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ORIGINAL ARTICLE
Year : 2019  |  Volume : 8  |  Issue : 2  |  Page : 83-88

Cardiotoxicity with sequential use of Anthracycline and Trastuzumab in carcinoma breast patients in a North Indian tertiary care centre


1 Department of Oncology, Command Hospital (CC), Lucknow, UP, India
2 Malignant Disease Treatment Centre, Army Hospital Research and Referral, New Delhi, India

Date of Submission19-Feb-2019
Date of Acceptance14-Apr-2019
Date of Web Publication30-Jul-2019

Correspondence Address:
Dr. Dharmesh Soneji
Malignant Diseases Treatment Centre, Army Hospital Research and Referral, New Delhi - 110 010
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JDRNTRUHS.JDRNTRUHS_114_18

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  Abstract 


Background: Anthracycline and Trastuzumab containing regimens demonstrate significant efficacy in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. The utility of this strategy is limited by significant cardiotoxicity associated with these drugs. This study was conducted to study the cardiotoxicity with sequential use of Anthracyclines and Trastuzumab to identify early signs of carditoxicity and tailor therapy for these patients.
Materials and Methods: A total of 45 cases of breast cancer patients who expressed HER 2 by immunohistochemistry (IHC) (3+) or fluorescent in situ hybridisation (FISH) were included in this study. The patients were evaluated for cardiotoxicity by clinical examination, echocardiography and Multigated acquisition (MUGA) scan at periodic intervals.
Results: Fall in ejection fraction was noticed in 20% of patients. Most of these patients were asymptomatic. Two dimensional echocardiography (2 D Echo) and MUGA scans were complimentary to each other. The fall of ejection fraction was reversible in 89% of these patients on stopping Trastuzumab for median of 6 weeks duration. All these patients completed planned treatment on reintroduction of Trastuzumab.
Conclusion: The sequential use of Anthracyclines and Trastuzumab has cardiotoxic potential. Detecting early signs of cardiotoxicity and monitoring asymptomatic fall in ejection fraction can prevent long term cardiotoxic side effects. Due to reversible nature of cardiotoxicity of Trastuzumab, it can be reintroduced in most of the patients. Benefits of Trastuzumab therapy can be achieved by keeping close observation on cardiotoxicity and tailor treatment accordingly.

Keywords: Anthracycline, Human epidermal growth factor receptor 2 (HER2), left ventricular ejection fraction, Multigated acquisition (MUGA), Trastuzumab, Two dimensional echocardiography (2D Echo)


How to cite this article:
Prashar M, Soneji D, Viswanath S, Singh S. Cardiotoxicity with sequential use of Anthracycline and Trastuzumab in carcinoma breast patients in a North Indian tertiary care centre. J NTR Univ Health Sci 2019;8:83-8

How to cite this URL:
Prashar M, Soneji D, Viswanath S, Singh S. Cardiotoxicity with sequential use of Anthracycline and Trastuzumab in carcinoma breast patients in a North Indian tertiary care centre. J NTR Univ Health Sci [serial online] 2019 [cited 2019 Aug 25];8:83-8. Available from: http://www.jdrntruhs.org/text.asp?2019/8/2/83/263630




  Introduction Top


Breast carcinoma is most frequently diagnosed cancer and is leading cause of cancer related death in women worldwide.[1] Human epidermal growth factor receptor 2 (HER-2) expression is an adverse prognostic factor associated with a higher and early risk of recurrence of breast carcinoma. They have relative resistance to established cytotoxic chemotherapy. HER 2 overexpression is seen in 30% of patients of breast carcinoma patients.[2] These patients have shorter overall and disease-free survival and experience a higher incidence of brain metastasis. Patients with HER2 positive tumours respond favourably to monoclonal antibody Trastuzumab that selectively target the extracellular domain of human epidermal growth factor receptor 2.[3] Multiple retrospective analyses have suggested that HER-2 overexpression is associated with a relative benefit from anthracycline based chemotherapy in carcinoma breast patients. Both Anthracyclines and Trastuzumab are cardiotoxic drugs. Anthracycline-Trastuzumab containing regimens demonstrate significant clinical activity in human epidermal growth factor receptor 2 (HER2) positive breast cancer, but the utility of this strategy is limited by unacceptably high rates of significant cardiotoxicity.[4] The Doppler echocardiography is the most commonly used investigation to measure ejection fraction. MUGA is also used to assess ejection fraction and complements echocardiography. With careful treatment and surveillance strategies, the benefits of combining Trastuzumab with anthracyclines outweigh the risk of fatal cardiac events during the follow up periods.[5] The studies have been carried out worldwide to assess cardiotoxicity in patients on sequential use of anthracycline and Trastuzmab. Data from India are lacking on this subject. This study will assess cardiotoxicity of sequential use of anthracycline and Trastuzumab in Indian patients.


  Materials and Methods Top


This prospective, nonrandomised, single arm study was conducted in the department of Medical oncology, in collaboration with the other departments, at a tertiary care centre in North India. All consecutive HER2 positive patients presenting to Oncology OPD were included in the study. Patients enrolled were from both urban and rural background.

A total of 45 confirmed cases of breast carcinoma, who expressed HER 2 by IHC (3+) or positive by FISH were included in present study. A detailed history of the present illness along with past, family, menstrual and obstetric history was recorded. Patients with known history of congestive cardiac failure or ischemic heart disease were not included in our study. The patients were then staged clinically as per TNM staging system. The clinical examination including blood pressure measurement was carried out during each visit. Clinical staging was complemented by exact pathological staging. The patients were then subjected to Anthracyclines followed by Trastuzumab for one year duration in adjuvant, neoadjuvant or metastatic setting. Baseline ECG was done in all patients and was repeated whenever indicated. 2D-Echocardiography and MUGA scan were done before starting anthracycline, before starting Trastuzumab, and at 3 months intervals thereafter on Trastuzumab. Patients who developed significant fall in ejection fraction (EF) required more frequent cardiac evaluation. Significant fall in ejection fraction was defined as fall in LVEF >10% or when EF falls to less than 50%.

Statistical tools

Data analysis was done by using SPSS, version 16. Pearson chi square test was used for nominal data comparison. t-test was used to compare mean values between two groups. Significant value was P less than 0.05.


  Observations and Results Top


Age of the patients ranged from 28-70 years, with the mean age of 47.82 years and standard deviation of 10.4 years. There are about 44 patients who were female and one was male. About 24 patients were treated in adjuvant, 14 in neoadjuvant and 7 patients were treated in metastatic setting. As per AJCC staging 20 patients were in stage II, 17 in stage III, 7 in stage IV and one patient had stage I carcinoma breast. About 25 patients had left sided breast cancer, 19 had right sided whereas one patient had bilateral breast cancer.

Fall in ejection fraction

Nine patients (20%) developed significant fall in ejection fraction. 2D echocardiography detected fall in 6 patients, whereas MUGA detected fall in 7 patients. Four patients had fall in EF by both modalities. [Figure 1] Eight of these nine patients had asymptomatic fall in ejection fraction. In this study, 4 out of 18 patients (22%), who developed fall in ejection fraction (EF) were more than 50 years of age, whereas 5 out of 27 (18%) were less than 50 years of age. There is slightly higher fall in ejection fraction in patients more than 50 years of age, although statistically it is not significant (p-0.76). One patient developed symptoms of congestive heart failure. All these patients were referred for cardiologist consultation. Six of these patients (67%) required conservative management for congestive heart failure. Other 3 (33%) patients were kept under observation and close monitoring.
Figure 1: Fall in ejection fraction by 2D-Echo and MUGA

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Time period for significant fall in ejection fraction

Two out of nine patients had significant fall in EF at 3 months. Five patients were detected to have decrease in EF at 6 months. Two of the patients had fall in EF were detected at 9 months. Median duration for fall in ejection fraction was 6 months after starting Trastuzumab. [Figure 2]
Figure 2: Time period for significant fall in ejection fraction after starting Trastuzumab

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Recovery after stopping Trastuzumab

Trastuzumab was stopped in all 9 patients who had significant fall in ejection fraction. Ejection fraction was measured at two weekly intervals in these patients. Four out of these nine patients recovered from fall in EF by 4 weeks. Three patients recovered by 6 weeks and one patient showed recovery by 8 weeks. [Figure 3] One patient could not recover till 6 months.
Figure 3: Time to recovery in EF after stopping Trastuzumab

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Recurrence after restarting Trastuzumab

All 8 patients who recovered from fall in EF were restarted on Trastuzumab under close monitoring. None of these patients had recurrent fall in ejection fraction.

Risk factors

The patients having hypertension, hyperlipidemia and smokers were studied for fall in ejection fraction. Seven out of 45 patients were hypertensive. All of them were on antihypertensive medication and had controlled blood pressure. Two patients (2/7) had significant fall in ejection fraction. Patients with hypertension had higher risk of fall in ejection fraction (28%), compared to (18%) for non hypertensives, although P value was not significant (p-0.53). Four patients had hyperlipidemia and were on statins. One patient (1/4) developed fall in ejection fraction. Four patients were reformed smokers, none of them was current smoker during treatment. None of these patients developed any cardiotoxicity. Six patients had prior LVH by voltage criteria. Two of these patients developed fall in EF who recovered after stopping Trastuzumab for 6 weeks. No significant arrhythmias were reported.

Radiation: About 30 patients received local radiotherapy to breast. Out of which 19 patients received local radiotherapy to left side of chest and 11 patients received radiotherapy to right side of chest. Four out of nineteen (4/19) patients developed fall in EF, who received radiotherapy to left side of chest, whereas two out of eleven (2/11) patients developed significant fall in EF received radiotherapy to left side of chest. Patients who received radiation to left side of chest had slightly higher risk of cardiotoxicity, although it is not significant (P value-0.845).

Anthracycline used: About 35 (35/45) patients received Doxorubicin, whereas 10 patients received Epirubicin. Eight (8/35) patients, who received Doxorubicin developed fall in ejection fraction. Only one patient (1/10) who received Epirubicin developed fall in EF.

Deaths: Two patients expired during illness. None of the deaths was related to cardiotoxicity. One patient died of neutropenic sepsis whereas other patient had progressive disease with brain metastasis. Both these patients had metastatic disease.


  Discussion Top


It has been recognized that 30% of patients with breast cancer have HER2 gene amplification. Overexpression of unaltered HER2 result in cellular transformation and tumorogenesis.[6] Women with malignancy in which the HER2 gene is overexpressed generally have a less favourable response to chemotherapy.[7] These patients have shorter periods of overall and disease-free survival and experience a higher incidence of brain metastasis. HER2 positive tumours respond favourably to Trastuzumab, a monoclonal antibody that selectively targets the extracellular domain of human epidermal growth factor receptor 2. In this subset of patients, Trastuzumab has been established as the standard of therapy for patients with early stage and metastatic breast cancer. Trastuzumab improves efficacy when given concurrently or sequentially with chemotherapy. Subclinical cardiotoxicity and sometimes cardiac failure has been noted in patients receiving Trastuzumab. Adjuvant studies demonstrated that Trastuzumab either following or in combination with chemotherapy reduced the risk of relapse by 50% and the risk of death by 33% in these patients.[8] Unfortunately, cardiotoxicity was recognized as an important side effect. It manifested as symptomatic heart failure or asymptomatic left ventricular ejection fraction decline. When Trastuzumab is combined with an anthracycline, cardiotoxicity is increased and has been reported to occur in up to 27% of patients.[9] While cardiac adverse events, such as a decreased left ventricular ejection fraction and congestive heart failure, are a concern, these effects are treatable and appear to be mostly reversible.

NSABP-31 and N9831 trials assessed cardiotoxicity with sequential use of anthracyclines followed by Trastuzumab. 14.2% of patients developed asymptomatic LVEF reduction and 4.7% had symptomatic congestive heart failure (CHF).[7] In BCIRG006 trial, 18% of patients developed significant fall in ejection fraction, who received anthracycline followed by Trastuzumab.[10] In our study, 9 out of 45 (20%) developed fall in ejection fraction. [Figure 4] Eight of 45 patients (17.7%) had asymptomatic fall in ejection fraction, whereas one (2.2%) had symptomatic heart failure. Hence fall in ejection fraction in this study was similar to major trials done in past.
Figure 4: Comparison of fall in ejection fraction

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Patients who develop cardiotoxicity while receiving Trastuzumab therapy generally improve on removal of the agent.[11] Data from patients with advanced disease demonstrated that cardiac dysfunction was reversible for the majority (75%) of those who received standard cardiac therapy. Further evidence for this symptom reversal comes from the MD Anderson series. In patients with reduction in LVEF, recovery occurred in majority of patients with or without treatment.[12] In our cohort, 8/9 patients (89%) recovered from fall in ejection fraction (P value-0.07). Recovery in fall of ejection fraction in this study was similar to landmark studies done in past. In a study by Slamon et al. 75% of patients received standard cardiac therapy. In our study 6 out of 9 patients (67%) patients required standard cardiac management. 3 out of 9 patients (33%) were only kept under close observation. In a study by Ewer et al., Trastuzumab was reintroduced to patients after LVEF recovery and stable CHF symptoms. In 88% of patients LVEF remained stable and Trastuzumab was continued.[13] In the remainder of patients, LVEF deteriorated and CHF reoccurred, necessitating permanent Trastuzumab withdrawal. In our cohort all 8 patients (100%) who recovered, did not show significant fall in EF after reintroduction of Trastuzumab. Close monitoring of LVEF is necessary after reintroduction of Trastuzumab. Median time to recovery of ejection fraction in different studies was 1.5 to 2 months. In our study, four out of these nine patients recovered from fall in EF by 4 weeks. Three patients recovered by 6 weeks and one patient showed recovery by 8 weeks. Median time to recovery in this study was 5 weeks. One patient could not recover till 6 months. Trastuzumab can be safely restarted in most of patients after drug vacation and standard cardiac management.

There is no clear international opinion on the method of LVEF assessment. Both echocardiography and MUGA scanning can be used to assess LVEF. Both techniques have relative advantages and disadvantages. MUGA scans assess LVEF but might not assess regional wall motion or diastolic function, both of which can impact on cardiotoxicity. By contrast, echocardiography can assess all these parameters and avoids ionizing radiation exposure. Calculation of LVEF, however, is dependent on assumptions made from two-dimensional images, operator dependent and reproducibility can be more difficult than with MUGA scanning. In our study both these modalities were used simultaneously. 2 D Echocardiography detected fall in 6 patients, whereas MUGA detected fall in 7 patients. Four patients had fall in EF by both modalities. Hence additional cases were detected using both modalities for evaluation.

Factors associated with increased risk of cardiac events included older age, lower baseline LVEF, and prior/current use of antihypertensive medications.[14] In our series 4 out of 18 patients (22%), who developed fall in EF were more than 50 years of age, whereas 5 out of 27 (18%) were less than 50 years of age. There is slightly higher risk of fall in ejection fraction in patients more than 50 years of age. The fall in ejection fraction in hyperlipidemia patients was not significant in this study. Prior radiotherapy had no significant effect on increased cardiotoxicity in a study.[12] Left side irradiation was associated with increased cardiotoxicity after use of concurrent Trastuzumab.[15] In our series, 4/19 (21%) developed cardiotoxicity, who received radiation to left side of chest compared to 2/11 (18%) of patients who received radiation to right side of chest. Patients who received radiation to left side of breast had slightly higher risk of cardiotoxicity. In studies by both Slamon et al. and M.D Anderson, hypertension did not significantly affect outcome. In our study, all patients of hypertension were on antihypertensive medication and had controlled blood pressure. Two hypertensive patients out of 7 (28%) had fall in ejection fraction, in comparison to 16% in patients without hypertension. The use of Epirubicin in combination with Trastuzumab indicated lower incidence of left ventricular dysfunction than Doxorubicin. In this study 23% of patients developed fall in ejection fraction who were treated with Doxorubicin in comparison to 10% in patients who received Epirubicin.


  Conclusion Top


Cardiotoxic effects of sequential use of anthracyclines followed by Trastuzumab in sequential manner were studied in carcinoma breast patients. Fall in ejection fraction was seen in 20% of patients treated with sequential use of anthracyclines followed by Trastuzumab in this study, which is similar to major studies done in past. 89% of patients who had fall in ejection fraction remained asymptomatic. Median time for fall in ejection fraction is 6 months. Fall in ejection fraction was reversible in 89% of these patients after stopping Trastuzumab, with median duration to recovery of 6 weeks. It is in concordance with major trials done earlier. Patients with significant fall in ejection fraction were managed with medical management. There is 8 out of 9 patients had recovery of ejection fraction and could be restated on Trastuzumab. All patients restarted on Trastuzumab maintained stable ejection fraction and could be continued on treatment with Trastuzumab along with standard cardiac management. Two dimensional echocardiography and MUGA were complimentary to each other and detected additional cases missed by one modality. Patients having variance in two modalities were discussed jointly and decision to withdraw or continue treatment was taken considering risk/benefit in individual case. Patients with more than 50 years of age and hypertensive patients (though adequately controlled) had higher risk of cardiotoxicity. Patients with hyperlipidemia on statins and past smokers were not at increased risk of cardiotoxicity. Patients who received radiation to left side of chest had slightly increased risk of cardiotoxicity compared to those with right sided breast malignancy, although it was not significant. Patients who received Doxorubicin had increased risk of cardiotoxicity when compared to those who received Epirubicin. The risk of cardiotoxicity can be reduced by strict periodic evaluation of ejection fraction. Trastuzumab should be stopped in those patients who have fall in ejection fraction. Due to reversible nature of cardiotoxicity of Trastuzumab, it can be reintroduced in most of patients under close supervision.

Acknowledgements

Army Hospital Research and Referral, New Delhi.

Financial support and sponsorship

Army Hospital Research and Referral, New Delhi.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Forouzanfar MH, Foreman KJ, Delossantos AM, Lozano R, Lopez AD, Murray CJ, et al. Breast and cervical cancer in 187 countries between 1980 and 2010: A systemic analysis. Lancet 2011;378:1461-84.  Back to cited text no. 1
    
2.
Slamon DJ, ClarkGM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: Correlation of relapse and survival with amplification of HER2/neu oncogene. 1987;235:177-82.  Back to cited text no. 2
    
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Suter TM, Procter M, van Veldhuisen DJ, Muscholl M, Bergh J, Carlomagno C, et al. Trastuzumab associated cardiac adverse effects in the Herceptin adjuvant trial. J Clin Oncol 2007;25:3859-65.  Back to cited text no. 5
    
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Hudziak RM, Schlessinger J, Ullrich A. Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells. Proc Natl Acad Sci U S A 1987;84:7159-63.  Back to cited text no. 6
    
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Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. BCIRG 006 study: 2nd Interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC-T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC-TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients [abstract #52]. San Antonio Breast Cancer Symposium, 2006.  Back to cited text no. 10
    
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Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783-92.  Back to cited text no. 11
    
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Guarneri V, Daniel J, Valero V, Durand JB, Broglio K, Kanneth R, et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: The MD Anderson Cancer Center experience. J Clin Oncol 2006;24:4107-15.  Back to cited text no. 12
    
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Ewer MS, Vooletich MT, Durand J-B, Woods ML, Davis JR, Valero V, et al. Reversibility of trastuzumab related cardiotoxicity: New insights based on clinical course and response to medical treatment. J Clin Oncol 2005;23:7820-6.  Back to cited text no. 13
    
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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