TABLE 2.
Types of cardiotoxicity and their corresponding number of frequencies reported per publication.
| References (publication year) | Drug combination | Dose escalation study | Arrhythmia | Cardiac arrest | Cardiac failure | Cardiotoxicity (Grade 1–4) | Hypertension | Hypotension | Ischaemia | Myocardial infarction | Palpitations | Pericardial effusion | Thromboembolic event (both arterial/venous) | Other cardiovascular event | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arrhythmia (general) | Atrial/Supra-ventricular arrhythmia | Ventricular arrhythmia | |||||||||||||||||
| Atrial fibrillation | Atrial flutter | Bradycardia | Tachycardia | QT prolongation | |||||||||||||||
| Mizugaki et al. (2015) | Carboplatin, Paclitaxel, Veliparib | V-40 mg | 0 | ||||||||||||||||
| V-80 mg | 2 | ||||||||||||||||||
| V-120 mg | 0 | ||||||||||||||||||
| Huang et al. (2020) | Apatinib, Carboplatin, Pemetrexed | A-750 mg | 2 | ||||||||||||||||
| A-500 mg | 2 | ||||||||||||||||||
| A-500 mg 2/1 (500 mg/day 2 weeks on 1 week off) | 1 | ||||||||||||||||||
| Sebastian et al. (2019) | CV9201 | CI - 400 μg | 0 | ||||||||||||||||
| CII - 800 μg | 0 | ||||||||||||||||||
| CIII - 1600 μg | 0 | ||||||||||||||||||
| Phase IIA - 1600 μg | 1 | ||||||||||||||||||
| Novello et al. (2014a) | Cisplatin, Iniparib, Gemcitabine | GC | 9 | ||||||||||||||||
| GCI | 12 | ||||||||||||||||||
| Cappuzzo et al. (2006) | Chemotherapy, Gemcitabine | Standard 50 mg/min | 16 | ||||||||||||||||
| Low 10 mg/min | 11 | ||||||||||||||||||
| Srinivasa et al. (2020) | Carboplatin, Cisplatin, Etoposide, Paclitaxel | Cis-Etop | 0 | ||||||||||||||||
| Car-Pac | 0 | ||||||||||||||||||
| Yoshioka et al. (2017) | Amrubicin, Docetaxel | Amrubicin | 1 | 1 | 2 | 1 | Ventricular extrasystole: 2 Cardiac tamponade: 1 |
||||||||||||
| Docetaxel | 0 | 0 | 0 | 0 | |||||||||||||||
| Johnson et al. (2013) | Bevacizumab, Erlotinib (CT prior to trial) | Bev-Plac | 31 | 85 | |||||||||||||||
| Bev-Erlo | 29 | 88 | |||||||||||||||||
| Gridelli et al. (2001) | Gemcitabine, Vinorelbine | Gem | 0 | ||||||||||||||||
| Gem-Vin | 6 | ||||||||||||||||||
| Martoni et al. (1991) | Epirubicin | 120Epi | LVEF value decrease | ||||||||||||||||
| 135Epi | |||||||||||||||||||
| 150Epi | |||||||||||||||||||
| 165Epi | 1 | ||||||||||||||||||
| Sequist et al. (2013), Boehringer Ingelheim (2018a), Wu et al. (2018) | Afatinib, Cisplatin, Pemetrexed | Afatinib | 0 | 14 | 1 | 0 | 1 | 1 | Mitral valve incompetence: 1 | ||||||||||
| Pemetrexed/Cisplatin Chemotherapy | 1 | 14 | 0 | 1 | 0 | 2 | |||||||||||||
| Boehringer Ingelheim (2018b) | Afatinib, Cisplatin, Gemcitabine | Afatinib | 0 | 0 | |||||||||||||||
| Cisplatin, Gemcitabine Chemotherapy | 1 | 1 | |||||||||||||||||
| Boehringer Ingelheim (2020) | Afatinib, Gefitinib | Afatinib | 0 | 0 | 2 | 1 | Acute coronary syndrome: 1 Angina pectoris: 1 Coronary heart disease: 1 |
||||||||||||
| Gefitinib | 1 | 1 | 0 | 3 | Coronary heart disease: 1 Coronary artery occlusion: 1 |
||||||||||||||
| Hida et al. (2017) | Alectinib, Crizotinib | Alectinib | 1 | ||||||||||||||||
| Crizotinib | 6 | ||||||||||||||||||
| Berghmans et al. (2013) | Cisplatin, Docetaxel, Gemcitabine, Ifosfamide | IG | 10 | ||||||||||||||||
| GIP | 8 | ||||||||||||||||||
| DP | 20 | ||||||||||||||||||
| EU Clinical Trials Register, (2011); GlaxoSmithKline, (2014) | Docetaxel, GSK1120212 (Trametinib) | Doc | 1 | ||||||||||||||||
| Tra | 13 | ||||||||||||||||||
| Martoni et al. (1999) | Epirubicin, Cisplatinum, Vinorelbine | HDEpi-Cis | 3 | >15% LVEF decrease: 9 | |||||||||||||||
| Vin-Cis | 0 | >15% LVEF decrease: 3 | |||||||||||||||||
| Reck et al. (2015) | Docetaxel, Nintedanib | Doc-Nin | 23 | 22 | |||||||||||||||
| Doc-Plac | 6 | 19 | |||||||||||||||||
| Saito et al. (2003) | Carboplatin, Docetaxel, Paclitaxel | Car-Doc | 4 | ||||||||||||||||
| Car-Pac | 2 | ||||||||||||||||||
| Barlesi et al. (2018) | Avelumab, Docetaxel | Avelumab | 1 | Person with acute cardiac failure also suffered from autoimmune myocarditis | |||||||||||||||
| Docetaxel | 0 | Cardiovascular insufficiency: 1 | |||||||||||||||||
| Camidge et al. (2018) | Brigatinib, Crizotinib | Brigatinib, | 7 | 31 | 0 | ||||||||||||||
| Crizotinib | 17 | 10 | 8 | ||||||||||||||||
| Wachters et al. (2003) | Cisplatin, Epirubicin, Gemcitabine | Gem-Cis | 7 | 0 | |||||||||||||||
| Gem-Epi | 21 | 1 | |||||||||||||||||
| Shaw et al. (2013) | Crizotinib, Docetaxel, Pemetrexed | Criz | 1 | 9 | 0 | 1 | 1 | 1 | Cardiac tamponade: 1 Coronary artery disease: 1 Syncope: 1 |
||||||||||
| Doc-Pem | 0 | 0 | 1 | 0 | 0 | 2 | Cardiac tamponade: 1 | ||||||||||||
| Solomon et al. (2014) | Crizotinib, Carboplatin, Cisplatin, Pemetrexed | Criz | 1 | 33 | 0 | 0 | 0 | Atrioventricular block: 1 Cardiac tamponade: 2 |
|||||||||||
| Pem-Car/Cis | 1 | 1 | 1 | 1 | 1 | Pericarditis: 1 Syncope: 2 |
|||||||||||||
| Bonomi et al. (2000) | Cisplain, Etoposide, Paclitaxel | Cis-Etop | Fatal cardiac events: 1 | ||||||||||||||||
| Cis-250Pac | Fatal cardiac events: 1 | ||||||||||||||||||
| Cis-135Pac | Fatal cardiac events: 4 | ||||||||||||||||||
| *The six fatal Grade 5 cardiac events listed above were summarised overall instead of by treatment group - sudden death in 3 patients, myocardial infarction in 2 patients, and hypotension with acute pericarditis in 1 patient | |||||||||||||||||||
| Zatloukal et al. (2004) | Cisplatin, Vinorelbine | Con | 1 | ||||||||||||||||
| Seq | 0 | ||||||||||||||||||
| Zarogoulidis et al. (2013) | Bevacizumab, Carboplatin, Docetaxel, Erlotinib | Car-Doc | 2 | ||||||||||||||||
| Car-Doc-Erlo | |||||||||||||||||||
| Bev-Car-Doc | 3 | ||||||||||||||||||
| Bev-Car-Doc-Erlo | 2 | ||||||||||||||||||
| Koch et al. (2011) | Celecoxib, Chemotherapy (carboplatin/cisplatin/gemcitabine/vinorelbine) | Celecoxib | 2 | 17 | Cerebrovascular ischaemia: 4 | ||||||||||||||
| Placebo | 1 | 12 | Cerebrovascular ischaemia: 1 | ||||||||||||||||
| Bi et al. (2019) | Celecoxib, Cisplatin, Etoposide | CE | 5 | ||||||||||||||||
| CE-Cele | 0 | ||||||||||||||||||
| Herbst et al. (2011) | Bevacizumab, Erlotinib | Erlo | 4 | 1 | |||||||||||||||
| Erlo-Bev | 15 | 12 | |||||||||||||||||
| Seto et al. (2014), Kato et al. (2018) | Bevacizumab, Erlotinib | Erlo | 2 | 11 | 3 | ||||||||||||||
| Erlo-Bev | 1 | 58 | 3 | ||||||||||||||||
| National Cancer Institute, (2019) | Carboplatin, Erlotinib, Paclitaxel | Erlo | 1 | 1 | 0 | 1 | 1 | 8 | 0 | 0 | 3 | 0 | 3 | ||||||
| Erlo-Car-Pac | 1 | 0 | 1 | 4 | 0 | 9 | 6 | 1 | 2 | 1 | 12 | ||||||||
| Stathopoulos et al. (2004) | Carboplatin, Paclitaxel, Vinorelbine | Pac-Car | 3 | ||||||||||||||||
| Pac-Vin | 6 | ||||||||||||||||||
| Valdivieso et al. (1984) | Cisplatin, Cyclo-phosphamide, Doxorubicin, Ftorafur | Weekly-Dox | |||||||||||||||||
| Standard-Dox | |||||||||||||||||||
| * By an objective grading system of myocardial damage by endomyocardial biopsy, it was suggested that the weekly administration of doxorubicin was associated with lower cardiac toxicity than that of the standard/tri-weekly administration of doxorubicin | |||||||||||||||||||
| Baggstrom et al. (2017a) | Chemotherapy, Sunitinib | CT-Placebo | 9 | 1 | |||||||||||||||
| CT- Sunitinib | 27 | 0 | |||||||||||||||||
| Paz-Ares et al. (2015) | Best supportive care, Sorafenib | BSC-Placebo | 16 | ||||||||||||||||
| BSC-Sorafenib | 68 | ||||||||||||||||||
| Novello et al. (2014b) | Carboplatin, Paclitaxel, Motesanib | Car-Pac-Placebo | 15 | 2 | |||||||||||||||
| Car-Pac-Mote | 47 | 3 | |||||||||||||||||
| Akamatsu et al. (2018) | Carboplatin, Cisplatin, Pemetrexed, Osimertinib | Osim | 7 | 9 | |||||||||||||||
| Plat (car/cis)-Pem | 1 | 0 | |||||||||||||||||
| Kosmidis et al. (2008) | Carboplatin, Paclitaxel, Gemcitabine | Gem-Pac | 2 | ||||||||||||||||
| Gem-Car | 1 | ||||||||||||||||||
| Reinmuth et al. (2019) | Bevacizumab, Carboplatin, Paclitaxel, PF-06439535 | Car-Pac-Bev | 3 | 32 | 10 | Cardiac disorders: 12 | |||||||||||||
| Car-Pac-PF06439535 | 1 | 34 | 14 | Cardiac disorders: 10 | |||||||||||||||
| Blumenschein et al. (2010) | Carboplatin, Paclitaxel, Panitumumab, Motesanib | Mote(E)-CP | 1 | 0 | 10 | Conduction disorder: 1 | |||||||||||||
| Mote(E)-Pani | 1 | 1 | 6 | ||||||||||||||||
| Mote(125)-CP-Pani | 0 | 0 | 1 | ||||||||||||||||
| Choy et al. (2013) | Carboplatin, Cisplatin, Pemetrexed | Pem-Car | 2 | ||||||||||||||||
| Pem-Cis | 4 | ||||||||||||||||||
| William et al. (2007) | Cisplatin, Docetaxel, Motexafin gadolinium | MGd-2.5 | 0 | 0 | |||||||||||||||
| MGd-5 | 1 | 1 | |||||||||||||||||
| MGd-10 | 1 | 1 | |||||||||||||||||
| MGd-15 | 2 | 0 | |||||||||||||||||
| Chang et al. (1993) | Merbarone, Piroxantrone, Taxol | Merba | 3 | ||||||||||||||||
| Piro | 1 | ||||||||||||||||||
| Taxol | 4 | ||||||||||||||||||
| Kubota et al. (2017) | Carboplatin, Motesanib, Paclitaxel | Car-Pac-Placebo | 29 | ||||||||||||||||
| Car-Pac-Mote | 86 | ||||||||||||||||||
| Zinner et al. (2015) | Bevacizumab, Carboplatin, Paclitaxel, Pemetrexed | Car-Pem | 0 | 0 | |||||||||||||||
| Car-Bev-Pac | 4 | 1 | 4 | ||||||||||||||||
| Heigener et al. (2013) | Chemotherapy, Sagopilone | S-16,3 h | 0 | ||||||||||||||||
| S-22, 0.5 h | 1 | ||||||||||||||||||
| S-22,3 h | 0 | ||||||||||||||||||
| Jie Wang et al. (2018) | Cisplatin, Endostar, Pemetrexed | Cis-Pem | 40 | ||||||||||||||||
| Cis-Pem-Endostar | 54 | ||||||||||||||||||
| Eli Lilly and Company (2019a) | Gefitinib, Pemetrexed | Gef | 0 | 1 | 4 | 0 | 1 | 0 | Angine pectoris: 0 | ||||||||||
| Gef-Pem | 1 | 0 | 8 | 1 | 1 | 1 | Angina pectoris: 1 | ||||||||||||
| Douillard (2004) | BMS-275291, Carboplatin, Paclitaxel | Car-Pac-Placebo | 0 | 0 | 1 | 2 | |||||||||||||
| Car-Pac-BMS275291 | 1 | 1 | 0 | 1 | |||||||||||||||
| Butts et al. (2007) | Carboplatin, Cisplatin, Cetuximab, Gemcitabine | Car-Cis-Gem | 2 | ||||||||||||||||
| Car-Cis-Gem-Cet | 2 | ||||||||||||||||||
| Fukuda et al. (2019) | Bevacizumab, Pemetrexed | CT-Pem | 0 | 0 | |||||||||||||||
| CT-Pem-Bev | 0 | 0 | |||||||||||||||||
| Passardi et al. (2008) | Docetaxel, Gemcitabine | Gem3,8-Doc1 | 0 | ||||||||||||||||
| Gem1,8-Doc8 | 1 | ||||||||||||||||||
| Gatzemeier et al. (2004) | Cisplatin, Gemcitabine, Trastuzumab | Cis-Gem | LVEF decrease >15%: 0 LVEF <30%: 0 |
||||||||||||||||
| Cis-Gem-Tras | LVEF decrease >15%: 8 LVEF <30%: 0 |
||||||||||||||||||
| Park et al. (2017) | Cisplatin, Docetaxel, Pemetrexed | Cis-Doc | 1 | ||||||||||||||||
| Cis-Pem | 2 | ||||||||||||||||||
| Movsas et al. (2005) | Amifostine, Carboplatin, Paclitaxel | Car-Pac | 11 | ||||||||||||||||
| Car-Pac-Ami | 30 | ||||||||||||||||||
| Jänne et al. (2014) | Cisplatin, Gemcitabine, LY293111 | Cis-Gem-Placebo | |||||||||||||||||
| Cis-Gem-200LY | Cardiorespiratory arrest: 1 | ||||||||||||||||||
| Cis-Gem-600LY | |||||||||||||||||||
| Groen et al. (2011) | Carboplatin, Celecoxib, Docetaxel | Car-Doc | 0 | 0 | 1 | 0 | Pulmonary embolism: 2 | ||||||||||||
| Car-Doc-Celeco | 1 | 1 | 0 | 1 | Pulmonary embolism: 3 | ||||||||||||||
| Currow et al. (2017) | Anamorelin, Placebo | Anamorelin | 13 | Electrocardiogram:4 Ischemic Heart Disease: 4 |
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| Placebo | 4 | Electrocardiogram:7 Ischemic Heart Disease: 0 |
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| Langer et al. (2017) | Cisplatin, Pemetrexed, Placebo | Induction: Cis-Pem | 1 | 1 | 3 | 3 | 1 | 2 | 3 | 3 | 1 | 2 | 2 | Acute coronary syndrome: 1 Cardiac tamponade: 1 Cardio-respiratory arrest: 3 Diastolic dysfunction: 1 Pericarditis: 1 |
|||||
| Maintenance: Pem | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | Pericarditis: 2 Ventricular fibrillation: 1 |
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| Maintenance: Place | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | ||||||||
| Kotsakis et al. (2015) | Bevacizumab, Cisplatin, Docetaxel, Gemcitabine, Vinorelbine | VCB - > DGB | 0 | ||||||||||||||||
| DCB | 1 | ||||||||||||||||||
| Eli Lilly and Company (2015) | Carboplatin, Cetuximab, Taxane (Paclitaxel/Docetaxel) | Tax-Car | 1 | 1 | 1 | 7 | 3 | 20 | 0 | 2 | 1 | 5 | |||||||
| Tax-Car-Cel | 1 | 6 | 0 | 27 | 3 | 39 | 1 | 5 | 4 | 3 | Cardio-respiratory arrest: 2 | ||||||||
| GlaxoSmithKline (2019) | Carboplatin, Cisplatin, Docetaxel, GSK3052230, Paclitaxel, Pemetrexed | 5GSK-Car-Pac | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||||||||
| 10GSK-Car-Pac | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||||||||||
| 20GSK-Car-Pac | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 0 | 1 | Cardiomegaly: 1 | |||||||||
| 5GSK-Doc | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 0 | Acute Coronary Syndrome: 1 Angina Pectoris: 1 |
|||||||||
| 10GSK-Doc | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | ||||||||||
| 20GSK-Doc | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||||||||||
| 10GSK-Cis-Pem | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | ||||||||||
| 15GSK-Cis-Pem | 0 | 0 | 0 | 5 | 1 | 0 | 1 | 0 | 0 | Conduction disorder: 1 | |||||||||
| 20GSK-Cis-Pem | 0 | 0 | 1 | 2 | 1 | 0 | 0 | 0 | 0 | Conduction disorder: 1 Left ventricular hypertrophy: 1 Ventricular extrasystoles: 1 |
|||||||||
| Lara et al. (2016) | Carboplatin, Erlotinib, Paclitaxel | Erlo | 3 | ||||||||||||||||
| Erlo-Car-Pac | 3 | ||||||||||||||||||
| Wu et al. (2020) | Carboplatin, Cisplatin, Gefitinib, Pemetrexed, Tepotinib, | 1b-300Tep-Gef | 0 | 0 | 0 | ||||||||||||||
| 1b-500Tep-Gef | 1 | 1 | 1 | Cardiac discomfort: 1 | |||||||||||||||
| 2Neg-Tep-Gef | 0 | 0 | 0 | ||||||||||||||||
| 2Neg-Pem-Car/Cis | 0 | 0 | 0 | ||||||||||||||||
| 2Pos-Tep-Gef | 0 | 0 | 0 | Supraventricular extrasystoles: 1 | |||||||||||||||
| Umsawasdi et al. (1989) | Cisplatin, Cyclophosphamide, Doxorubicin | Weekly-Dox | |||||||||||||||||
| Triweekly-Dox | |||||||||||||||||||
| * Endomyocardial biopsies were done when a total cumulative doxorubicin dose of 300 or 480 mg/m2 was reached. Results showed an increase in cardiotoxicity with an increase dosage of doxorubicin, and that the weekly administration of doxorubicin was less toxic than that of the standard/tri-weekly administration of doxorubicin | |||||||||||||||||||
| Cortot et al. (2020) | Bevacizumab, Docetaxel, Paclitaxel | Bev-Pac | 22 | Ischaemic stroke leading to death: 1 | |||||||||||||||
| Doc | 0 | ||||||||||||||||||
| AstraZeneca (2021) | Docetaxel, Selumetinib | Doc-Plac | 4 | 0 | 10 | 2 | 3 | 8 | 0 | 5 | 4 | Cardiovascular insufficiency: 1 Cardiomegaly: 1 |
|||||||
| Doc-Selu | 5 | 2 | 6 | 8 (1 is congestive) | 4 | 15 | 1 | 0 | 7 | Bundle branch block left: 1 Coronary artery dissection: 1 Diastolic dysfunction: 1 Left Ventricular Dysfunction:1 Mitral valve imcopetence: 1 Pericarditis constrictive: 1 |
|||||||||
| Johnson et al. (2004) | Bevacizumab, Carboplatin, Paclitaxel | Car-Pac | 1 | 3 | |||||||||||||||
| Car-Pac-7.5Bev | 5 | 4 | |||||||||||||||||
| Car-Pac-15Bev | 6 | 6 | |||||||||||||||||
| Eli Lilly and Company (2022) | Cisplatin, Gemcitabine, Necitumumab | Cis-Gem | 4 | 1 | 0 | 0 | 4* | 0 | 1 | 3 | 1 | 4 | Acute Coronary Syndrome: 1 Cardio-respiratory arrest: 1 Pericarditis: 1 * including 1 acute, 1 congestive |
||||||
| Cis-Gem-Nec | 3 | 0 | 2 | 2 | 1* | 2 | 0 | 4 | 0 | 9 | Cardiac Tamponade: 1 Cardio-respiratory arrest: 3 Coronary artery disease: 1 * including 1 congestive |
||||||||
| Eli Lilly and Company (2021) | Cisplatin, Pemetrexed, Necitumumab | Cis-Pem | 0 | 2 | 0 | 1 | 0 | 30 | 1 | 2 | 2 | Angina pectoris: 1 Cardiomyopathy: 1 |
|||||||
| Cis-Pem-Nec | 1 | 2 | 2 | 1 | 2 | 17 | 2 | 3 | 6 | Cardiac tamponade: 2 Cardio-respiratory arrest: 1 Cardiopulmonary failure: 1 |
|||||||||
| Eli Lilly and Company (2019b) | Carboplatin, Paclitaxel, Necitumumab | Car-Pac | 4 | 0 | 0 | 7 | 0 | 1 | |||||||||||
| Car-Pac-Nec | 4 | 1 | 1* | 13 | 2 | 1 | * including 1 congestive | ||||||||||||
Remarks: All cardiovascular events with ≤3 studies reported are include in “others”.