Today, lung cancer is the major cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for more than eighty percent of all cases. Based on the current guidelines, surgical resection is the first choice in the management of the patients with early-stage NSCLC. Moreover, adjuvant platinum-based chemotherapy (paclitaxel plus carboplatin (PC) or vinorelbine plus cisplatin (VC)) is the standard option for treating completely resected NSCLC.1–4 Although, chemotherapy regimens have improved the survival of patients with cancer, these regimens may induce cardiotoxicity in some patients. Platinum-based chemotherapy may cause cardiotoxicity and increase in mortality leading to cessation of chemotherapy.5 Early detection of chemotherapy-induced cardiotoxicity is important for patient prognosis.

With advances in ultrasound deformation imaging techniques, speckle tracking echocardiography (STE) has been proposed as an alternative to conventional echocardiographic measures, mainly left ventricular (LV) ejection fraction (EF) for detecting myocardial dysfunction.6 STE is less dependent on Doppler beam angle, which decreases intra- and interobserver variability. Moreover, it provides a global approach, including information on the three spatial dimensions of cardiac contraction, to myocardial mechanics.7

The aim of this study was to evaluate the effects of PC and VC chemotherapy regimens on LV mechanical functions in patients with NSCLC by STE.

The study included 71 consecutive patients with NSCLC (mean age: 63.1±6.0 years; 49 males (69.0%)) and 34 controls (mean age: 61.1±5.8 years; men, 19 male (55.8%)). Patients with NSCLC were divided into two groups based on their chemotherapy regimens: PC group (patients treated with the PC regimen) and VC group (patients treated with the VC regimen). The clinical and demographic characteristics of the patients are shown in Table 1. Clinical examination of the patients performed during and after the chemotherapy did not detect any major cardiac side effects, including the signs and symptoms of HF. 2D echocardiographic measurements of the patients with NSCLC and control subjects are shown in Table 2. E/é ratio was significantly increased in the PC group (6.4±2.7 vs. 7.0±3.1; p=0.02). However, no statistically significant difference was observed in conventional measurements of the NSCLC patients obtained before and after the chemotherapy with controls.

Speckle tracking echocardiography measurements for the patients with NSCLC and controls are shown in Table 3. There were not any significant differences in the baseline LV GLS, RS or CS between NSCLC patients and controls. LV GLS, LV RS, and LV CS decreased significantly in PC group after the PC regimen (Figure 2) while LV GLS, LV RS and LV CS showed insignificant decrease in VC group. The relative percentage reduction of LV GLS was 19.4% in PC group, which was a marker of early LV subclinical dysfunction based on ESC position paper on cancer treatments and cardiovascular toxicity. In PC group, 21 patients had a relative percentage reduction >15%.9,10 After the chemotherapy regimens, the PC group had significantly lower LV GLS, LV RS and LV CS compared to both VC group and controls.

Figure 2.

Comparison of left ventricular global longitudinal strain before and after chemotherapy in patients with non-small cell lung carcinoma.

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In the electrocardiography assessment, four patients had sinus bradycardia (10.2%), one patient had first-degree atrioventricular block (2.5%) after PC regimen therapy. One patient had sinus bradycardia (2.9%) and one patient had left bundle branch block (%2.9) after VC regimen therapy.

At present, the PC and VC combinations are the frequently used chemotherapy regimens for treating NSCLC. We conducted a prospective study to evaluate the potential cardiotoxicity of these chemotherapy regimens by performing conventional and advanced echocardiography techniques. While conventional 2D echocardiography did not detect any LV systolic dysfunction after chemotherapy, STE revealed significant decreases in LV GLS, RS, and CS in NSCLC patients receiving the PC regimen. This suggests that the PC regimen might induce subclinical cardiotoxicity in these patients. There were no significant decreases in strain measures after the VC regimen.

The ESC position paper on cancer treatments and cardiovascular toxicity indicated the importance of identifying cardiotoxicity in its early stage.9 Early identification of chemo-cardiotoxicity mainly relies on cardiac imaging which detects an impairment in LV systolic function without any apparent signs or symptoms of HF.16 LVEF is currently used to detect chemotherapy-induced cardiotoxicity. STE, on the other hand, enables accurate quantification of myocardial function and shows better agreement with cardiac magnetic resonance imaging (CMRI) measurements than conventional 2D echocardiographic measurements.17,18 Moreover, STE detects discrete and localized impairments in contractility that are deficient to affect the global LV systolic function but have potential diagnostic and prognostic implications.18–20 The ability of STE to detect subclinical LV dysfunction in the absence of a reduced LV EF has enhanced its value in recent chemo-cardiotoxicity studies. Previous studies detected a decrease in STE-measured GLS in the absence of a reduced LV EF in asymptomatic patients with breast cancer who received anthracycline chemotherapy.21,22 A meta-analysis assessing the early detection of cardiotoxicity in patients who had received cancer chemotherapy suggested that STE-measured LV GLS is a better measure than conventional 2D echocardiographic measurements and Doppler-derived indexes.23 The SUCCOUR study showed that a STE-guided strategy might prevent subclinical cardiotoxicity compared with current EF-guided management in patients receiving cardiotoxic chemotherapy.24 However, the recent guideline9 has not been updated and in our study, we did not revise the CT of the patients according to their strain measurements.

Cardiotoxicity is one of the most serious adverse effects of chemotherapy, associated with increased morbidity and mortality.9 Acute cardiotoxicity develops any time from the onset of treatment up to two to four weeks after the end of therapy. It is characterized by reversible arrhythmias, acute coronary syndrome, pericarditis, and LV systolic dysfunction.25,26 Chronic cardiotoxicity occurs four weeks after treatment and is divided into early cardiotoxicity, which appears within the first year after treatment, and late cardiotoxicity, which appears more than one year after chemotherapy. Chronic cardiotoxicity includes type I myocardial damage which means it is irreversible and cumulative dose-related (e.g., doxorubicin) and type II myocardial damage, which is reversible and not dose-related cardiac dysfunction (e.g., trastuzumab).27,28

Paclitaxel was discovered in 1962 as a mitotic spindle inhibitor. Since then, paclitaxel has showed efficacy in many type of cancers including breast, ovarian, gastric, and also non-small cell lung cancers.29,30 Current studies have showed that paclitaxel leads to congestive heart failure in 5–15% at conventional doses31,32. Del Mastro et al. showed cardiotoxicity in 9% of the patients with breast cancer after weekly paclitaxel treatment.33 The type of myocardial damage caused by paclitaxel has not yet been determined in large-scale clinical trials. Some studies have reported severe reductions in EF in 1–2% of patients.31,32 Osman et al. revealed a decrease in LVEF in patients with gynecological malignancy or breast cancer treated with paclitaxel after 30 months.34 PC regimen-induced subclinical cardiotoxicity has also been shown by STE in patients with gynecologic malignancy.35 To the best of our knowledge, the present study is the first to show a decrease in deformation imaging measurements (STE-measured LV GLS, RS, and CS) in patients with NSCLC who received the PC regimens.

The paclitaxel plus carboplatin regimen, but not VC regimen, may be associated with subclinical cardiotoxicity which is detected earlier and more successfully by STE in patients with NSCLC. Long term studies are needed to clarify the importance of strain measurements in the management of NSCLC patients.

Our study was approved by the local Ethics Committee with regard to the Helsinki declaration and written informed consent was obtained from all participants.

All authors contributed to the study conception and design. Dr. Batur Gonenc Kanar was the primary investigator of the study. He was responsible for the design of the study, data collection, analysis of the data and drafting of the article. Dr. Beste Ozben, Dr. Kursat Tigen and Dr. Alğer Kepez were responsible for the critical revision of the article. Dr. Akın Ozturk, Dr. Bahar Dalkılıc and Dr. Dursun Akaslan were responsible for analysis of the data and drafting of the article. Dr. Erhan Ogur, Dr. Dursun Akaslan, Dr. Ayhan Küp and Dr. Kamil Gülşen were responsible for data collection and analysis of the data. The first draft of the manuscript was written by Dr. Batur Gonenc Kanar and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

None declared.

The authors declare that they have no conflict of interest.