Med Oncol (2012) 29:3232–3239 DOI 10.1007/s12032-012-0253-5
ORIGINAL PAPER
Evaluation of cardiac safety of lapatinib therapy for ErbB2-positive metastatic breast cancer: A single center experience Erkan Dogan • Hikmet Yorgun • Ibrahim Petekkaya Necla Ozer • Kadri Altundag • Yavuz Ozisik
•
Received: 21 April 2012 / Accepted: 5 May 2012 / Published online: 22 May 2012 Ó Springer Science+Business Media, LLC 2012
Abstract Lapatinib is a dual tyrosine kinase inhibitor (TKI) that has a considerable efficacy in ErbB2-positive metastatic breast cancer (MBC). Previous studies revealed that TKIs caused cardiotoxicity in approximately 10 % of the patients. This study assessed the cardiac safety of lapatinib in women with ErbB2-positive MBC. In this observational single center study, all patients with ErbB2positive MBC who were previously treated with anthracycline, taxanes, and trastuzumab in the adjuvant and/or metastatic setting were assigned to receive lapatinib at a dose of 1,250 mg per day continuously plus capecitabine at a dose of 2,000 mg/m2 in two divided doses on days 1 through 14 of a 21-day cycle. Cardiac toxicity was assessed with symptoms, transthoracic echocardiography, electrocardiography and biochemical markers (brain natriuretic peptide (BNP), creatine kinase (CK) and creatine kinaseMB) at baseline and every 9 weeks until disease progression. Twenty-six patients were treated with lapatinib and capecitabine therapy for a median of 18 (range 3–60) weeks. The median age was 48 (range 28–83) years. All patients had ErbB2-positive MBC. Among 25 eligible patients, 5 (19.2 %) patients experienced new cardiac events compared with baseline findings. Of these 5 patients, 1 (3.8 %) had T wave negativity, 1 (3.8 %) had sinus tachycardia, 1 (3.8 %) had grade 1 (453 ms) QT prolongation, and 2 (7.7 %) had decreased LVEF below the critical level. Among eligible 21 patients, 2 (7.7 %) had E. Dogan I. Petekkaya K. Altundag (&) Y. Ozisik Department of Medical Oncology, Institute of Oncology, Hacettepe University, Sihhiye Ankara 06100, Turkey e-mail:
[email protected] H. Yorgun N. Ozer Department of Cardiology, Faculty of Medicine, Hacettepe University, Sihhiye Ankara, Turkey
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increased BNP, 1 (3.8 %) had increased CK, and 1 (3.8 %) had increased CK–MB level compared with baseline. No serious cardiac events that required monitorization or medication occurred. There was no statistically significant relationship between the duration of lapatinib administration and LVEF changes, QT prolongation, BNP, CK, and CK–MB level. According to our findings, lapatinib was safe and well tolerated and has a low incidence of cardiac side effects. Therefore, it seemed that cardiotoxicity was not a class effect of TKIs. However, despite the absence of clinically significant adverse cardiac effects under lapatinib therapy, the incidence of cardiotoxicity reported in our study was higher than previous lapatinib studies. Keywords Breast cancer Cardiotoxicity Tyrosine kinase inhibitor Lapatinib
Introduction Cardiotoxicity is one of the well-defined adverse effect of systemic chemotherapy. It was firstly defined by Tan et al. [1] in patients who were treated by doxorubicine in 1967. Many conventional chemotherapeutic drugs may cause cardiotoxicity such as anthracycline, cyclophosphamide, platins, and 5-fluorourasil. In the last decade, a new therapeutic option which is known as targeted therapy has been developed in cancer treatment. Targeted therapy mainly compromises drugs that target tyrosine kinases. These agents fall into two general classes: humanized monoclonal antibodies directed against receptor tyrosine kinases or their ligands and small molecule tyrosine kinase inhibitors (TKIs) [2]. TKIs are small molecules that disrupt the function of kinase activity. They compete with ATP binding site of catalytic domain of
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several oncogenic tyrosine kinase. Using TKIs in cancer treatment, it has been realized that these small molecules have also been associated with a certain degree cardiotoxicity. Cardiac side effects of TKIs range from asymptomatic QT prolongation to reduction in left ventricular ejection fraction (LVEF), symptomatic congestive heart failure (CHF), acute coronary syndromes and myocardial infarction (MI) [3–6]. Hypertension and sudden death also have been noted during treatment with these drugs. Schmindinger et al. [7] stated that cardiotoxicity due to TKI treatment was an underestimated phenomenon and cardiotoxicity of TKI might mimic oncologic disease progression by causing symptoms such as a dyspnea, pleural/ pericardial effusion and a decline in ECOG PS. Therefore, integration of cardiologic examination is essential during treatment and allows continuation of cancer therapy. The ErbB2 (HER2) proto-oncogene is amplified in 25–30 percent of human primary breast cancers and it is associated with poorer prognosis, greater risk of disease progression, and reductions in both progression-free survival (PFS) and overall survival (OS) [8]. The HER2 pathway is also involved in normal cardiac function and inhibition of this pathway can cause cardiac dysfunction [9, 10]. Hence, any drug that can block this pathway can precipitate serious clinical cardiac problems in the patients with cancer. Lapatinib ditosylate is one of the important drug which acts on the HER2 pathway. It is an orally acitive 4-anilinoquinazoline derivative, small molecule tyrosine kinase inhibitor which reversibly inhibits both ErbB1 and ErbB2 transmembrane receptors. Evidence for the efficacy of lapatinib in metastatic breast cancer was derived from Phase I–III trials of monotherapy and concurrent administration of lapatinib with cytotoxic chemotherapy, other targeted treatments or endocrine agents [11–16]. In a previous study by Geyer et al. [17], it was shown that lapatinib plus capecitabine combination therapy had considerable efficacy in patients with HER2-positive, metastatic breast cancer. The drug is also in accelerated FDA approval in combination with the aromatase inhibitor letrozole for the treatment of postmenopausal women with ErbB2 overexpressing hormone receptor positive metastatic breast cancer [18]. During all of these studies, the most common adverse effects of lapatinib that had been reported were diarrhea, rash, alopecia, nausea/vomiting, stomatitis, anorexia, headache, abnormal liver function and gastrointestinal events. Cardiac adverse effects of lapatinib seemed to appear far less frequently, although some TKIs have induced cardiotoxicity to a certain degree including sunitinib, sorafenib, and imatinib [3, 5, 6, 19, 20]. The clinical studies, which have been conducted until now, have not pursued cardiac end points, and the identification of cardiac adverse effects was predominantly based on the occurence
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clinical symptoms. Therefore, the precise rate of cardiotoxicity associated with TKIs is unknown. In light of those data, we aimed to investigate the cardiotoxic potential of lapatinib evaluated either by clinical and/or biochemical signs in patients with metastatic breast cancer who were progressed on a minimum of an anthracycline, a taxane, and trastuzumab treatment in a real-world setting.
Patients and methods Between January 2009 and September 2010, we enrolled a total of 26 patients with ErbB2-positive metastatic breast cancer (MBC) who had progressed after treatment with chemotherapy regimens that included an anthracycline, a taxane, and trastuzumab in the adjuvant and/or metastatic setting that were assigned to receive lapatinib plus capecitabine combination therapy. The HER2 status was considered positive if the local institution reported grade 3? staining intensity (on scale of 0–3) by means of immunohistochemical analysis or grade 2? staining intensity by means of immunohistochemical analysis with gene amplification on fluorescence in situ hybridization. All patients were assigned to receive lapatinib at a dose of 1,250 mg per day continuously plus capecitabine at a dose of 2,000 mg/m2 in two divided doses on days 1 through 14 of a 21-day cycle. The therapy was continued until progression or intolerablity to regimen among responder patients. For both drugs, a 25 % dose reduction was made at the occurence of grade 3 toxicity. Response evaluation was performed every 9 weeks. Before the treatment, all patients were evaluated for cardiovascular risk factors, the presence of coronary artery disease (CAD), rhythm disturbances and heart failure. Cardiac toxicity was assessed at baseline and every 9 weeks until disease progression. A cardiac event was defined as the occurrence of increased biochemical markers (if normal at baseline), decreased left ventricular ejection fraction (LVEF) of more than 15 % relative to baseline or newly occurred left ventricular dysfunction, symptomatic arrhythmia that requires treatment or acute coronary syndrome. Cardiovascular monitorization included the following assessments. Cardiac symptoms were assessed at baseline and every 9 weeks during the entire treatment which were defined as the occurrence of dyspnea at exertion and typical angina that were not related to specific metastatic locations. Transthoracic echocardiography was performed at baseline and every 9 weeks during the treatment period in all patients. LVEF was defined as normal (greater than 56 %), slightly reduced (between 55 and 45 %), moderately reduced (between 45 and 30 %) and severely reduced (less than 30 %). The patients who had LEVF greater than 45 % were included in this study. Electrocardiography (ECG)
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was assessed at baseline, every 9 weeks and any time at the occurence of cardiac symptoms during the entire treatment period. Left ventricular hypertrophy analyzed with Sokolow index and Romlith-Estes grading system. The QT interval was measured in lead II and was corrected for heart rate by using the Bazett formula. The QT interval above 450 millisecond (msn) was accepted as abnormal. PR interval above 200 msn was accepted as abnormal. Biochemical markers (brain natriuretic peptide (BNP), creatine kinase (CK), and creatine kinase-MB) were assessed at baseline, every 9 week and any time at the occurence of clinical symptoms during treatment period. At the beginning of therapy, there were no patients with cardiac failure. All the patients had normal cardiac biochemical markers (BNP, CK, and CK–MB) level, ECG findings and echocardiography results. All statistical analyses were performed using SPSS for Window software (RE SPSS 13.0; SPSS Chicago, IL). Descriptive statistics of relevant demographic and clinical features were performed. The paired t test was used for normally distributed variables, such as baseline LEVF and LEVF after therapy. Wilcoxon signed rank test was used for variables that was not normally distributed. A two tailed P value less than 0.05 was considered significant in all tests.
Med Oncol (2012) 29:3232–3239 Table 1 Baseline demographics and clinical characteristics of patients Variables
Assessable patients [26](%)
Age (years) Median (range) Menopausal situation Premenopausal
48 (28–83) 12 (% 46.2)
Postmenopausal Breast Ca localization
14 (% 53.8)
Right
5 (% 19.2)
Left
20 (% 76.9)
Anthracycline usage Yes
21 (% 80.8)
No
2 (% 7.7)
Anthracycline interval (months) Mean (range)
23.90 (6–96)
Adjuvant trastuzumab usage Yes
10 (% 38.5)
No
14 (5% 3.8)
Histology Invasive ductal carcinoma (IDC) Invasive lobular carcinoma (ILC)
23 (% 88.5) 1 (% 3.8)
Mixed (IDC?ILC) carcinoma
1 (% 3.8)
Mucinous carcinoma
1 (% 3.8)
ER status
Results In this study, we enrolled a total of 26 women with ErbB2positive metastatic breast cancer that had progressed after treatment with conventional chemotherapy and treated with lapatinib and capecitabine combination therapy for a median of 18 (range 3–60) weeks. Most of the patients had good Eastern Cooperative Oncology Group performance score (ECOG PS; 0–1). The median age was 48 (range 28–83) years. Twelve patients were premenopausal and 14 patients were postmenopausal among them. The tumors were left-sided in 20 (76.9 %) and right-sided in 5 (19.2 %) of the patients. Histopathologically, 23 (88.5 %) patients had invasive ductal carcinoma (IDC), one (3.8 %) patient had invasive lobular carcinoma (ILC), one (3.8 %) patient had mixed type (IDC?ILC) carcinoma and one (3.8 %) patient had mucinous carcinoma of breast. Baseline demographics and clinical characteristics of the patients are listed in Tables 1 and 2. Among 25 eligible patients, five (19.2 %) patients had experienced cardiac events. Among those 5 patients, 1 (3.8 %) had sinus tachycardia, 1 (3.8 %) had T wave negativity, 1 (3.8 %) had grade 1 (453 ms) QT prolongation, and 2 (7.7 %) had decreased LVEF below the critical level. Cardiac side effects which had reported during the study are listed in Table 3.
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Positive
10 (% 38.5)
Negative
13 (% 50.0)
Unknown
3 (% 11.5)
PR status Positive
9 (% 34.6)
Negative
15 (% 57.7)
Unknown
2 (% 7.7)
Grade G1
0
G2
6 (% 23.1)
G3
15 (% 57.7)
Unknown Comorbidities
5 (% 19.2)
Diabetes mellitus (DM)
2 (% 7.7)
Hypertension (HT)
2 (% 7.7)
Cardiac disease (CD)
0
DM?HT
4 (% 15.4)
No comorbidity
18 (% 69.2)
DM Diabetes mellitus, HT Hypertension, CD Cardiac disease
Therapy with lapatinib and capecitabine was discontinued in 1 patient who had decreased LVEF more than 15 % relative to baseline, although there were no clinically observed cardiac symptoms. After 3 cycles of capecitabine monotherapy, the LVEF returned to normal, and then,
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Table 2 Baseline demographics and clinical characteristics of patients Variables
Assessable patients [26](%)
Adjuvant chemotherapy Yes
22 (84.6)
No Adjuvant radiotherapy
4 (15.4)
Unknown
5 (% 19.2)
Yes
15 (% 57.7)
No
6 (% 23.1)
Adjuvant radiotherapy site Right
4 (% 15.4)
Left
11 (% 42.3)
No
11 (% 42.3)
Adjuvant hormonotherapy Unknown
7 (% 26.9)
No
7 (% 26.9)
Yes
12 (% 46.2)
Table 3 Cardiac side effects at baseline and after lapatinid and capecitabine Side effect
Baseline n (%)
After lapatinib and capecitabine n (%)
No side effect
14 (53.8 %)
15 (57.7 %)
Nonspecific ST changes
4 (15.4 %)
2 (7.7 %)
Sinus tachycardia T negativity
2 (7.7 %) 1 (3.8 %)
1 (3.8 %) 1 (3.8 %)
Loss of R progression
2 (7.7 %)
2 (7.7 %)
LV hypertrophy
1 (3.8 %)
1 (3.8 %)
QT prolongation
0
1 (3.8 %)
LVEF decrease
0
2 (7.7 %)
lapatinib was restarted. She received lapatinib and capecitabine therapy until disease progression without any complication. The other patient who had decreased LVEF continued lapatinib and capecitabine therapy without interruption. There were no clinical symptoms, and the LVEF returned to normal after 3 cycles. Both patients are still alive without cardiac problems. In the patient who had grade 1 QT prolongation, therapy was continued, and after 3 cycles, the QT interval returned to normal limits. Among eligible 21 patients, 2 (7.7 %) had increased BNP, 1 (3.8 %) had increased CK, and 1 (3.8 %) had increased CK–MB level compared with baseline. No serious cardiac events that required monitorization or medication were occurred. There was no statistically significant relationship between the duration of lapatinib administration and LVEF changes, QT prolongation, BNP, CK, and
CK–MB level. The only statistically significant difference was found between baseline total bilirubin level and total bilirubin level at end of treatment (P \ 0.01). But this finding was not clinically important. All changing biochemical parameters, before and after therapy, were listed in Table 4. Common side effects that had developed during the treatment period were listed in Table 5. Three (11.5 %) patients had grade 3 diarrhea. In these patients, therapy was stopped for a week and supportive treatment was started and all of the patients were recovered after treatment. In those patients, capecitabine dose was reduced by 25 % and then lapatinib and capecitabine combination therapy restarted. In one patient who also had insulin dependent diabetes mellitus due to the development of diabetic foot, anticancer therapy was stopped. There were no findings of hand-foot syndrome in other extremities. She had undergone to partial right first finger amputation. After 3.5 months of lost to follow-up period without any treatment, progressive disease was documented in that patient. She had also hypertension, uncontrolled blood glucose and ECOG PS 3; therefore, lapatinib and capecitabine therapy was not initiated. After 1.5 month from last visit, the patient was died due to the progressive disease. Grade 1 hand-foot syndrome was developed in 3 (11.5 %) patients. By the time with dermatological treatment including moisturizing creams, hand-foot syndrome was recovered. In one patient after 2 cycle of therapy, grade 3 hand-foot syndrome developed. Capecitabine dose was reduced by 25 % and moisture cream was started on and during the follow-up, hand-foot syndrome was recovered. In two (7.7 %) patients, grade 1 acneiform skin reaction was developed. The patients were followed up without any treatment. In two (7.7 %) patients, grade 1 fatigue-weakness was reported, but they had continued therapy without any problem. Individual results of cardiac events of all patients are represented in Table 6.
Discussion Targeted therapy has been an important development in cancer treatment during the last decade. Trastuzumab was the first drug that has been introduced in this area in patients with metastatic breast cancer [21]. Although, trastuzumab has considerable effect on median overall survival (OS), it has been realized that primary and secondary resistance was not rare during trastuzumab treatment. Therefore, alternative drugs that can be used in breast cancer patient are needed. Lapatinib ditosylate is one of the important alternative drugs that had been developed in this area [14]. In phase-III prospective clinical trial, Geyer et al. [17] showed that lapatinib and capecitabine
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Table 4 Changing biochemical parameters before and after therapy
Table 4 continued
Parameters
Parameters
All groups Mean
P SD
Last
Baseline
5511.54
1507.40
Last
6212.50
3275.64
0.11
Hemoglobin Baseline
12.58
1.10
Last
12.72
1.08
253923.08
66273.93
236045.83
69077.70
Last
P
Mean
Leukocytes
Platelet count Baseline
All groups
0.40
0.22
Glucose Baseline
110.70
41.91
Last
116.79
59.89
0.22
SD
418.63
21.44
Echocardiography EF (%) Baseline
65.54
5.05
Last
63.56
4.77
0.14
QTc Corrected QT interval, EF Ejaction Fraction, msn millisecond
Table 5 Common side effects that reported during therapy
Adverse effects
n (%)
No
13 (50 %)
Diarrhea Grade 1
0
Creatinine
Grade 2
0
Baseline
Grade 3
3 (11.5 %)
Grade 4
0
Last
0.69 0.70
0.19
0.66
0.18
Fatigue-weakness
AST Baseline
24.96
7.28
Last
29.04
10.73
0.07
ALT Baseline Last
24.63 25.52
Lactate dehydrogenase (LDH) Baseline 405.00 Last
13.63
0.47
127.04 151.44
99.79
54.29
102.83
42.19
2.15
0.67
0.09
Creatine kinase (CK) Baseline Last
0.84
CK–MB Baseline Last
1.81
2 (7.7 %)
Grade 2
0
Grade 3
0
Grade 4
0
Hand-foot syndrome
11.10
433.81
Grade 1
0.18
0.73
Grade 1
3 (11.5 %)
Grade 2
1 (3.8 %)
Grade 3 Grade 4
1 (3.8 %) 0
Rash Grade 1
2 (7.7 %)
Grade 2
0
Grade 3
0
Grade 4
0
Total bilirubin Baseline
0.58
0.37
Last
1.08
0.77
0.01*
Total cholesterol Baseline
205.13
40.75
Last
194.95
34.26
0.45
143.29 156.45
65.66 81.72
0.52
0.32
Triglyceride Baseline Last
Low density lipoprotein (LDL) cholesterol Baseline
130.00
38.07
Last
118.42
27.06
BNP Baseline
47.29
38.03
Last
53.67
38.46
410.00
20.97
0.69
QTc interval (msn) Baseline
123
0.09
combination therapy had better median time to progression compared with capesitabine monotherapy. By that important development, lapatinib has became an important antiHER2 drug in breast cancer. According to those studies, TKIs had lesser rate of adverse effects compared with the classical cytotoxic drugs. However, TKIs are not completely innocent drugs with considerable side effects [3–6]. Therefore, we designed a study that have primary end point with cardiotoxicity in patients who were treated with lapatinib. This observational study investigated the occurence of cardiotoxicity in 26 patients with metastatic breast cancer who were treated with lapatinib and capecitabine combination therapy for a median of 18 (range 3–60) weeks. During the study, the principal finding was five (19.2 %) patients had experienced cardiac events of varying degrees with these drugs. Of these five patients, two (7.7 %) had
3 1
2
0
1
0
1
0
2
0
0
0
3
0
0
0 0
0
1
0
0
1
0
0
3
1
1 2
3
4
5
6
7
8
9
10
11
12
13
14
15
16 17
18
19
20
21
22
23
24
25
26
No
No
No
No
No
No
No
No
No
No No
No
No
No
No
No
No
No
No
No
No
No
No
No
No No
Cardiac abnormalities at baseline
1,250
1,250
1,250
1,250
1,250
1,250
1,250
1,250
1,250
1,250 1,250
1,250
1,250
1,250
1,250
1,250
1,250
1,250
1,250
1,250
1,250
1,250
1,250
1,250
1,250 1,250
Daily dose of lapatinib (mg)
S
R
S
S
S
S
S
S
S
S S
S
S
S
S
S
R
R
S
S
S
S
S
S
S S
Dose reduction
18
18
18
18
18
Weeks of TX at event
3.75
2.55
1.66
3.06
1.39
2.25
1.63
1.17
1.74 2.71
1.21
2.03
2.19
2.28
2.63
2.70
1.74
3.75
CK–MBa baseline
1.210
2.270
1.540
1.230
1.410
1.350 2.940
1.360
2.220
2.660
1.290
1.350
2.200
.956
3.480
2.270 1.210
CK–MB after lapatinib
358
511
495
376
758
411
439
388
383
301 403
440
333
322
429
136
301
326
612 378
LDHb baseline
436
562
357
425
409
392
414 379
480
679
417
565
173
131
286
409
498
466
544 370
LDH after lapatinib
59.62
137.63
10.26
24.72
6.72
44.23
111.2
26.02
104.3 56.42
.00
.00
59.97
21.76
27.31
50.62
41.04
39.88
112.5
61.35
38.31
5.33 48.24
BNPc basal
59.36
91.48
40.03
70.49
53.70
75.98
39.63
112.30 52.24
20.60
100.23
53.17
7.72
52.29
11.87
35.47
131.91
50.54
55.89
16.71 .00
BNP after lapatinib
No
No
No
No
No
No
No
No
No
No No
No
No
No
No
No
No
No
Yes
Yes
No
No
No
No
No Yes
ECG change
66
64
67
60
65
68
72
66
58
69 76
60
67
75
60
72
70
65
63
54
65
68
65
64
70 60
LVEF (%) Baseline
66
67
61
58
64
55
68
72
63 58
55
68
67
68
67
65
68
60
56
67
66
61
64
67 58
LVEF (%) after lapatinib
Normal \480 U/l
Normal \100 pg/ml
b
c
Normal \2.88 ng/ml
a
CADRF Coronary artery disease risk factors, TX treatment, LVEF left ventricular ejection fraction, S same, R reduced, CK creatine kinase, CK–MB creatine kinase-MB, LDH lactate dehydrogenase, BNP brain natruretic peptide
No of CAD RFs
Patients
Table 6 Individual results of cardiac events of all patients
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decreased LVEF below the critical level, one (3.8 %) had grade 1 (453 msn) QT prolongation, one (3.8 %) had sinus tachycardia and one (3.8 %) had T wave negativity. Although, there was not any clinically symptomatic patient, cardiac side effects that were reported during the study were more often than the results of previous clinical trials [17, 22, 23]. In our opinion, the high rate of cardiotoxicity was related to our definition of cardiac event. This definition was based on the intention to detect the signs of myocardial damage as early as possible which may increase with the longer treatment periods. In previous studies, definition of cardiac event was accepted as the occurence of heart failure, edema or conduction disturbances which were less strict than our study [24]. However, these variables often do not reflect the true situation. Additionally, Sanderson [25] stated that nearly half of patients who had myocardial injury do not show any congestive heart failure symptoms. In our study, among all patients, 2 (7.7 %) patients had decreased LVEF below critical level but they did not have any symptoms of congestive heart failure (CHF). This rate was higher than the previous studies. Capri et al. [26] reported that the rate of decreasing LVEF was approximately 1 % among 4,283 breast cancer patients who were treated with lapatinib. In another study, Perez et al. [23] state that among 3,689 patients who enrolled into prospective clinical studies 60 (2 %) had experienced cardiac event and only 7 (0.2 %) had symptomatic cardiac event. Furthermore, according to Goss et al. [24], there was no significant differences of cardiac events between lapatinib and placebo arms in adjuvant setting. Although in these studies cardiotoxicity was not the primary end point, they showed that lapatinib had very low rate of cardiac adverse effects. The higher rate of cardiotoxicity in our study probably associated with strict definition of cardiac events and close follow-up. In our study, both patients who had decreased LVEF at 18 weeks; however, because of the absence of clinical symptoms, therapy was continued and at 27 week of follow-up and LVEF returned to normal limits. This means that lapatinib may cause transient decrease in LVEF. Electrocardiographic abnormalities are frequently observed in patients with cancer. Meinardi et al. [27] stated that in women treated with radiotherapy for breast cancer, 19 % were found to have T wave changes before treatment. In our study, after lapatinib therapy, one patient had T wave negativity and one patient had sinus tachycardia. Because of the absence of any symptomatic clinical adverse effect threatening the patients’ life, chemotherapy was continued in those patients. One of the other most threatening complications of TKIs could be QT prolongation with the risk of torsade de pointes (TdP) and sudden cardiac death [28]. Although lapatinib is associated with the risk of QT prolongation (http://www.qtdrugs.org), its effects on cellular
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cardiac electrical properties or on cardiac ion channels have not been studied. Currently, mechanisms how lapatinib affects ion channels are not exactly known. However, the most common mechanism of drug-induced QT prolongation and associated ventricular arrythmias is blockade of rapidly activating delayed rectifier K? current (IKr). The finding that HERG encoding IKr channels provides a mechanistic link between certain forms of inherited and acquired long QT syndrome [29]. In a preclinical study, Lee et al. [30] found that lapatinib predominantly blocks the rapid (hERG) current but also slightly affects the slow component (IKs) of the delayed rectifier K? current and also prolongs the action potential duration of the rabbit Purkinje fibers. Therefore, this drug may cause QT prolongation. In clinical studies, QT prolongation after lapatinib use was also reported in some patients [14, 17]. In the current study, grade 1 QT prolongation was observed in one (3.8 %) patient at the end of 18 week. Therapy was continued without interruption and dose reduction. During follow–up, prolonged QT interval turned into normal limits. In addition to electrocardiographic and echocardiographic changes, serum biochemical parameters such as BNP, CK and CK–MB are also used for the monitorization of adverse cardiac effects of chemotherapeutic agents [31–33]. Although some challenges are present between authors, it is generally accepted that TKIs can cause elevated cardiac biochemical markers. According to some studies, BNP elevation can be used early diagnostic marker of cardiotoxicity [32]. However, in our study, correlation between serum biochemical and cardiac adverse effects was insignificant. Conclusion In the present study, we described common features of patients that have been followed up in our Medical Oncology Department. According to our findings, lapatinib is a safe and its cardiotoxicity potential is low. Therefore, it seems that cardiotoxicity is not a class effect of TKIs. Although our study population is small, the rate of cardiotoxicity is higher than previous studies. In our opinion, during chemotherapy which compromises lapatinid and/or other TKIS, patients should be carefully evaluated for risk factors for cardiotoxicity and should be regularly followed up. Conflict of interest
There is no conflict of interest.
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