Role of Biomarkers in Chemotherapy-Induced Cardiotoxicity

doi:10.1016/j.pcad.2010.04.002

Progress in Cardiovascular Diseases

Volume 53, Issue 2, September–October 2010, Pages 121-129

https://doi.org/10.1016/j.pcad.2010.04.002 Get rights and content

Abstract

Chemotherapy-induced cardiotoxicity remains an unresolved problem strongly impacting the quality of life and the overall survival of cancer patients. The main strategy for minimizing cardiotoxicity is early detection of high-risk patients and prompt prophylactic treatment. The current standard for monitoring cardiac function detects cardiotoxicity only when a functional impairment has already occurred, not allowing for any early preventive strategies. Measurement of cardiospecific biomarkers can be a valid diagnostic tool for early identification, assessment, and monitoring of cardiotoxicity. In particular, the role of troponin in identifying patients at risk of cardiotoxicity and of angiotensin-converting enzyme inhibitors in preventing cardiac dysfunction and cardiac events is clearly emerging as a new effective approach. Therefore, we propose troponin as a criterion standard marker for the assessment of cardiac risk of both old and new antineoplastic treatments, and its evaluation should be included among the criteria utilized to define cardiotoxicity.

Section snippets

Current approach

The most typical clinical manifestation of cardiotoxicity is asymptomatic or symptomatic cardiac dysfunction. In clinical practice, regular cardiac function assessment is recommended by oncologic guidelines to detect early cardiotoxicity,5, 6, 7 by the evaluation of left ventricular ejection function (LVEF) and by either echocardiography or multigated acquisition scanning. However, some major limitations of this approach must be highlighted. First, not all patients treated with CT require LVEF

Possible strategies for cardioprotection

The best treatment for CT-induced cardiotoxicity is its prevention in the first instance. Currently, several preventive measures are being used, including close monitoring of cardiac function, limiting cumulative CT dose, using AC analogues, adding cardioprotectants to the CT regimen, using nutritional supplements, and planning preventive pharmacologic therapies in high-risk patients selected by means of biomarkers.⁶² In all this, of course, the oncologic effectiveness must be maintained.

Conclusions

Cardiotoxicity is a frequent complication of CT and has a strong impact, in clinical and prognostic terms, on patients with cancer. The main strategy for minimizing cardiotoxicity is still early detection of high-risk patients and the initiation of prompt prophylactic treatment. Measurement of serum cardiospecific biomarkers may therefore become a useful routine method for identifying patients more prone to developing cardiotoxicity and in whom a preventive pharmacologic strategy and closer

Statement of Conflict of Interest

All authors declare that there are no conflicts of interest.

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Carfilzomib (CFZ), a chemotherapeutic agent used for multiple myeloma treatments reported to cause high incidence of cardiac events either new onset and/or exacerbate formerly diagnosed heart failure with ventricular and myocardial dysfunction.
Purpose: Current research designed to explore and examine the preventive effect of oxyphenbutazone in the CFZ -instigated cardiotoxicity. Methodology: Female Wistar Rats weighing 200–250 g selected randomly and grouped as follows: Group 1 designated as the Normal control and receive normal saline only. Group 2 served toxic control and exposed to CFZ (4 mg/kg, intraperitoneally [i.p.]). Group 3 & 4 served as treatment groups and administered with CFZ concomitantly orally fed with oxyphenbutazone at doses of 35 and 70 mg/kg/three times a week, respectively. The total duration of experimental protocol was of 21 days. After completion of the experiments animals subjected to blood collection using light ether anesthesia and serum was separated for biochemical analysis further. The serum levels of Mg⁺², Ca⁺² and cardiac enzymes (aspartate transaminase (AST), lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase-MB (CK-MB) levels were estimated. Later animals sacrificed and heart tissue isolated for further examinations. Intracellular proteins NFkB and IkBα were estimated by western blot. Results: The serum analysis revealed that CFZ administration significantly elevated the levels of LDH, CK and CKMB in CFZ exposed animals when compared to normal animals while administration of oxyphenbutazone significantly reduced these biochemical changes, Intracellular antioxidant enzymes and NF-kB in treatment groups as compared to disease control animals. Conclusion: Findings of the research protocol suggests significant injuries to cardiac tissues when animals exposed to CFZ and Oxyphenbutazone protected the cardiac tissues.
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It has been reported that early detection and treatment of cancer therapy- related cardiac dysfunction (CTRCD) improves its prognosis. The detailed relationships between electrocardiographic repolarization indices and decreased left ventricular function in CTRCD have not been elucidated. We closely assessed such relationships in patients with doxorubicin (DOX)-induced CTRCD.
This retrospective, single-center, cohort study included 471 consecutive patients with malignant lymphoma who received chemotherapy including DOX. Of them, 17 patients with CTRCD and 68 patients without CTRCD who underwent 12‑lead electrocardiogram and an echocardiogram before and after chemotherapy were eventually analyzed. The fluctuations of the following electrocardiographic repolarization indices were evaluated in lead V5: QT, JT, T peak to T end interval (Tp-e), and activation recovery interval (ARI). These indices were corrected by heart rate with the Fridericia formula.
The median period from the end of chemotherapy to the diagnosis of the CTRCD group was 346 days (IQR 170–1283 days). After chemotherapy, the QT interval was significantly prolonged in both with and without CTRCD groups compared with that before chemotherapy (pre QTc vs. post QTc in CTRCD group, 386 ± 27 ms vs. 411 ± 37 ms, p = 0.03, pre QTc vs. post QTc in non-CTRCD group, 388 ± 24 ms vs. 395 ± 25 ms, p = 0.04, respectively). ARIc after chemotherapy was characteristically observed only in the CTRCD group (pre ARIc vs. post ARIc in CTRCD group, 258 ± 53 ms vs. 211 ± 28 ms, p = 0.03, pre ARIc vs. post ARIc in non-CTRCD group, 221 ± 19 ms vs. 225 ± 23 ms, NS, respectively) and had negative correlations with left ventricular ejection fraction (r = −0.56, p < 0.001). Using the receiver-operating characteristic curve, the relationship between ARIc and CTRCD morbidity was examined. The optimal cut-off point of ARIc prolongation between before and after chemotherapy was 18 ms (sensitivity 75 %, specificity 79 %, area under the curve 0.76).
ARIc prolongation may be useful in the early detection of developing late-onset chronic DOX-induced CTRCD and lead to early treatment for cardiac protection.
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Citation Excerpt :
Biomarkers of cardiac injury, including hs-cTnT, brain natriuretic peptide (BNP), and C-reactive protein (CRP), also predict a higher likelihood of myocardial ischemia. Several studies have shown that hs-cTnT assays enable the early detection and prediction of chemo- or radiation therapy-induced cardiac toxicity.34-37 Among patients with cancer receiving radiation therapy, a meta-analysis suggested that BNP could be useful as a biomarker of cardiac damage.38,39
Cardiotoxicities induced by cancer therapy can negatively affect quality of life and survival. We investigated whether high-sensitivity cardiac troponin T (hs-cTnT) levels could serve as biomarker for early detection of cardiac adverse events (CAEs) after chemoradiation therapy (CRT) for non-small cell lung cancer (NSCLC).
This study included 225 patients who received concurrent platinum and taxane-doublet chemotherapy with thoracic radiation therapy to a total dose of 60 to 74 Gy for NSCLC. All patients were evaluated for CAEs; 190 patients also had serial hs-cTnT measurements.
Grade ≥3 CAEs occurred in 24 patients (11%) at a median interval of 9 months after CRT. Pretreatment hs-cTnT levels were higher in men, in patients aged ≥64 years, and in patients with pre-existing heart disease or poor performance status (P < .05). hs-cTnT levels increased at 4 weeks during CRT (P < .05) and decreased after completion of CRT but did not return to pretreatment levels (P = .002). The change (Δ) in hs-cTnT levels during CRT correlated with mean heart dose (P = .0004), the heart volumes receiving 5 to 55 Gy (P < .05), and tumor location (P = .006). Risks of severe CAEs and mortality were significantly increased if the pretreatment hs-cTnT was >10 ng/L or the Δ during CRT was ≥5 ng/L.
Elevation of hs-cTnT during CRT was radiation heart dose-dependent, and high hs-cTnT levels during the course of CRT were associated with CAEs and mortality. Routine monitoring of hs-cTnT could identify patients who are at high risk of CRT-induced CAEs early to guide modifications of cancer therapy and possible interventions to mitigate cardiotoxicity.
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: Statement of Conflict of Interest: see page 127.

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Role of Biomarkers in Chemotherapy-Induced Cardiotoxicity

Abstract

Section snippets

Current approach

Possible strategies for cardioprotection

Conclusions

Statement of Conflict of Interest

Cancer Treat Rev

J Am Coll Cardiol

Ann Oncol

Toxicology

Toxicology

J Am Coll Cardiol

Ann Oncol

J Lab Clin Med

Ann Oncol

Lancet

Am Heart J

Int J Cardiol

Ann Oncol

Eur J Cancer

Lancet Oncol

Jpn J Pharmacol

Eur J Pharmacol

J Mol Cell Cardiol

J Am Coll Cardiol

Clinical cancer advances 2005: major research advances in cancer treatment, prevention, and screening. A report from the American Society of Clinical Oncology

J Clin Oncol

Cardiovascular complications of cancer therapy. Diagnosis, pathogenesis and management

Circulation

Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management

Expert Opin Pharmacother

Cardiac and cardiovascular toxicity of nonanthracycline anticancer drugs

Expert Rev Anticancer Ther

Circulation

Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Children Cancer Study Group

Pediatrics

Is MUGA scan necessary in patients with low-risk breast cancer before doxorubicin-based adjuvant therapy?

Am J Clin Oncol

Cardiac toxicity in breast cancer survivors: review of potential cardiac problems

Clin Cancer Res

Epirubicin cardiotoxicity: a study of 135 patients with advanced breast cancer

J Clin Oncol

Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction

J Am Coll Cardiol

Cardioprotective effects of ACE-inhibitor (Cilazapril) on adriamycin cardiotoxicity in spontaneous hypertensive rats

Circulation

Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin

J Clin Oncol

Cardiac troponin T as an indicator of reduced left ventricular contractility in experimental anthracycline-induced cardiomyopathy

Cancer Chemother Pharmacol

Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury

Circulation

Minor increases in plasma troponin I predict decreased left ventricular ejection fraction after high-dose chemotherapy

Clin Chem

Prognostic value of Troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy

Circulation

Prolonged monitoring of troponin T for the detection of anthracycline cardiotoxicity in adults with hematological malignancies

Ann Hematol