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Cardiotoxicity associated with targeted cancer therapies


Compared with traditional chemotherapy, targeted cancer therapy is a novel strategy in which key molecules in signaling pathways involved in carcinogenesis and tumor spread are inhibited.
Targeted cancer therapy has fewer adverse effects on normal cells and is considered to be the future of chemotherapy.
However, targeted cancer therapy‑induced cardiovascular toxicities are occasionally critical issues in patients who receive novel anticancer agents, such as Trastuzumab, Bevacizumab, Sunitinib and Imatinib.

Introduction

Cardiotoxicity, a commonly encountered adverse effect, may be associated with traditional as well as novel targeted chemotherapeutic agents, and is grouped into two categories, namely type I ( traditional ) and type II ( targeted ), based on distinct pathological changes and clinical characteristics.

Anthracyclines are the prototype of type I agents. Anthracycline-based chemotherapy is associated with a significant risk of left ventricular dysfunction ( LVD ) or congestive heart failure ( CHF ), compared with non-anthracycline regimens [ odds ratio ( OR )=5.43; 95% confidence interval ( CI ): 2.34–12.62, P less than 0.0001 ].
The incidence of subclinical left ventricular dysfunction may be as high as 36% in patients with a history of prior anthracycline therapy.
Type I agents cause irreversible ultrastructural damage to cardiomyocytes, such as vacuole formation, contractile element disarray, or even necrosis.

Trastuzumab ( Herceptin ) is the representative agent in the type II category, resulting in cardiac dysfunction with an incidence reportedly ranging from 3 to 64% in single-agent or combination regimens.
Type II agents result in benign ultrastructural changes in cardiomyocytes, with reversible cardiac function changes.

In addition to cardiac dysfunction, targeted cancer therapy-induced cardiotoxicities may manifest as elevated blood pressure, thromboembolism, pericardial thickening and arrhythmia.

Trastuzumab

Human epidermal growth factor receptor 2 ( HER2 ) is a 185-kd transmembrane glycoprotein receptor, encoded by the ErbB2 proto-oncogene. Overexpression of HER2 promotes tumorigenesis in a variety of cancers, such as breast and colon cancer.
Being a humanized monoclonal antibody against human HER2 with reduced immunogenicity, Trastuzumab is highly effective in treating primary as well as metastatic breast cancer, thereby improving survival.
Trastuzumab may be used as first-line therapy in combination with Paclitaxel chemotherapy, and also as a single agent for patients who have priorly received chemotherapeutic regimens.

Trastuzumab was a significant breakthrough in the treatment of breast cancer overexpressing HER2 receptors ( ~25–30% of breast cancers ).

Cardiac dysfunction, either asymptomatic ( decreased LV ejection fraction ) or symptomatic ( congestive heart failure ), has been reported in pivotal phase II and III clinical trials, with a range from 3 to 64% when used alone or as part of combination regimens.
Trastuzumab significantly increases the incidence of cardiotoxicity when combined with other agents. For example, in clinical trial H0648g, anthracycline and Trastuzumab-treated patients experienced cardiac dysfunction at a rate of 27%, compared with a rate of 8% in patients treated with anthracyclines alone.

In the majority of the cases ( 79% ), the cardiac dysfunction improved after receiving treatment for heart failure, and reintroducing Trastuzumab after recovery from cardiac dysfunction is considered acceptable.

Trastuzumab is also safe when administered concurrently with postoperative radiotherapy, without an increased risk of cardiac events.

Although there is no consensus on the onset of cardiotoxicity, it appeared that administering Trastuzumab for more than 6 months was more likely to lead to a decline in the ejection fraction, whereas shorter treatment ( less than or equal to 6 months ) did not appear to be associated with an increased risk of heart failure.

Bevacizumab

Several types of tumor cells secrete angiogenic molecules, such as vascular endothelial growth factor ( VEGF ), to promote new vessel formation in order to meet the increased demands on oxygen and nutrients.
By blocking VEGF/VEGF receptor ( VEGFR ) signaling, Bevacizumab ( Avastin ) was the first FDA-approved humanized monoclonal anti-VEGF antibody to treat metastatic malignancies, including metastatic colorectal cancer and non-squamous, non-small-cell lung cancer.

In addition to Bevacizumab, the FDA-approved small molecules that target VEGFR include Lapatinib, Sunitinib and Sorefenib.

The downstream targets of VEGF/VEGFR include phosphoinositide 3-kinase (PI3K)/Akt/protein kinase (PK) B and PKC/Erk, all of which are critical for endothelial cell survival and proliferation.

Cardiotoxicity was observed in several clinical trials, although Bevacizumab is not as widely used as Trastuzumab.
The three most commonly reported cardiovascular adverse effects are hypertension, congestive heart failure and thromboembolism.
In rare instances, myocardial infarction was reported.

The incidence of Bevacizumab-related hypertension was reported to be 16–47% in several clinical trials and it appears to be dose-dependent.
When Bevacizumab was used together with Irinotecan, Fluorouracil and Leucovorin in metastatic colorectal cancer, the incidence of grade 3 hypertension increased by 8 points.
Hypertension associated with Bevacizumab may be effectively controlled by an angiotensin-converting enzyme ( ACE ) inhibitor.

As a rare adverse effect, congestive heart failure was reported in ~1.7–3% of patients following Bevacizumab treatment.
The incidence of congestive heart failure was higher among patients with prior anthracycline treatment, cardiomyopathy, or chest wall irradiation.

Thromboembolism is another severe adverse effect of Bevacizumab treatment and the combination of Bevacizumab and chemotherapy increases the risk of arterial thromboembolic events ( hazard ratio, HR = 2.0, 95% CI: 1.05–3.75, P=0.31 ) more than chemotherapy alone.
Prior arterial thromboembolic events and age more than 65 years were also reported as risk factors.

Bevacizumab was also reported to be associated with the development of venous thromboembolism in cancer treatment ( relative risk, RR = 1.33, 95% CI: 1.13–1.56, P less than 0.001 ).
The type of tumor is associated with venous thromboembolism and the dose of Bevacizumab is another potential risk factor.

Imatinib

BCR-ABL is present in more than 90% of chronic myeloid leukemia ( CML ) cases. ABL is a non-receptor TK, and a fusion product, BCR-ABL, increases the TK activity of ABL.
In CML cells, BCR-ABL activates a variety of signaling pathways, such as RAS, PI3K-Akt and signal transducer and activator of transcription 5A, to promote proliferation and prevent apoptosis.

Imatinib ( Glivec; Gleevec ) efficiently inhibits BCR-ABL+ CML cells, blocks phosphorylation and induces apoptotic cell death. Anti-apoptotic factors, such as B-cell lymphoma 2 ( Bcl-2 ) and Bcl-xL, are inhibited.
Although Imatinib cannot cure chronic myeloid leukemia, it converts CML into a manageable, chronic disease.

Imatinib has been approved by the FDA as an oral drug for the treatment of chronic myeloid leukemia, gastrointestinal stromal tumors ( GISTs ) and hypereosinophilic syndrome.

Overall, Imatinib is well tolerated. Although the incidence of edema and dyspnea are reported to be as high as 66 and 16%, respectively, left ventricular dysfunction was overlooked during the first few years that Imatinib was in the market.
A review of 1,276 patients with hematological malignancies who were receiving Imatinib, found that 22/1,276 ( 1.7%) had CHF symptoms; however, only 8 cases were considered possibly associated with Imatinib treatment.

Overall, Imatinib-induced cardiotoxicity is a very uncommon adverse event. For those with a prior history, cardiac function should be closely followed up.
Beta blockers, ACE inhibitors and diuretics may be used in the management of congestive heart failure.

Sunitinib

Sunitinib ( Sutent ) is a multiple TK inhibitor, with more than 50 known targets, including VEGFR 1–3, PDGFR alpha and beta and RET.
Sunitinib is the first TKI approved by the FDA to be used in two different cancers, namely GIST and metastatic renal cell carcinoma ( mRCC ), with significant survival benefits.

Sunitinib is overall well-tolerated and its adverse events are considered as manageable. The most common adverse events in Sunitinib-treated patients are hypertension and congestive heart failure.

The incidence of Sunitinib-associated congestive heart failure ranges from 2.7 to 15%.

In a study on 750 patients with mRCC in a phase III trial of Sunitinib; the incidence of grade 3 reduction in left ventricular ejection fraction ( LVEF ) was similar in the two groups ( 2 and 1%, respectively ).

In another research study on Imatinib-resistant GIST, 8 of the 75 ( 11% ) patients receiving Imatinib had a cardiovascular event and 6 of the 75 ( 8% ) patients had congestive heart failure; furthermore, 12 ( 18% ) had elevated troponin levels. This incidence is higher compared with that reported by other groups, possibly because patients in this study had received prior anticancer treatment ( all their patients had been priorly treated with Imatinib and 15 of the 75 patients had an anthracycline treatment history ).

A longer exposure to Sunitinib may be required for patients to develop congestive heart failure.

Hypertension is another cardiovascular toxicity associated with the administration of Sunitinib. The incidence of this adverse event is ~17–43%.

Hypertension was found to be a biomarker of efficacy in patients with mRCC treated with Sunitinib.
Patients with mRCC and Sunitinib-induced hypertension had better outcomes compared with those without treatment-induced hypertension. ( Xagena )

Chen, Z., Ai, D, Molecular and Clinical Oncology 2016: 675-681

XagenaMedicine_2016



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