Edited by: Monica Montopoli, University of Padua, Italy
Reviewed by: Roberta Frapolli, Istituto di Ricerche Farmacologiche Mario Negri (IRCCS), Italy; Giovanni Grignani, Institute for Cancer Research and Treatment (IRCC), Italy
*Correspondence: Bogdan Grigoriu,
This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology
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New drugs come not only with benefits but also with unexpected toxicities which need to be promptly recognized and managed. Starting from a scholar case of acute heart failure with preserved ejection fraction following the administration of trabectedin (ET-743, Yondelis®) in a patient with a metastatic solitary fibrous tumor, we performed a systematic review of the literature encompassing the results of previous cardiac safety analysis published ten years ago, a review of clinical trials published during the last 10 years as well as single-case descriptions related to trabectedin cardiotoxicity. The estimated incidence of cardiac toxicity was 3,4% among patients receiving trabectedin, with recent data suggesting a higher rate of heart failure than previously recognized. Previous or concomitant anthracyclines exposure may represent a risk factor. Assaying for NT-pro-BNP may be useful for the early detection of individuals with trabectedin-induced heart failure.
Trabectedin (code ATC L01CX01, also known as ecteinascidin 743 or ET-743 – Yondelis ®) is a synthetically produced tetrahydroisoquinoline alkaloid originally derived from the Caribbean marine tunicate, Ecteinascidia turbinata (
The most common adverse events associated with Tbt are myelosuppression, digestive toxicity (anorexia, nausea, vomiting, diarrhea or constipation), general condition decline and hepatic toxicity (hyperbilirubinemia, elevation of alanine aminotransferase or/and aspartate aminotransferase) (
We report a case of acute cardiac toxicity which is not classically acknowledged and infrequently described during early phases of drug development. A systematic review of the literature addressing Tbt-associated cardiac adverse effects (CAE) is presented.
A 53-year-old man with a metastatic solitary fibrous tumor (SFT) was admitted because of recent onset dyspnea. Two days before admission and one day after a third Tbt cycle, he presented abrupt shortness of breath with orthopnea and ankle swelling without chest pain, fever or chills. The same symptoms have already been present after the previous Tbt administrations with increased severity with each cycle, but resolved spontaneously after five to seven days.
He suffered from arterial hypertension, hypercholesterolemia, type 2 diabetes and hypothyroidism. He had been diagnosed with a cerebral SFT ten years earlier in the setting of seizures, revealing a right occipital mass which was surgically removed immediately followed by whole brain irradiation. Five years later, hepatic and pancreatic relapses were managed by surgical resection. One year later, liver and lung progression mandated weekly adriamycin (cumulative dose 375 mg/m2), with disease control for 9 months. He then received a combination of ramucirumab and an angiopoietin 2 inhibitor (phase I trial), discontinued after 4 months for grade III hypertension. After 4 months of therapeutic break he received pazopanib for metastatic progression. After a new multi-site metastatic progression, a fourth line of cyclophosphamide (200 mg daily) and a fifth line of paclitaxel (80 mg/m2 weekly) were administered, both without anti-tumoral effect. Three months before the current admission Tbt 1.5 mg/m2 every three weeks was initiated for disease progression.
Upon hospital admission, physical examination revealed tachypnea, bilateral jugular veins distention and inferior limb edema with crackles in the left lower lung area. Arterial blood gases, breathing room air, showed pH 7,47; PaCO2 33 mmHg; PaO2 68 mmHg and blood analysis a grade 2 anemia, grade 1 acute renal failure and NT-pro-BNP at 2800 pg/mL (N < 143 pg/mL). D-dimers and troponin were within normal range while EKG showed only a left atrial hypertrophy. An angiographic chest CT revealed already known bilateral pulmonary metastases and no arguments for any infectious process, pleural or pericardial effusion. NT-pro-BNP measurements gradually increased since receiving Tbt (from 356 pg/mL after the first cycle to 2800 pg/mL four days after the third cycle). A drug-related cardiac failure was suspected and intravenous furosemide. Intravenous furosemide (40 mg) resulted in rapid clinical improvement. Four days later an echocardiography was unremarkable. Subsequent coronary computed tomographic angiography and an isotopic evaluation of left ventricular ejection fraction were normal. He was discharged with oral furosemide with symptoms relief. Tbt was permanently discontinued.
The literature search was performed by a scientific librarian (VD) experienced in searching for medical and scientific publications and by a physician (BG) trained in evidence-based medicine. Ovid Medline (
In 2011, Lebedinsky et al. (
To complete the cardiac safety analysis of Lebedinsky et al., we initially reviewed all clinical trials testing Tbt alone or in combination with other agents published between 2010 and 2020. Among the 36 clinical trials retrieved from the literature during this period, CAE were reported in 13 publications, mostly phase II trials, regrouping 1061 patients, which are detailed in
Clinical trials using trabectedin alone or in combination with other agents and reporting cardiac adverse effects.
| 1st author, year of publication | Cancer type | Study design | Incidence of CAE | Hypertension | Arrythmia/EKG abnormalities | Myocardial infarction | Heart failure | TTE abnormalities | Comments | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| G1-2 | G3-4 | G1-2 | G3-4 | G1-2 | G3-4 | G1-2 | G3-4 | ||||||
| Monk, 2010 ( |
Ovarian | Phase III, Tbt + PDL |
6/337 (Tbt+PLD arm) | – | – | – | – | – | – | 6 | 7/337 LVEF reduction, not graded | ||
| Monk, 2011 ( |
Ovarian | Phase II, Tbt+docetaxel | 3/71 | – | – | – | – | – | – | – | – | – | 3 grade I CAE not described |
| Michaelson, 2012 ( |
Prostate | Phase II, Tbt alone | 3/58 | – | – | – | 1 | – | 1 | – | 1 | – | |
| Sessa, 2013 ( |
Solid tumors | Phase I, Tbt alone, dose esc. | 3/12 | – | – | 1 | 1 | – | – | – | – | 1 grade 1 or 2 LVEF reduction | |
| Delaloge, 2014 ( |
Breast | Phase II, Tbt alone | 2/38 | – | – | – | – | – | – | – | 1 | 1 LVEF reduction, not graded | |
| Ueda, 2014 ( |
Sarcoma | Phase I, Tbt dose esc. | 3/15 | – | – | 2 | 1 | – | – | – | – | – | 3 QT interval prolongation |
| Bui-Nguyen, 2015 ( |
Sarcoma | Phase IIb, Doxo |
3/90 (Tbt arm) | – | – | – | – | – | – | – | – | – | 3 grade 3 or 4 CAE, not described |
| Pautier, 2015 ( |
Sarcoma | Phase II, Tbt+Doxo | 1/108 | – | – | 1 | – | – | – | – | – | – | |
| Kawai, 2015 ( |
Sarcoma | Phase II, Tbt |
2/39 (Tbt arm) | – | – | 1 | 1 | – | – | – | – | – | 2 QT interval pronlongation |
| Le Cesne, 2015 ( |
Sarcoma | Phase II, Tbt alone interruption |
2/46 | – | – | – | 1 | – | – | 1 | – | HF occurred in continuation arm | |
| Gaducci, 2018 ( |
Sarcoma | Phase II, Tbt alone | 2/126 | – | – | 1 | – | – | – | – | 1 | – | |
| Grignani, 2018 ( |
Sarcoma | Phase Ib, Tbt+olaparib | 3/50 | 1 | 2 | – | – | – | – | – | – | – | |
| Colombo, 2019 ( |
Ovarian | Phase II, Tbt + bevacizumab +/- carboplatin | 2/71 | – | – | – | – | – | – | – | 1 | 1 grade 3 LVEF reduction | Both cases occurred in patients receiving the 3 agents |
| Total | 36/1061 | 1 | 2 | 6 | 5 | 0 | 2 | 11 | |||||
BSC, best supportive care; Dose esc., dose escalation; Doxo, doxorubicin; LVEF, left ventricular heart failure; PLD, pegylated liposomal doxorubicin; Tbt, Trabectedin; TTE, transthoracic echocardiography; vs\, versus. “-” Not reported.
A review of clinical studies, case reports and small case series was performed to gain insight into the clinical pattern of Tbt-induced CAE (
Detailed analysis of single cases of trabectedin-induced cardiotoxicity reported in clinical trials, case series and case reports.
| 1st author, year of publication | Study design | Nb of subjects | Incidence | Indication | Sex, age | Nb of cycles* | CV risk factors | Previous chemotherapy | Presentation | Evolution | Other cause suspected |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Krasner, 2007 ( |
Phase II trial, Tbt alone | 147 | 1/147 | Ovarian cancer | F, 58y | 7th | NM | Yes, Carboplatin Taxane | Grade 3 dyspnea, pulmonary edema, central chest pain, bilateral pleural effusion, pulmonary hypertension, and left cardiac failure | Fatal | No |
| Messersmith, 2008 ( |
Phase I trial, Tbt + gemcitabine | 15 | 1/15 | Solid tumor | NM | NM | NM | Yes, NM | Congestive heart failure and pulmonary edema | Not fatal | NM |
| Ferrandina, 2013 ( |
Retrospective, multicenter, Tbt alone | 98 | 2/98 | Ovarian cancer | F, > 70y | NM | Yes | Yes, |
Grade 3 arrythmia | Not fatal | NM |
| F, > 70y | NM | Yes | Yes, |
Myocardial infarction | Not fatal | NM | |||||
| Moriceau, 2015 ( |
Retrospective, monocenter, Tbt alone | 59 | 2/59 | Soft tissue sarcomas | NM | NM | NM | Yes, NM | Acute cardiac failure, pulmonary edema | Not fatal | Sodium overload, pulmonary embolism |
| NM | NM | NM | Yes, NM | Acute cardiac failure, pulmonary edema | Not fatal | None | |||||
| Blum, 2016 ( |
Phase II trial, Tbt alone | 87 | 1/87 | Breast cancer | F, NM | NM | Yes | Yes, NM | Congestive heart failure | Not fatal | Presumed |
| Doherty, 2019 ( |
Case series about cardiac toxicity, monocenter, Tbt alone | 6 | – | Uterine myosarcoma | F, 71y | 5th | None | Yes, Anthracyclines | Pulmonary edema, myocardial infarction | Not fatal | No |
| Spindle cell and pleomorphic sarcoma of thigh | F, 81y | 2nd | Yes (AF, ventricular pacing) | NM (no anthracyclines) | Pulmonary edema | Not fatal | No | ||||
| Carcinosarcoma | F, 72y | 3rd | None | Yes, Anthracyclines | Myocardial infarction | Not fatal | No | ||||
| Spindle cell and pleomorphic sarcoma of thigh | F, 68y | 1st | None | Yes, Anthracyclines | Cardiac arrest | Fatal | No | ||||
| Diaphragmatic leiomyosarcoma | M, 75y | 2nd | Yes (AF) | Yes, |
Fast atrial fibrillation | Fatal | Yes, Lesion abutting heart may have predisposed as well as pneumonia | ||||
| Vulval leiomyosarcoma | F, 73y | 2nd | None | Yes, Anthracyclines | Fast atrial fibrillation | Not fatal | Lesion abutting heart may have predisposed |
*Number of trabectedin cycles administered before cardiac adverse event onset.
AF, atrial fibrillation; F, female; M, male; Nb, number; NM, not mentioned; y, year.
Myocardial infarction occurred in three patients. In all cases, patients had received anthracyclines in their past history, age was between (71-72 years and one of them presented an acute HF (pulmonary edema) but no fatal issue occurred. In two cases, no other causative mechanism was suspected and Tbt-associated cardiac ischemia was suggested as mechanism.
Finally, three patients presented with cardiac arrhythmia including 2 patients with AF and one with a grade 3 arrhythmia not otherwise specified. Both patients with AF had neoplastic lesions abutting the heart which may predispose to arrhythmia and one patient had a concurrent infection as well as prior AF history, potentially explaining AF recurrence.
Overall, among these thirteen patients, three died from their CAE, including one patient with acute HF and one patient with fast AF. One patient had a cardiac arrest after an acute chest pain on day 10 of the first Tbt cycle. He suffered from arterial hypertension, statin-treated hypercholesterolemia, deep vein thrombosis with ongoing therapeutic coagulation and had previously received liposomal doxorubicin. A cardiac cause was suspected rather than a venous thrombo-embolic event given the therapeutic anticoagulation.
We report here a case of acute heart failure following Tbt administration in a heavily pretreated man with a SFT. Despite major cardiovascular risk factors, the work-up allowed us to exclude the most frequent etiologies of acute HF. The combination of acute NT-pro-BNP elevation concomitant with chemotherapy course, recurrence with increased clinical severity with each cycle, the exclusion of other causative conditions and ultimately the favorable evolution suggested the diagnosis of Tbt-induced HF. Acute heart failure has not been sufficiently recognized during initial phases of drug development and in practice, more than 3-4 Tbt cycles are given before such a potential severe side effect is recognized and assigned to the drug.
The emergence of new therapeutic options is a windfall for patients facing rare neoplasms. These advances go hand in hand with a prolonged survival which prompt clinicians to prevent or at least reduce long term drug-induced toxicity. However, ageing and the increase in the prevalence of cardiovascular risk factors face us to a population with high cardiovascular risk, precipitating the acute or delayed adverse cardiovascular effects of antineoplastic agents.
Chemotherapy-induced cardiac toxicity is a well-known phenomenon and can be divided into two major types. Type 1 cardiac toxicity is irreversible and is often dose dependent. Anthracyclines are typically associated with this kind of toxicity with an incidence of left ventricular dysfunction ranging from 3 to 5% with a cumulative doxorubicin dose of 400 mg/m2 to 18 to 48% for 700 mg/m2 (
Recently, Nadruz et al. compared the characteristics of patients with HF induced by anti-neoplastic therapies (most of them had received anthracyclines, anthracyclines and radiotherapy (RT) or RT alone; 25% had breast cancer) and patients with HF unrelated to cancer (
During its preclinical development, Tbt was not associated with relevant macroscopic, microscopic or functional cardiac alterations (
Detailed analysis of single cases of Tbt-induced cardiotoxicity was in agreement with our previous findings, with HF representing the most commonly reported picture. Prior anthracyclines treatment, initial presentation of acute pulmonary edema and the non-fatal issue, are characteristics shared by most cases reported. Our patient was younger but had more cardiovascular risk factors than those previously reported. Lebedinsky et al. suggested that age > 70 years, previous anthracycline or cardiac radiotherapy exposure and cardiovascular risk factors (including hypertension, hypercholesterolemia, obesity and type II diabetes) may represent potential risk factors for CAE occurrence. Even if suggested, female gender cannot be included in this list given the overrepresentation of women in trials in which Tbt was evaluated (ovarian and breast cancer, uterine leiomyosarcoma).
Finally, our case raises the question of the utility of monitoring cardiac biomarkers which could identify cardiotoxicity earlier and allow prompt management. Numerous studies have evaluated available cardiac biomarkers, mainly troponins and natriuretic peptides (
More recently, Demissei et al. published the largest prospective study to date assessing clinical data, echocardiography and cardiac biomarkers in breast cancer patients receiving cardiotoxic agents (namely doxorubicin, cyclophosphamide and/or trastuzumab) with an extended follow-up period of 3.7 years (
Our study has several limitations. First, its retrospective nature and the heterogeneity of CAE reporting among clinical studies, may result in underestimation of the real incidence of Tbt-induced CAE. Second, stating a definite causal relationship between Tbt-administration and the onset of HF is difficult given the large number of confounding factors involved in cancer patients.
In conclusion, our systematic literature review suggested a Tbt-induced CAE incidence of 3.4% Data from more recent clinical trials and case reports highlight a higher rate of heart failure than previously reported as well as a possible interaction with anthracyclines. Data concerning the cardiac outcome is lacking but as suggested by our case and some others, HF could be completely reversible after drug discontinuation. Clinicians should be aware of such Tbt-associated acute cardiac toxicity and consider the risk-benefit ratio in patients with pre-existing cardiovascular disease. We suggest a possible interest of NT-pro-BNP for the early recognition of Tbt-associated heart failure.
JC, CJ, and BG managed the case and wrote the manuscript. VD performed the initial literature search and provided full text articles. CD performed database toxicologic research. All authors were involved in development of the manuscript, revising it critically for important intellectual content. All authors contributed to the article and approved the submitted version.
CJ received travel grants from PharmaMar S.A.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Equations for literature search
(Trabectedin/OR Trabectedin.ti,ab,kw,nm OR Yondelis.ti,ab,kw,nm) AND (exp Heart Failure/OR Heart Failure*.ti,ab,kw OR Cardiac Failure*.ti,ab,kw OR Myocardial Failure*.ti,ab,kw OR Heart Decompensation*.ti,ab,kw OR cardiac edema*.ti,ab,kw OR ventricular dysfunction*.ti,ab,kw OR pulmonary edema*.ti,ab,kw OR diastolic dysfunction*.ti,ab,kw OR HFrEF.ti,ab,kw OR HRpEF.ti,ab,kw OR exp Cardiotoxicity/
OR exp Hypertension, Pulmonary/OR exp Natriuretic Peptides/OR cardiotoxicit*.ti,ab,kw OR cardio-toxicit*.ti,ab,kw OR Cardiac Toxicit*.ti,ab,kw OR cardio-oncolog*.ti,ab,kw OR cardiooncolog*.ti,ab,kw OR pulmonary hypertension*.ti,ab,kw OR natriuretic peptide*.ti,ab,kw OR Atrial Natriuretic Factor*.ti,ab,kw OR Auriculin.ti,ab,kw OR Atriopeptin*.ti,ab,kw OR Cardionatrin.ti,ab,kw OR Cardiodilatin.ti,ab,kw OR Atriopeptigen.ti,ab,kw)
TITLE-ABS-KEY [(Trabectedin OR Yondelis) AND (“Heart Failure” OR “Heart Failures” OR “Cardiac Failure” OR “Cardiac Failures” OR “insuffisance cardiaque” OR “insuffisances cardiaques” OR “Défaillance cardiaque” OR “Défaillances cardiaques” OR “Décompensation cardiaque” OR “Défaillance myocardique” OR “Défaillances myocardiques” OR “Myocardial Failure” OR “Myocardial Failures” OR “Heart Decompensation” OR “Heart Decompensations” OR “cardiac edema” OR “cardiac edemas” OR “oedème cardiaque” OR “oedèmes cardiaques” OR “ventricular dysfunction” OR “ventricular dysfunctions” OR “dysfonction ventriculaire” OR “dysfonctions ventriculaires” OR “pulmonary edema” OR “pulmonary edemas” OR “oedème pulmonaire” OR “oedèmes pulmonaires” OR “diastolic dysfunction” OR “diastolic dysfunctions” OR “dysfonction diastolique” OR “dysfonctions diastoliques” OR HFrEF OR HRpEF OR cardiotoxicit* OR cardio-toxicit* OR “Cardiac Toxicity” OR “Cardiac Toxicities” OR “Toxicité cardiaque” OR “Toxicités cardiaques” OR cardio-oncolog* OR cardiooncolog* OR “pulmonary hypertension” OR “pulmonary hypertensions” OR “hypertension pulmonaire” OR “hypertensions pulmonaires” OR “Cardiaques noirs” OR “maladie d’Ayerza” OR “syndrome d’Ayerza” OR “natriuretic peptide” OR “natriuretic peptides” OR “peptides natriurétiques” OR “Atrial Natriuretic Factor” OR “Atrial Natriuretic Factors” OR “facteur atrial natriurétique” OR “Facteur auriculaire natriurétique” OR Auriculin OR Atriopeptin* OR Cardionatrin OR Cardiodilatin* OR Atriopeptigen)]