BNP did not predict subsequent development of cardiac dysfunction. |
| B-type naturetic peptide | ||
| Papers demonstrating correlation between increase in biomarker and cardiotoxicity |
||
| Anthracycline containing regimens | ||
| Hayakawa et al. [114] | 34 patients received DOX-based chemotherapy more than 1 month prior. |
Both ANP and BNP levels correlated with both the cumulative dose of anthracycline and LV systolic dysfunction. |
| Lipshultz et al. [107] | 100 patients received DOX, 105 received DOX and dexrazoxane. | TnT levels rose during treatment in the DOX group and to a lesser extent the group with dexrazoxane coadministration, NT-proBNP levels were initially elevated, fell in both groups although to a lesser extent in the group without dexrazone, NT-proBNP rose again post- treatment in the DOX group but continued to fall in the dexrazosin coadministration group. hsCRP was not significantly different between groups. TnI and NTproBNP levels during the first 90 days of treatment predicted the development of cardiac dysfunction 4 years later. |
| Sandri et al. [109] | 52 patients received HDC | Persistently elevated NT-proBNP levels strongly associated with the development of systolic and diastolic dysfunction following HDC. |
| Nakamae et al. [150] | 40 patients received CYC–DOX–VCR–prednisolone (CHOP therapy). | CHOP induced transient increases in the LV end-diastolic diameter on echocardiogram and in the plasma BNP and ANP. Valsartan therapy prevented elevation in BNP and LV end-diastolic diameter, but not ANP. |
| Pichon et al. [115] | 50 patients received anthracycline based therapy, 17 patients were pre-treated with anthracycline-based therapy followed by TZT and taxanes or vinorelbine. |
BNP concentrations correlated with anthracycline cumulative dose and LVEF. |
| Lee et al. [70] | 67 patients received DOX, 15 received daunorubicin, 1 received EPI, 1 received idarubicin, 1 received DOX and EPI, 1 received DOX and idarubicin. |
BNP and TnI concentrations correlated with cumulative anthracycline dose and LVEF. Heart failure was more common if BNP levels reached 100 pg/mL at least once. |
| Romano et al. [86] | 34 patients received liposomal DOX–docetaxel and 37 received EPI– 5-FU–CYC. |
Persistently elevated NT-proBNP levels were associated with subsequent impairment of LV function. |
| Feola et al. [87] | 53 patients received six 21 day cycles of CYC–EPI–5-FU. | BNP levels correlated with LV systolic dysfunction |
| Kouloubinis et al. [117] | 26 patients received six 21 day cycles of EPI–paclitaxel, 14 received six 21 day cycles of mitoxantrone–docetaxel. |
proANP and NT-proBNP levels correlated with LV dysfunction. |
| Gimeno et al. [103] | 35 patients received modified-CHOP regimen with or without rituximab. |
Patients with initially elevated NT-proBNP levels had a significantly higher risk of heart failure progression and death from all causes in comparison to those with lower levels. |
| Mladosievicova et al. [123] | 69 patients who had previously received DOX, daunorubicin, or EPI based therapy or non-anthracycline therapy were compared to 44 health controls. |
NT-proBNP elevations were more common in childhood cancer survivors exposed to anthracyclines compared to unexposed survivors. |
| Geiger et al. [104] | 40 patients received DOX, 6 received mitoxantrone–daunorubicin, 2 received mitoxantrone, 1 received liposomal DOX. |
NT-proBNP levels increased more in patients who subsequently developed reduced EF, TnT levels increased following chemotherapy and were also associated with reduced EF. |
| Sherief et al. [118] | 50 patients who had previously received anthracycline based chemotherapy. |
NT-proBNP levels correlated with the total anthracycline dose previously received. |
| Lipshultz et al. [119] | 102 patients received anthracycline based therapy vs. other protocols not containing anthracyclines. |
Increased NT-proBNP levels were associated with decreased LV function. |
| Aggarwal et al. [105] | 63 patients previously received anthracycline based chemotherapy at least 1 year prior to enrollment. |
Elevated BNP levels were associated with cardiac dysfunction on echocardiography. |
| Soker et al. [95] | 31 patients received DOX based therapy. | NT-proBNP levels were significantly more elevated in patients with LV dysfunction, cTnI levels remained undetectable throughout the study. |
| Zver et al. [21] | 30 patients received VCR–EPI–dexamethasone followed by CYC– melphalan followed by autologous hematopoietic stem cell transplantation. |
Increased levels of BNP and ET-1 were associated with worsening LV diastolic dysfunction. TnI remained within the normal range. |
| Nakamae et al. [150] | 40 patients received CYC–DOX–VCR–prednisolone (CHOP therapy). | CHOP induced transient increases in the LV end-diastolic diameter on echocardiogram and in the plasma BNP and ANP. Valsartan therapy prevented elevations in BNP and LV end-diastolic diameter, but not ANP. |
| Feola et al. [87] | 53 patients received six 21 day cycles of CYC–EPI–5-FU. | BNP levels correlated with left ventricular systolic dysfunction in this patient population. |
| Kuittinen et al. [22] | 30 patients received carmustine–ETO–cytarabine–CYC–MESNA followed by stem cell transplantation. |
LV dysfunction correlated with NT-proANP and NT-proBNP levels. |
| Romano et al. [86] | 34 patients received Liposomal DOX–docetaxel and 37 received EPI–5-FU–CYC. |
Persistently elevated NT-proBNP levels were associated with subsequent impairment of LV function. |
| Pichon et al. [115] | 50 patients received anthracycline based therapy, 17 patients were pre-treated with anthracycline-based therapy followed by TZT and taxanes or vinorelbine |
BNP concentrations correlated with anthracycline cumulative dose and LVEF. |
| Ribeiro et al. [50] | 103 patients received imatinib. | 4 patients receiving imatinib had elevated BNP with one showing depressed LVEF, however this small number of patients precluded the comparison of their features with the whole study sample. |
| Troponin-I | ||
| Papers failing to demonstrate correlation between increase in biomarker and cardiotoxicity |
||
| Meinardi et al. [112] | 21 patients received five cycles of 5-FU–EPI–CYC (FEC), 19 received four cycles of FEC followed by high-dose chemotherapy consisting of CYC–thiotepa–carboplatin. Both groups subsequently underwent locoregional radiotherapy. |
No statistically significant correlation was found between BNP levels and prediction of LVEF dysfunction. |
| Garrone et al. [79] | 50 patients received six 21 day cycles of CYC–EPI–5-FU. | Kinetics of Tn rise correlated with LVEF reduction. There was no correlation between BNP and change in LVEF. |
| Mavinkurve-Groothuis et al. [71] | 60 patients received 120 mg/m2 of anthracyclines and were then stratified to low (n = 20), moderate (n = 30) or high risk (n = 10) based on response with moderate risk receiving an additional 180 mg/m2 of anthracycline and high risk receiving either an additional 120 mg/m2 anthracycline +18 mg/m2 idarubicin +52.5 mg/m2 mitoxantrone or consideration of bone marrow transplantation. |
TnT elevations predicted LV dysfunction, NT-proBNP levels were not predictive. |
| Drafts et al. [85] | 37 patients received DOX and 16 received daunorubicin. | TnI trended upward with 26% showing positivity by the end of 6 months, BNP levels fell during therapy. |
| Mornos et al. [80] | 100 patients received anthracycline containing therapy. | Changes in TnT levels predicted the development of cardiac toxicity while changes in NT-proBNP did not show significant predictive value. |
| Poutanen et al. [113] | 39 patients received anthracycline based therapy with or without radiotherapy 5 to 7 years prior to evaluation. |
NT-proANP is a useful method to evaluate cardiac function in cancer survivors, BNP levels did not correlate with cardiac function. |
| Daugaard et al. [111] | 66 patients received EPI, 41 received DOX. 13 patients additionally received radiotherapy of the left chest wall. |
Neither changes in NT proANP nor BNP correlated with a change in EF. |
| Sawaya et al. [69] | 82 patients received DOX or EPI for 3 months followed by weekly PAC–TZT for 3 months followed by 9 more months of TZT. |
TnI and peak systolic myocardial strain predicted cardiotoxicity, no significant associations observed for LVEF, NT-proBNP, or ST-2 and the development of heart failure. |
| Dodos et al. [91] | 100 patients received anthracycline containing chemotherapy, 53 received DOX, 29 received EPI, 15 received daunorubicin, 2 received mitoxantrone, and 1 received idarubicin. |
TnT and BNP did not predict subsequent development of cardiac dysfunction |
| Atrial naturetic peptide | ||
| Papers demonstrating correlation between increase in biomarker and cardiotoxicity |
||
| Hayakawa et al. [114] | 34 patients received DOX-based chemotherapy more than 1 month prior. |
ANP and BNP levels correlated with both the cumulative dose of anthracycline and LV systolic function. |
| Nakamae et al. [150] | 40 patients received CYC–DOX–VCR–prednisolone (CHOP therapy). | CHOP induced transient increases in the LV end-diastolic diameter on echocardiogram and in the plasma BNP and ANP. Valsartan therapy prevented elevation in BNP and LV end-diastolic diameter, but not ANP. |
| Poutanen et al. [113] | 39 patients received anthracycline based therapy with or without radiotherapy 5 to 7 years prior to evaluation. |
NT-proANP levels corresponded with cardiac function in cancer survivors, BNP levels did not correlate with cardiac function. |
| Kouloubinis et al. [117] | 26 patients received six 21 day cycles of EPI–PAC, 14 received six 21 day cycles of mitoxantrone and docetaxel. |
NT-proANP and NT-proBNP levels correlated with LV dysfunction. |
| Kuittinen et al. [22] | 30 patients received carmustine–ETO–cytarabine–CYC–MESNA followed by stem cell transplantation. |
LV dysfunction was associated with NT-proANP and NT-proBNP levels. |
| Papers failing to demonstrate correlation between increase in biomarker and cardiotoxicity |
||
| Daugaard et al. [111] | 66 patients received EPI, 41 received DOX. 13 patients additionally received radiotherapy of the left chest wall. |
Neither changes in NT-ANP nor BNP correlated were predictive of a change in EF. |
| C-reactive protein | ||
| Papers demonstrating correlation between increase in biomarker and cardiotoxicity |
||
| Onitilo et al. [35] | 49 patients received adjuvant TZT therapy (24 had prior exposure to anthracycline). |
hs-CRP correlated with subsequent reduction in LVEF. |
| Papers failing to demonstrate correlation between increase in biomarker and cardiotoxicity |
||
| Lipshultz et al. [107] | 100 patients received DOX, 105 received DOX–dexrazoxane. | TnT levels rose during treatment in the DOX and to a lesser extent in the group with dexrazoxane coadministration, NT-proBNP levels were initially elevated, fell in both groups although to a lesser extent in the group without dexrazone, NT-proBNP rose again post- treatment in the DOX group but continued to fall in the dexrazosin coadministration group. Increases in hsCRP were not associated with changes on echocardiography. TnI and NTproBNP levels during the first 90 days of treatment predicted the development of cardiac dysfunction 4 years later. |
| Morris et al. [124] | 95 patients enrolled initially receiving DOX–CYC (DC) followed by PAC–TZT–lapatinib for 3 months with continuation of TZT-lapatinib for 1 year. |
TnI rise preceded maximal decline in left ventricular function, CRP did not correlate with cardiotoxicity |
| Troponin-I | ||
| Grover et al. [92] | 46 patients received three to six 21 day cycles of EPI, DOX and/or TZT with or without taxanes. |
TnI and CRP increased with therapy but did not correlate with subsequent LV dysfunction. |
| Myeloperoxidase | ||
| Papers demonstrating correlation between increase in biomarker and cardiotoxicity |
||
| Ky et al. [77] | 78 patients received DOX–CYC every 3 weeks for 4 cycles, followed by PAC–TZT weekly for 12 weeks, followed by TZT every 3 weeks totaling a full year of therapy. |
Increases in TnI and MPO levels were associated with the development of cardiac dysfunction. |
| Endothelin-1 | ||
| Papers demonstrating correlation between increase in biomarker and cardiotoxicity |
||
| Zver et al. [21] | 30 patients received VCR–EPI–dexamethasone followed by CYC– melphalan followed by autologous hematopoietic stem cell transplantation. |
Increased levels of BNP and ET-1 were associated with worsening LV diastolic dysfunction. TnI levels remained within the normal range. |
| ST-2 | ||
| Papers failing to demonstrate correlation between increase in biomarker and cardiotoxicity |
||
| Sawaya et al. [69] | 82 patients received DOX or EPI for 3 months followed by weekly PAC–TZT for 3 months followed by 9 more months of TZT. |
TnI and peak systolic myocardial strain predicted cardiotoxicity, no significant associations observed for LVEF, NT-proBNP, or ST-2 and the development of heart failure. |
Abbreviations used within the table. Biomarkers: Tn = troponin, TnI = cardiac troponin I, TnT = cardiac troponin T, BNP = B-type natriuretic peptide, ANP = atrial natriuretic peptide, NT-proBNP = N-Terminal pro B-type natriuretic peptide, NT-proANP = N-terminal pro atrial natriuretic peptide, CRP = C-reactive protein, hsCRP = high sensitivity C-reactive protein, ET-1 = endothelin-1, MPO = myeloperoxidase. Chemotherapy: 5-FU = 5-fluorouracil, CARB = carboplatin, CYC = cyclophosphamide, DOX = doxorubicin, EPI = epirubicin, ETO = etoposide, HDC = high dose chemotherapy, MTX = methotrexate, ONC = oncovorin, PAC = paclitaxel, TZT = trastuzumab, VCR = vincristine. Cardiovascular parameters: EF = ejection fraction, LVEF = left ventricular ejection fraction, LV = Left ventricle.
Search criteria: chemotherapy and cardiac biomarkers over the past 10 years, in humans, available in English. Hand-searching of articles was performed to locate additional studies. Inclusion criteria: studies containing greater than 30 patients evaluating the use of biomarkers to detect cardiac toxicity in the setting of chemotherapy.