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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 1  |  Issue : 1  |  Page : 36-39

Detection of subclinical anthracycline induced cardiotoxicity in breast cancer survivors


1 Department of Radiotherapy, Christian Medical College, Ludhiana, Punjab, India
2 Department of Cardiology, Christian Medical College, Ludhiana, Punjab, India
3 Department of General Surgery, Christian Medical College, Ludhiana, Punjab, India

Date of Web Publication11-Feb-2014

Correspondence Address:
Pamela Alice Kingsley
Department of Radiotherapy, Christian Medical College, Ludhiana 141 008, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2348-3334.126789

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  Abstract 

Aims : To assess the chronic cardiac effects of anthracycline-based chemotherapy regimens on atrial and ventricular diameter, ejection fraction, and valvular abnormalities in relation to cumulative dose in breast cancer patients. Materials and Methods: Breast cancer patients who had received anthracycline-based chemotherapy and radiation therapy were enrolled. All patients had undergone a baseline and follow-up electrocardiogrphy, echocardiography, and clinical cardiac evaluation. Any changes in cardiac parameters were noted. Statistical Analysis Used: Statistical measures used were Chi-square test and independent t-test. Results: A total of 75 breast cancer patients were assessed. Out of these, 56 patients who received cumulative dose of doxorubicin ≥300 mg/m 2 showed increased cardiac dysfunction. Patients with left side breast cancer had greater cardiac abnormalities compared with right side. Conclusion: Cardiac dysfunction was significant with cumulative dose of doxorubicin ≥300 mg/m 2 and also was observed more in left side breast cancer patients.

Keywords: Anthracycline, breast cancer, cumulative dose


How to cite this article:
Negi P, Kingsley PA, Chopra S, Chaudhry NK, Mahajan MK. Detection of subclinical anthracycline induced cardiotoxicity in breast cancer survivors. CHRISMED J Health Res 2014;1:36-9

How to cite this URL:
Negi P, Kingsley PA, Chopra S, Chaudhry NK, Mahajan MK. Detection of subclinical anthracycline induced cardiotoxicity in breast cancer survivors. CHRISMED J Health Res [serial online] 2014 [cited 2019 Oct 14];1:36-9. Available from: http://www.cjhr.org/text.asp?2014/1/1/36/126789


  Introduction Top


Breast cancer is the most frequent cancer in women worldwide with 1.05 million new cases diagnosed every year. [1] Conventional doxorubicin has demonstrated improvements in response rates, time to disease progression, and overall survival in patients with metastatic breast cancer. [2] The most comprehensively evaluated cardiotoxicity of doxorubicin is cumulative and dose-related progressive myocardial damage ranging from an asymptomatic reduction in left ventricular ejection fraction (LVEF) to irreversible life-threatening congestive heart failure. [3] The probability of developing congestive heart failure (CHF) increases substantially at cumulative doses of 450-550 mg/m 2 and higher [4],[5],[6] and may also occur at lower cumulative doses and with a greater frequency than previously observed. [7] Thus, we aimed to evaluate the cumulative dose of anthracyclines, leading to subclinical cardiotoxicity in breast cancer patients.


  Materials and Methods Top


The present study was conducted in the Department of Radiotherapy of a tertiary referral hospital in Northwest India from 1 st September 2003 to 31 st August 2009. All patients who had a histopathological diagnosis of carcinoma breast and who had received anthracycline-based chemotherapy with external beam radiotherapy to chest wall and draining nodal areas were included. Relevant clinical information, cardiac history, baseline electrocardiography (ECG), and echocardiography (ECHO) recordings were collected from the medical records for patients treated from 2003 to 2009. Patients were excluded if they had history of myocardial infarction, New York Heart Association Class II or greater angina pectoris, congestive heart failure, serious cardiac arrhythmia requiring medication, abnormal baseline ECG or evidence of left ventricular dysfunction or resting wall motion abnormalities on ECHO, no prior exposure to anthracycline-based chemotherapy and Karnofsky performance score <80. All evaluable patients were followed-up for the next 1 year. During this period, the cardiac function of all patients who were enrolled in this study was assessed by complete physical examination, ECG and ECHO which were compared from the baseline findings. ECG was done using single channel BPL- 108 machine. ECHO was done using M-mode, two-dimensional color Doppler echocardiogram.

Anthracycline-based chemotherapy regimens included 5-fluorouracil, doxorubicin and cyclophosphamide or doxorubicin and cyclophosphamide every 3 weeks. Extended beam radiation therapy was delivered to all patients Theratron 80R, Cobalt-60 unit. A dose of 45-50 Gray (Gy) was delivered to the anterior chest wall in 20-25 F by tangential fields, over 4-5 weeks. The anterior axillary and supraclavicular region were treated to incident dose of 45-55 Gy/20 − 25 F/4-5 weeks.

In our study, a total of 135 patients of locally advanced breast cancer were treated from 2003 to 2009 with chemoradiation as per the protocol and there were 75 evaluable patients.

Statistical analysis

Statistical analysis was done using SPSS version 21. Statistical measures used were Chi-square test and independent t-test. P < 0.05 was considered statistically significant.


  Results Top


This study recruited 135 patients, 75 were enrolled for the study which included clinical cardiac examination, ECG and ECHO during follow-up. The main reasons for nonenrolment included patient refusal (n = 4), patient lost to follow-up (n = 44), and the patient who expired (n = 12) during the study period. The evaluable patients were grouped into two categories depending upon the cumulative dose of doxorubicin received during the course of chemotherapy. Group I included patients receiving cumulative dose <300 mg/m 2 and Group II included patients receiving ≥300 mg/m 2 cumulative dose. The two groups had unequal number of patients as majority of these patients received six cycles of chemotherapy according to the standard chemotherapy regimen followed. The baseline characteristics of patients enrolled in this study are given in [Table 1].
Table 1: Baseline characteristics

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Group I had 19 patients who received cumulative dose of doxorubicin <300 mg/m 2 and group II had 56 patients with cumulative dose ≥300 mg/m 2 . The median age of group I patients was 50.5 years (range: 33-60) versus 53.5 years (27-66) for group II. Both the groups were comparable with respect to age. Out of 19 patients receiving <300 mg/m 2 dose, 11 had right side and 8 had left side disease. On the contrary, out of the 56 patients who received≥300 mg/m 2 dose, equal number (28) patients had right and left side breast cancer. Among the concomitant comorbidities, hypertension was seen in 6 patients in group I and in 12 patients in group II. Two patients in group I and 7 patients in group II had diabetes mellitus [Table 1]. There were no ECG changes in both the groups.

In group I, the mean increase in left atrial diameter (LAD) was 0.15 mm, whereas in group II, increase was 1.52 mm. Similarly, the mean increase in left ventricular diastolic diameter (LVDD) was 1.34 mm in group I patients in comparison to 2.03 mm in group II patients. On comparing the mean decrease in LVEF, the decrease was more for group II patients (1.46%) in comparison to group I patients (0.95%). It was also seen that the patients receiving ≥300 mg/m 2 cumulative dose had more (8.9%) valvular abnormalities [mild mitral regurgitation (MR), Tricuspid regurgitation (TR), Aortic regurgitation (AR)] compared with those who received dose <300 mg/m 2 (5.2%) [Table 2].
Table 2: Cardiac parameters based on the cumulative dose

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The patients were grouped further on the basis of side of involvement and cumulative dose in group I, there were no significant changes in cardiac parameters whereas in group II, there was a statistically significant increase in LAD in patients with left side breast cancer (P = 0.023) and valvular abnormalities were also more in these patients, whereas the changes in left ventricular diameter and ejection fraction were also present but not statistically significant [Table 3].
Table 3: Cardiac parameters: Laterality and cumulative dose

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  Discussion Top


Chemotherapy-induced cardiotoxicity strongly affects the quality of life and overall survival of cancer patients. The probability of developing CHF increases substantially at cumulative doses of 450-550 mg/m 2 and higher. Several studies have shown that beyond clinically overt CHF, anthracycline-based adjuvant therapy is also associated with subclinical cardiomyopathy and this cardiotoxicity may still occur at relatively low levels of drug administration.

On comparing the patients in both the groups, the mean increase in LAD was 0.15 mm versus 1.52 mm. It was also seen that the patients receiving ≥300 mg/m 2 dose had more (8.9%) valvular abnormalities compared with those who received <300 mg/m 2 dose (5.2%). In our study, the valvular abnormalities seen included mild MR, mild TR, mild-moderate AR. A study by Sasayama et al., [8] on the left atrial function in acute mitral regurgitation suggests an increase in LAD if there was presence of mitral regurgitation. In our study, 8.9% patients had valvular regurgitations but whether this is responsible for the increase in LAD is uncertain. Similarly, the mean increase in LVDD was 1.34 mm versus 2.03 mm in Group I and Group II patients, respectively. On comparing the mean decrease in LVEF, the decrease was more for Group II patients (1.46%) in comparison to Group I patients (0.95%) but it was not significant statistically. None of the evaluable patients experienced clinical CHF secondary to cardiomyopathy. The LVEF was reduced more than 10% in two patients (2.67%). Our study showed a decrease of 13% in one patient and this patient had an increase in left atrial and ventricular diameter by 13 and 23 mm, respectively. Another patient had a decrease in ejection fraction of 10% and an increase in left atrial and ventricular diameter by 29 and 13 mm, respectively. These patients were asymptomatic similar to a study by Speyer et al., [9] where it was reported that the decrease in LVEF was often within the "normal range" (LVEF 50% or greater), but these changes were progressive and appeared to be a part of a continuum of doxorubicin-induced myocardial damage. Longer follow-up of adjuvant anthracycline-based clinical trials has demonstrated that administration of "safe" cumulative doses of doxorubicin below 450 mg/m 2 may predispose to asymptomatic systolic dysfunction, regarded as a reduction of 10% or more from baseline in LVEF. [10]

It was seen that patients who received <300 mg/m 2 dose had no significant changes in cardiac parameters. A statistically significant increase in LAD was seen in patients with left side breast cancer in Group II (P = 0.023). Subclinical late cardiomyopathy was reported to occur in 39 of 141 patients of lymphoma after a median cumulative dose of 300 mg/m 2 doxorubicin. [11] Although this study was based on patients with lymphoma, patients with breast cancer are likely to experience similar subclinical cardiotoxicity after similar doxorubicin doses in adjuvant chemotherapy. It has been seen in various studies that diastolic function and indirect measurements of elevated left-atrial pressure generally precede a fall in systolic function. Valvular abnormalities were also more in these patients, whereas the changes in left ventricular diameter and ejection fraction were also present but not statistically significant. It has been seen that as the cardiac function deteriorates, there is associated myocyte loss, which leads to left ventricular (LV) wall thinning and in some cases progressive LV dilation. [12],[13]

The findings in our study suggest that subclinical cardiotoxicity can occur at even lower cumulative dose of more than 300 mg/m 2 in the form of dilatation of atrial and ventricular diastolic diameter, without significant decrease in LVEF. However, there is an uncertainty about the long-term clinical impact of subclinical cardiotoxicity. Thus, there is so far no need to change the clinical practice, but early detection of subclinical cardiac damage is warranted. More studies are needed to address the long-term cardiac impact and to develop a more cost-effective clinical tool to assess cardiac risk during treatment.

 
  References Top

1.Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocon 2000. Int J Cancer 2001;94:153-6.  Back to cited text no. 1
    
2.Yau TK. Cardiotoxicity after adjuvant anthracycline-based chemotherapy and radiotherapy for breast cancer. J HK Coll Radiol 2005;8:26-9.  Back to cited text no. 2
    
3.Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials. Cancer 2003;97:2869-79.  Back to cited text no. 3
    
4.Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91:710-7.  Back to cited text no. 4
    
5.Anderson WF, Pfeiffer RM, Dores GM, Sherman ME. Comparison of age distribution patterns for different histopathologic types of breast carcinoma. Cancer Epidemiol Biomarkers Prev 2006;15:1899-905.  Back to cited text no. 5
    
6.Peeters PH, van Noord PA, Hoes AW, Fracheboud J, Gimbrere CH, Grobbee DE. Hypertension and breast cancer risk in a 19-year follow-up study (the DOM cohort). J Hypertens 2000;18:249-54.  Back to cited text no. 6
    
7.Michels KB, Solomon CG, Hu FB, Rosner BA, Hankinson SE, Colditz GA, et al.; Nurses' Health Study. Type 2 diabetes and subsequent incidence of breast cancer in the Nurses' Health study. Diabetes Care 2003;26:1752-8.  Back to cited text no. 7
    
8.Sasayama S, Takahashi M, Kawai C. Left atrial function in acute mitral regurgitation- Factors which modify the regurgitant volume. Herz 1981;6:156-65.  Back to cited text no. 8
    
9.Speyer JL, Green MD, Dubin N, Blum RH, Wernz JC, Roses D, et al. Prospective evaluation of cardiotoxicity during a six-hour doxorubicin infusion regimen in women with adenocarcinoma of the breast. Am J Med 1985;78:555-63.  Back to cited text no. 9
    
10.Towns K, Bedard PL, Verma S. Matters of the heart: Cardiac toxicity of adjuvant systemic therapy for early-stage breast cancer. Curr Oncol 2008;15:S16-29.  Back to cited text no. 10
    
11.Hequet O, Le QH, Moullet I, Pauli E, Salles G, Espinouse D, et al. Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults. J Clin Oncol 2004;22:1864-71.  Back to cited text no. 11
    
12.Lipshultz SE, Lipsitz SR, Sallan SE, Dalton VM, Mone SM, Gelber RD, et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 2005;23:2629-36.  Back to cited text no. 12
    
13.Steinherz LJ, Steinherz PG, Tan C. Cardiac failure and dysrhythmias 6-19 years after anthracycline therapy: A series of 15 patients. Med Pediatr Oncol 1995;24:352-61.  Back to cited text no. 13
    



 
 
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  [Table 1], [Table 2], [Table 3]



 

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