Conditions: Breast Cancer Stage I Breast Cancer Stage II Breast Cancer Stage III Breast Cancer
Keywords: Breast cancer Adriamycin Simvastatin Statin Echocardiogram
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 34
Healthy volunteers: no

Brief summary:
Doxorubicin (Adriamycin), one of the drugs commonly used for the treatment of breast cancer, is in a class of medications called anthracyclines. Anthracyclines may cause heart damage that can lead to weakening of the heart muscle. This heart damage may happen right away or may occur many years after the anthracycline is given

Simvastatin is an oral medication approved by the FDA to lower cholesterol. Simvastatin is in a class of medications called statins. Some research has shown that statins may prevent heart damage that can be caused by anthracyclines like Doxorubicin (Adriamycin).

The purpose of this study is to determine if taking simvastatin while receiving the chemotherapy Doxorubicin (Adriamycin) will minimize damage to the heart.

This study is for women who will be receiving the anthracycline doxorubicin (Adriamycin) as part of their breast cancer treatment.

Detailed description:

Arms:
arm 1: Simvastatin will be administered on an outpatient basis orally at a dose of 40 mg once daily. Treatment will start 7 days prior to the planned doxorubicin/cyclophosphamide chemotherapy initiation and will continue for a total of 25 weeks. arm 2: Participant not randomized to simvastatin will participate in all aspects of the study, including planned doxorubicin/cyclophosphamide chemotherapy, with the exception of simvastatin administration.

Interventions: intervention 1: Simvastatin intervention 2: Doxorubicin/cyclophosphamide
Intervention descriptions: intervention 1: Simvastatin will be administered on an outpatient basis orally at a dose of 40 mg once daily. intervention 2: The standard chemotherapy regimen that must be planned for all participants in order to take part in this study. The regimen is given every 2 or 3 weeks per standard of care, at the direction of the treating physician.

Protocol document:
Prot_SAP_000.pdf: 
Detection and Prevention of Anthracycline-Related Cardiac Toxicity  
with Concurrent Simvastatin 
Principal Investigator 
Karen Lisa Smith, M.D., M.P.H. 
Johns Hopkins Sidney Kimmel Cancer Center 
 at Sibley Memorial Hospital 
5215 Loughboro Road NW, Suite 330 
Washington, D.C. 20016  
Phone: 202-660-6500 
Fax: 202-660-6501 
Email:  ksmith60@jhmi.edu 
Co-Principal Investigator 
Allison Hays, M.D. 
Johns Hopkins Hospital 
600 N. Wolfe Street, Carnegie 583 
Baltimore, MD 21287 410 502 7283 
 ahays2@jhmi.edu 
Co-Investigators 
Vered Stearns, M.D. 
Antonio Wolff, M.D. 
Kala Visvanathan, M.D., M.H.S. 
Members of the Breast Cancer Program 
Statistician 
Gary Rosner, ScD 
Supporters 
Avon Foundation 
Protocol Version:   
Amendment 11 Dated November 3, 2017 
NCT02096588


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 3 
AC 
Doxorubicin/Cyclophosphamide 
ACE 
Angiotensin Converting Enzyme 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ARB 
Angiotensin II Receptor Blocker 
AST 
Aspartate Aminotransferase 
BCIRG 
Breast Cancer International Research Group 
CK 
Creatine Kinase 
cTnI 
Cardiac Troponin I 
CRF 
Case Report Form 
CRO 
Clinical Research Office 
CRRMC 
Clinical Research Review and Monitoring Committee 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CYP3A4 
Cytochrome P450 3A4  
DNA 
Deoxyribonucleic Acid 
DSMP 
Data and Safety Monitoring Program 
ECOG 
Eastern Cooperative Oncology Group 
EF 
Ejection Fraction 
EKG 
Electrocardiogram 
ER 
Estrogen Receptor 
FDA 
Food and Drug Administration 
GLS 
Global Longitudinal Strain 
HER2 
Human Epidermal Growth Factor Receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HMG-CoA 
3-hydroxy-3-methylglutaryl-coenzyme A 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
JHM 
Johns Hopkins Medicine 
LV 
Left Ventricular 
MANTICORE Multidisciplinary Approach to Novel Therapies in Cardiology Oncology 
Research 
MUGA 
Multigated Acquisition 
NCI 
National Cancer Institute  
NSABP 
National Surgical Adjuvant Breast and Bowel Project 
NYHA 
New York Heart Association 
PRADA 
Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy 
PR 
Progesterone Receptor 
QA 
Quality Assurance 
RFS 
Recurrence Free Survival 
ROC 
Receiver Operating Curve 
SAE 
Serious Adverse Event 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 4 
SCUSF 
Sun Coast University of South Florida 
SKCCC 
Sidney Kimmel Comprehensive Cancer Center 
TOP2B 
Topoisomerase II Beta  
TOP2A 
Topoisomerase II Alpha 
ULN 
Upper Limit of Normal 
WMA 
Wall Motion Abnormality 
 
 
 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
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Detection and Prevention of Anthracycline-Related Cardiac Toxicity 
with Concurrent Simvastatin 
 
 
- PROTOCOL REVISION RECORD - 
 
Original Protocol: 
 
January 21, 2014 
 
 
Amendment #1:  
June 30, 2014 
Sections revised:  Title page, Sections 2, 6.2.16, 6.2.17, 7.3.4.1, 8.0, 9.8, 10.1, 
10.2, 10.4.1, References, Appendix (drug diary)  
 
 
Amendment #2:  
October 08, 2014 
 
 
 
 
Sections revised:  Title page, Sections 2, 6.1.4, 7.3.4.1, 8.0, 10.2.2,  
 
 
 
 
Appendix (drug diary) 
 
Amendment #3:  
November 04, 2014 
 
 
 
 
Sections revised:  Title page, Sections 2, 3.3.2, 5.2, 5.3, 7.3, 7.3.3.1, 7.3.3.2.1, 
 
 
 
 
 
7.3.3.2.2, 7.5, 8.0, 13.3 
 
Amendment #4:  
March 10, 2015 
 
 
 
 
Sections revised:  Title page, Sections 7.3.3.2, 8.0 
 
Amendment #5:   
September 11, 2015 
Sections revised: Title page, Sections 2, 5.2.2, 6.2.8, 7.3.4.1, 7.3.4.2, 7.4.2, 8, 
13.1, 13.2, 13.2.2, 13.5.1, 13.5.2, 13.5.3  
 
 
     Amendment #6:   
January 15, 2016 
 
 
 
 
Section revised: Title page, section 7.4.2 
 
    Amendment #7: 
 
February 24, 2016 
 
 
 
 
Section revised: Appendix C: Study Drug Diary   
 
    Amendment #8: 
 
March 14, 2016 
 
 
 
 
Section revised: Title page, Sections 7.4.2 and 8.0 (9)   
     Amendment #10:   
September 21, 2017 
 
 
 
 
Section revised: Title page, Sections 5.3.3, 13.5.3 and 13.5.6          
 
Amendment #11:  
 
November 3, 2017 
 
 
 
 
Section revised: Sections 5.3.3, 13.2.3, 13.5.3 
 
 
 
 
 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 6 
Table of Contents 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................................. 2 
1. 
SUMMARY ........................................................................................................................................................ 8 
2. 
SCHEMA ............................................................................................................................................................ 9 
3. 
BACKGROUND AND RATIONALE ............................................................................................................ 10 
3.1 
CARDIAC TOXICITY OF ADJUVANT ANTHRACYCLINE THERAPY FOR EARLY STAGE BREAST CANCER .......... 10 
3.2 
ASSESSMENT OF CARDIAC FUNCTION IN BREAST CANCER PATIENTS TREATED WITH ANTHRACYCLINES ..... 13 
3.3 
CARDIOPROTECTIVE INTERVENTIONS TO PREVENT ANTHRACYCLINE-INDUCED CARDIAC TOXICITY ............ 17 
3.4 
STUDY RATIONALE AND DESIGN ................................................................................................................... 23 
4. 
HYPOTHESIS .................................................................................................................................................. 25 
5. 
OBJECTIVES .................................................................................................................................................. 25 
5.1 
PRIMARY OBJECTIVE ..................................................................................................................................... 25 
5.2 
SECONDARY OBJECTIVES ............................................................................................................................... 25 
5.3 
EXPLORATORY OBJECTIVES ........................................................................................................................... 25 
6. 
PATIENT POPULATION .............................................................................................................................. 27 
6.1 
INCLUSION CRITERIA ..................................................................................................................................... 27 
6.2 
EXCLUSION CRITERIA .................................................................................................................................... 28 
6.3 
INCLUSION OF WOMEN AND MINORITIES ....................................................................................................... 29 
7. 
STUDY DESIGN AND TREATMENT PLAN .............................................................................................. 30 
7.1 
RECRUITMENT ................................................................................................................................................ 30 
7.2 
DETERMINATION OF ELIGIBILITY ................................................................................................................... 30 
7.3 
STUDY DRUG AND MANAGEMENT OF TOXICITIES .......................................................................................... 30 
7.4 
STUDY ASSESSMENTS .................................................................................................................................... 38 
7.5 
DURATION OF STUDY PARTICIPATION ............................................................................................................ 39 
7.6 
ADDITIONAL INFORMATION ........................................................................................................................... 40 
8. 
STUDY CALENDAR ...................................................................................................................................... 41 
9. 
PHARMACEUTICAL INFORMATION ...................................................................................................... 43 
9.1 
SIMVASTATIN PRODUCT IDENTIFICATION ...................................................................................................... 43 
9.2 
SIMVASTATIN PHARMACOKINETICS ............................................................................................................... 43 
9.3 
CONTRAINDICATIONS TO SIMVASTATIN THERAPY ......................................................................................... 44 
9.4 
DRUG INTERACTIONS WITH SIMVASTATIN ..................................................................................................... 44 
9.5 
REPORTED SIMVASTATIN TOXICITIES ............................................................................................................ 44 
9.6 
SIMVASTATIN MONITORING PARAMETERS..................................................................................................... 45 
9.7 
STORAGE AND STABILITY OF SIMVASTATIN ................................................................................................... 45 
9.8 
SIMVASTATIN PREPARATION AND ADMINISTRATION ..................................................................................... 45 
9.9 
SIMVASTATIN AVAILABILITY ......................................................................................................................... 45 
9.10 
ACCOUNTABILITY FOR STUDY DRUG ........................................................................................................ 45 
10. 
ADVERSE EVENTS ........................................................................................................................................ 46 
10.1 
GENERAL................................................................................................................................................... 46 
10.2 
DEFINITIONS .............................................................................................................................................. 46 
10.3 
RELATIONSHIP ......................................................................................................................................... 483 
10.4 
REPORTING PROCEDURES .......................................................................................................................... 49 
11. 
DATA AND SAFETY MONITORING .......................................................................................................... 50 
11.1 
DATA MANAGEMENT ................................................................................................................................ 50 


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11.2 
MEETINGS ................................................................................................................................................. 50 
11.3 
MONITORING ............................................................................................................................................. 50 
12. 
ADMINISTRATIVE PROCEDURES ........................................................................................................... 51 
12.1 
PROTOCOL AMENDMENTS ......................................................................................................................... 51 
12.2 
INFORMED CONSENT ................................................................................................................................. 51 
12.3 
ETHICS AND GOOD CLINICAL PRACTICE ................................................................................................... 51 
12.4 
REGULATORY AUTHORITIES...................................................................................................................... 51 
13. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 52 
13.1 
STUDY DESIGN .......................................................................................................................................... 52 
13.2 
ENDPOINTS ................................................................................................................................................ 53 
13.3 
SAMPLE SIZE AND ACCRUAL RATE ........................................................................................................... 53 
13.4 
STRATIFICATION FACTORS ........................................................................................................................ 55 
13.5 
ANALYSIS PLAN ........................................................................................................................................ 55 
13.6 
EARLY STOPPING ...................................................................................................................................... 57 
REFERENCES .......................................................................................................................................................... 59 
APPENDICES ............................................................................................................................................................ 66 
APPENDIX A:  AMERICAN JOINT COMMITTEE ON CANCER STAGING .................................................................... 67 
APPENDIX B:  PERFORMANCE STATUS CRITERIA ................................................................................................. 70 
APPENDIX C:  STUDY DRUG DIARY ...................................................................................................................... 71 
APPENDIX D:  NYHA FUNCTIONAL CLASSIFICATION .......................................................................................... 72 
APPENDIX E:  PARTICIPANT QUESTIONNAIRE ....................................................................................................... 73 
 
 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 8 
1. Summary 
Although rare, cardiac toxicity can be a late consequence of adjuvant anthracycline-based 
chemotherapy for early stage breast cancer.  Standard clinical practice dictates confirmation of a 
normal ejection fraction (EF) by echocardiogram or multigated acquisition (MUGA) scan prior 
to initiation of adjuvant anthracycline therapy. However, in the United States, cardiac monitoring 
beyond baseline confirmation of a normal EF is not routinely performed for adjuvant breast 
cancer patients unless additional potentially cardiotoxic agents, such as trastuzumab, are 
prescribed or possible signs or symptoms of heart failure are observed.   
 
A decline in EF is known to be a late stage in the development of cardiac toxicity and 
identification of cardiac damage at an earlier stage could offer the opportunity for an intervention 
to prevent potentially irreversible anthracycline-induced cardiac toxicity.  Myocardial strain is a 
new echocardiographic technique which can detect subclinical heart disease prior to a decline in 
EF.  Data suggests that statins may attenuate the cardiac toxicity of anthracyclines by minimizing 
anthracycline-induced mitochondrial damage.   
 
This is a prospective, randomized study to assess statin therapy for cardiac protection during 
anthracycline-based chemotherapy and myocardial strain for early detection of anthracycline-
induced cardiac toxicity.  Eligible patients include women with early stage invasive breast cancer 
(stage I-III) with normal organ function for whom adjuvant or neo-adjuvant anthracycline-based 
chemotherapy is planned.  Women with known cardiac disease and/or who are on therapy with a 
statin at baseline are not eligible.   Patients will undergo serial assessment of echocardiographic 
parameters including myocardial strain before, during, and after anthracycline therapy.  Patients 
will be randomized in a 1:1 ratio to the intervention group treated with simvastatin therapy (40 
mg daily) concurrently with doxorubicin/cyclophosphamide (AC) chemotherapy or to the control 
group treated with AC chemotherapy alone.   Echocardiographic parameters will be compared 
between the two groups. Patients will be monitored for hepatic and muscular toxicity and for 
signs or symptoms of heart failure. 
 
The overarching objective is to assess the detectable change in myocardial strain over time in the 
breast cancer patients receiving anthracycline-based adjuvant chemotherapy who do and do not 
receive simvastatin treatment.  The hypothesis is that statin therapy will minimize reduction in 
myocardial strain associated with anthracycline therapy.  Results gained from this study will be 
used in designing future definitive trials assessing the clinically important difference in strain 
between patients who do and do not receive statin therapy as well as the protective effect of 
statin on AC-induced cardiotoxicity with long-term follow-up. 
 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 9 
2. Schema 
 
 
 
 
 
Standard AC chemotherapy (doxorubicin and cyclophosphamide) in the 
preoperative/neoadjuvant or adjuvant setting, every 2-3 weeks, for up to 4 cycles 
 
Echocardiogram with strain analysis:  baseline, immediately before AC #2, 1-3weeks 
after AC #4, 24 weeks after AC #1, and 52 weeks after AC #1 
 
Blood sampling:  baseline and prior to cycles 2-4 of AC, 2-3 weeks after AC #4, and 
24 weeks after AC #1 (liver function tests to be drawn at each time point; creatine 
kinase, CBC and chemistry to be drawn at baseline only)
Key eligibility 
criteria: 
 Women 
 Invasive breast 
cancer, stages I-III 
 Any ER, PR, 
HER2 
 Initiating standard 
preoperative or 
adjuvant  AC 
Standard 
treatment 
regimens, 
such as 
taxane or 
trastuzumab 
(as clinically 
appropriate) 
Intervention Group: 
Simvastatin (40mg) x 24 weeks 
(starting concurrently withAC #1) 
Control Group: 
No simvastatin 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
End of 
Study 
 
AC
#1
 
AC
#2
 
AC
#3
 
AC
#4


Anthracycline-Related Cardiac Toxicity 
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Version: November 21, 2016 (Amendment #9)   
Page 10 
3. Background and Rationale 
3.1 
Cardiac Toxicity of Adjuvant Anthracycline Therapy for Early Stage Breast Cancer 
3.1.1 Clinical Presentation of Anthracycline-Induced Cardiac Toxicity 
The development of anthracycline-based chemotherapy regimens in the adjuvant treatment of 
early stage breast cancer resulted in reduced breast cancer recurrence and mortality.1 2 While 
non-anthracycline-based regimens are currently an option for some patients, anthracycline-based 
chemotherapy still remains a cornerstone of curative therapy for many women with early stage 
breast cancer.3   For women with human epidermal growth factor receptor-2 (HER2) -positive 
breast cancer, the addition of trastuzumab to adjuvant anthracycline-based chemotherapy further 
reduces breast cancer recurrence and mortality.4-6   
 
Unfortunately, cancer survivors are known to face increased risk of cardiovascular disease.7-9  
While cancer therapy may cause a variety of types of cardiovascular toxicity, the most frequent 
is left ventricular (LV) dysfunction leading to heart failure.10  Indeed, the American College of 
Cardiology and American Heart Association Guidelines have recently classified cancer patients 
receiving chemotherapy as having stage A heart failure, defined as being at increased risk for 
developing cardiac dysfunction but without structural heart disease or symptoms.11 
 
Cardiac toxicity is a rare, yet serious, complication of both anthracycline and trastuzumab 
therapies.  Anthracycline-associated cardiac toxicity has typically been described as left 
ventricular dysfunction and heart failure which can be asymptomatic or symptomatic and which 
presents long after chemotherapy.12-14  In contrast, trastuzumab-associated cardiac toxicity 
typically presents during trastuzumab therapy and is most frequently characterized by 
asymptomatic decline in EF which is reversible.15-21 
 
Anthracycline-associated cardiac toxicity has traditionally been considered irreversible, although 
recent data has challenged this notion.  A small case-control study demonstrated improvements 
in cardiac function in patients with anthracycline-induced heart failure with beta-blocker 
treatment comparable to that observed in patients with idiopathic heart failure.22  In addition, a 
small retrospective review and a small prospective study evaluating cardiac function in patients 
with anthracycline-associated heart failure who were treated with standard heart failure 
medications such as beta-blockers and angiotensin converting enzyme (ACE) inhibitors revealed 
improvements in EF over time. 23, 24  Despite the new findings that anthracycline-induced heart 
failure may indeed be reversible, it has historically been associated with inferior prognosis in 
comparison to heart failure of many other etiologies.25 
 
Cardiac toxicity associated with anthracyclines is dose-dependent with reported rates as high as 
18-48% in patients treated with a cumulative dose of 700 mg/m2 of doxorubicin.12,26  However, 
abnormalities in left ventricular performance after exposure to low-moderate doses of 
anthracyclines have recently been reported.27    Besides higher dose, risk factors for 
anthracycline-associated cardiac toxicity include coronary artery disease, diabetes, hypertension, 
concurrent treatment with trastuzumab, older age, cardiac exposure to radiation and black 
race.12,25,26,28  Duration of anthracycline infusion may also be linked to the risk for cardiac 
toxicity.29  In addition, animal data suggests that genetic alterations in genes involved in 


Anthracycline-Related Cardiac Toxicity 
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Version: November 21, 2016 (Amendment #9)   
Page 11 
intracellular doxorubicin transport, such as MRP1, and in free radical metabolism, such as 
NAD(P)H oxidase, may predispose to anthracycline-induced cardiac toxicity.30  
 
The clinical significance of asymptomatic reduction in EF after anthracycline therapy is 
unknown.  However, data indicates that asymptomatic reduction in EF due to causes other than 
anthracycline exposure is associated with substantial risk of future cardiovascular events and 
mortality.31,32  Thus, it would be expected that asymptomatic reduction in EF in patients treated 
with anthracyclines is associated with poor cardiovascular clinical outcomes also. 
3.1.2 Frequency of Anthracycline-Induced Cardiac Toxicity 
True rates of cardiac toxicity from anthracycline chemotherapy are difficult to discern as it may 
occur years after anthracycline exposure and may not be clinically detected because it often 
involves asymptomatic reduction in EF without symptomatic heart failure.  In addition, long-
term follow-up to assess for cardiac toxicity has not been performed for most recipients of 
anthracycline therapy and the definitions used for cardiac toxicity have varied in the studies 
which have been performed, making precise determination of the prevalence of cardiac toxicity 
from anthracyclines difficult to discern.33  According to a recent meta-analysis, rates of cardiac 
toxicity are more than 5-fold higher with anthracycline than non-anthracycline containing 
chemotherapy regimens.34  Data from long-term follow-up of children treated with 
anthracyclines reveals reported rates of subclinical heart failure ranging from 0-57% in 
comparison to rates of clinical heart failure generally reported as less than 5%.35-40  For example, 
the Childhood Cancer Survivor Study cohort revealed rates of heart failure of 1.7% among 
survivors compared to 0.2% among unaffected siblings, with heart failure rates continuing to rise 
over a 30-year follow-up period.38 
 
In the breast cancer setting, reported rates of clinical and subclinical anthracycline-induced 
cardiac toxicity have also varied.  The Early Breast Cancer Trialists’ Collaborative Group 
reported a 33% higher risk of death from heart disease among breast cancer patients treated with 
adjuvant anthracycline chemotherapy compared to those treated with non-anthracycline 
chemotherapy, but rates of heart failure were not reported.41  Estimates of short-term cardiac 
toxicity from modern anthracycline-based adjuvant chemotherapy for breast cancer can be 
determined from the adjuvant trastuzumab trials in which assessment of EF was performed 
immediately after completion of doxorubicin (cumulative dose 240 mg/m2) and 
cyclophosphamide.  In the N9831 study, 5% of patients were unable to continue to the 
trastuzumab-containing portion of therapy due to asymptomatic decline in EF after AC.  
Similarly, in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 study, 
6.6% of patients were unable to continue on to receive trastuzumab due to asymptomatic decline 
in EF or heart failure symptoms after AC.  A slightly lower rate of 2.1% was reported for 
patients in the Breast Cancer International Research Group (BCIRG) 006 trial who were unable 
to begin trastuzumab therapy after completion of AC due to reduced EF.4,15,16 
 
With longer follow-up, reported rates of cardiac toxicity after anthracycline therapy for early 
stage breast cancer patients have varied.  For example, Ganz et al evaluated EF in 180 patients 
who had previously participated in a trial comparing an anthracycline-based chemotherapy 
regimen to a non-anthracycline based regimen and found no difference in the proportion of 
patients with EF less than 50% 5-8 years after treatment (5% in the non-anthracycline arm versus 


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Page 12 
7% in the anthracycline arm, p-value 0.68) or 10-13 years after treatment (3% in the non-
anthracycline versus 0%,in the anthracycline arm,  p-value 0.16) between the two groups.  
Exploratory analysis, however, revealed that EF measured 5-8 years after treatment was lower in 
the women who received anthracycline therapy compared to those who did not (mean EF 61.4% 
versus 64.8%, p-value 0.01).42  These results, however, may underestimate long-term cardiac 
toxicity as recruitment for this follow-up study was likely biased towards healthy survivors.43  
Zambetti et al identified similarly low rates of cardiac toxicity in their report of cardiac outcomes 
in 1000 women treated on three adjuvant breast cancer trials with 14 years median follow-up.  In 
this report, 1% of patients treated with doxorubicin experienced heart failure and 0.6% 
experienced cardiac death. Reduced EF was noted in 8% of patients who received doxorubicin, 
with the majority being asymptomatic.44  
 
The results of Ganz and Zambetti differ substantially from the retrospective population-based 
analysis performed by Pinder et al which showed that as many as 38% of older women treated 
with anthracyclines for breast cancer had a subsequent diagnosis of heart failure.  In comparison 
to these rates of heart failure in older women who received anthracyclines, Pinder et al reported 
that 32.5% of older women treated with non-anthracycline chemotherapy for breast cancer and 
29% of older women with breast cancer not treated with chemotherapy had subsequent diagnoses 
of heart failure.28  Notably, these estimates are higher than the prevalence of heart failure in the 
general population of older women and raise concern regarding limitations of the population-
based data on which they are based, but they do suggest that cardiac toxicity from anthracyclines 
may be more common than previously suspected, especially among older women.45   In further 
support of this data are the findings of Du et al who also performed a population-based study of 
older women with breast cancer.  They concluded that the cumulative incidence of heart failure 
after 10 years of follow-up was 31.9% among anthracycline-treated patients compared to 26.4% 
among those who didn’t receive chemotherapy (4.7% excess risk).46 
3.1.3 Mechanism of Anthracycline-Induced Cardiac Toxicity 
Anthracycline-induced cardiac toxicity has traditionally been thought to result from reactive 
oxygen species generated from reduction-oxidation cycling of anthracycline quinones.  These 
reactive oxygen species damage deoxyribonucleic acid (DNA), proteins and lipids, ultimately 
resulting in cardiomyocyte dysfunction and death.  Recently, this theory has been challenged as 
research has revealed that anthracycline-induced cardiac toxicity is mediated via mitochondrial 
dysfunction resulting from the interaction between anthracyclines and cardiomyocyte 
topoisomerase II beta (TOP2B).  Anthracyclines block the function of both topoisomerase II 
alpha (TOP2A), which is often expressed in malignant cells, and of TOP2B, which is expressed 
in cardiomyocytes.  In the heart, anthracyclines intercalate into cardiomyocyte DNA, forming a 
complex with TOP2B which inhibits its action.  This results in reduced transcription of genes 
involved in the regulation of mitochondrial biogenesis and function, leading to changes in 


Anthracycline-Related Cardiac Toxicity 
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Version: November 21, 2016 (Amendment #9)   
Page 13 
mitochondrial structure and function and ultimately to the generation of reactive oxygen 
species.14,47,48 
3.2 
Assessment of Cardiac Function in Breast Cancer Patients Treated with 
Anthracyclines 
3.2.1 Traditional Approaches to Assessing Cardiac Function 
Traditionally, normal baseline cardiac function has been confirmed via echocardiographic or 
MUGA scan measurement of EF prior to the initiation of anthracycline therapy.  For breast 
cancer patients receiving current standard cumulative adjuvant doxorubicin doses of 240-300 
mg/m2, repeat assessment of cardiac function after completion of doxorubicin therapy is not 
typically performed unless therapy with trastuzumab is planned or signs or symptoms of heart 
failure are present.  However, recent guidelines suggest consideration of repeat assessment of EF 
over time for adult patients who have been treated with potentially cardiotoxic chemotherapy 
agents such as anthracyclines, although evidence to support these guidelines is currently 
lacking.11,49,50 
 
Unfortunately, standard echocardiography and MUGA imaging both have limitations and neither 
can reliability detect cardiac damage prior to a decline in EF.33  Research suggests that EF drops 
late in the process of anthracycline-induced cardiac toxicity with data revealing that extensive 
cardiac remodeling precedes overt clinical heart failure after an index event such as exposure to 
anthracycline therapy.43,51,52  Thus, even if performed at regular intervals after anthracycline 
therapy, standard echocardiography and MUGA imaging may not be able to detect early cases of 
anthracycline-induced cardiac toxicity.  Newer techniques to try to detect anthracycline-induced 
cardiac toxicity at an earlier stage at which it may be reversible are needed.   
3.2.2 Newer Approaches to Assessing Cardiac Function 
Multiple potential biomarkers for assessing cardiac function and risk are currently being 
evaluated.  These include advanced imaging techniques such as echocardiographic myocardial 
strain and cardiac magnetic resonance imaging and serum markers such as cardiac troponins, 
among others.  The optimal technique(s) and frequency of assessment are not known.  This 
protocol will further assess the role of echocardiographic myocardial strain. 
3.2.2.1 Echocardiographic Myocardial Strain 
Myocardial strain is an echocardiographic measure of myocardial tissue deformation or 
contractility.  During contraction, the myocardium shortens in the circumferential and 
longitudinal directions (resulting in negative circumferential and longitudinal strain) and 
lengthens in the radial direction (resulting in positive radial strain). Changes in myocardial strain 
can identify subclinical heart disease prior to a drop in EF and predict subsequent cardiovascular 
outcomes.53  Numerous studies have demonstrated that reduced global longitudinal strain (GLS) 
is associated with higher risk of death and hospitalization for cardiovascular problems in patients 
with cardiac diseases such as acute myocardial infarction, chronic ischemic cardiomyopathy and 
chronic heart failure.54-59 
 
As is the case in cardiac disease, evidence suggests that changes in myocardial strain can detect 
anthracycline-induced cardiac damage in the absence of a decline in EF.  In a pilot study of 16 


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elderly women treated with pegylated liposomal doxorubicin, the mean GLS was -22.7% at 
baseline and dropped to -18.8% after 6 cycles of chemotherapy.  No significant change in EF 
was noted in this time period.60  Ho et al performed a cross sectional study in 70 asymptomatic 
breast cancer survivors without known cardiovascular disease who had previously received 
anthracyclines with or without trastuzumab up to 6 years earlier and 50 asymptomatic controls 
without known cardiovascular disease.   Echocardiographic strain analysis performed in the 
study participants revealed reduced mean GLS in the chemotherapy group in comparison to the 
controls (- 18.1% versus -19.6%).  GLS was below the lower limit of normal in 26% of the 
patients previously treated with anthracyclines.  No significant differences were observed in EF 
between the two groups.61  Stoodley et al observed similar findings in a prospective study of 52 
breast cancer patients treated with anthracycline therapy.  Echocardiography with strain analysis 
was performed one week prior to initiating chemotherapy and one week after the completion of 
all cycles of chemotherapy.  Mean GLS decreased from -17.7% to -16.3% with 48% of patients 
experiencing at least 10% decrease in GLS.  Radial strain was also noted to decrease with mean 
values dropping from 40.5% to 34.5%.  No patients experienced greater than 10% decline in 
EF.62 
 
Stoodley et al recently reported a follow-up study in which 50 of the anthracycline-treated breast 
cancer patients underwent serial echocardiography over 12 months, thus providing, to the best of 
our knowledge, the first reported long-term prospective cardiac strain data in this population.  In 
comparison to baseline, reductions in LV longitudinal peak systolic strain were noted 
immediately after completing anthracycline therapy and at the 6-month time-point, but resolved 
by the 12-month time-point in 84% of patients, demonstrating that they tend to be transient.  
Among the eight patients with persistent reductions in LV longitudinal peak systolic strain 
exceeding one standard deviation at the 12-month time-point, no significant change in EF was 
noted.  A LV longitudinal peak systolic strain value < -17.2% at the 6 month time-point 
predicted a low LV longitudinal peak systolic strain value at the 12 month time-point with 100% 
sensitivity and 80% specificity.63     
 
Long-term prospective data associating a reduction in myocardial strain with subsequent drop in 
EF and inferior cardiac outcomes is not available for breast cancer patients treated with standard 
adjuvant anthracycline therapy alone, but several studies in breast cancer patients treated with 
trastuzumab, many of whom also received anthracyclines, demonstrate the prognostic capacity of 
echocardiographic myocardial strain measurements in the breast cancer population.  Hare et al 
performed echocardiograms measuring EF, strain and strain rate at baseline and every 3 months 
in 35 breast cancer patients receiving trastuzumab.  In this small study, 51% of patients 
experienced a drop in longitudinal strain rate and 37% experienced a drop in radial strain rate.  
Of those with decreased longitudinal strain rate, EF was noted to decrease more than 10% 
concurrently in three patients and subsequently in two additional patients.64   
 
Fallah-Rad et al performed a similar study of 42 breast cancer patients treated with adjuvant 
trastuzumab, most of whom also received anthracyclines.  Echocardiography with strain analysis 
was performed at baseline, prior to trastuzumab and every 3 months afterwards in these patients.   
Drug-induced cardiac toxicity, defined as symptomatic heart failure and a drop in EF of at least 
10% to below 55% necessitating discontinuation of trastuzumab was observed in 24% of the 
study population.  When compared to the patients who did not develop cardiac toxicity, those 


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who did were noted to have lower longitudinal and radial strain measurements after 3 months of 
trastuzumab (mean peak GLS in cardiac toxicity patients compared to patients without cardiac 
toxicity:  -16.4% versus  -19.9%; mean peak global radial strain in cardiac toxicity patients 
compared to patients without cardiac toxicity: 32.5% versus 42.4%).  Receiver operating curve 
(ROC) analysis of the ability of a 2% difference between baseline and 3 month peak GLS to 
identify subsequent development of cardiac toxicity revealed sensitivity, specificity, positive 
predictive value and negative predictive value of 79%, 82%, 60% and 92% respectively.  
Similarly, ROC analysis of the ability of a 0.8% difference between baseline and 3 month peak 
global radial strain to identify subsequent development of cardiac toxicity revealed sensitivity, 
specificity, positive predictive value and negative predictive value of 86%, 81%, 60% and 95% 
respectively.65   
 
Sawaya et al also prospectively followed echocardiographic measures in 81 breast cancer 
patients, all of whom received anthracyclines, taxanes and trastuzumab and underwent 
echocardiography with strain analysis every 3 months.  During the study period, 32% developed 
cardiac toxicity as defined by a drop in EF of at least 5% to less than 55% with symptoms of 
heart failure or by an asymptomatic drop in EF by at least 10% to less than 55%.  In this study, 
peak systolic longitudinal myocardial strain measured at the completion of anthracycline therapy 
was predictive of subsequent development of cardiac toxicity.  ROC analysis of a value of 
longitudinal strain < 19% after the completion of anthracycline chemotherapy revealed 
sensitivity 74%, specificity 73%, positive predictive value 53% and negative predictive value 
87%.  On multivariate analysis, GLS < 19% after anthracycline therapy was the only 
independent predictor of subsequent cardiac toxicity.  This study also revealed that a drop in 
GLS greater than 10% between baseline and the end of anthracycline therapy predicted 
subsequent development of cardiac toxicity.  Of note, radial and circumferential strain 
measurements were not predictive of cardiac toxicity in this study.66   
 
More recently, Negishi et al performed a similar study of echocardiographic assessment every 6 
months in 81 women treated with trastuzumab, 37 of whom also received anthracyclines.  In this 
study, 24% of women experienced cardiac toxicity, defined as a reduction in EF exceeding 10%.  
The strongest predictor of a subsequent decline in EF was the difference between GLS at 
baseline and after 6 months of therapy, with the optimal cut point of an 11% reduction 
(sensitivity 65%, specificity 94%).  Changes in global longitudinal peak systolic strain rate and 
global longitudinal early diastolic strain rate between baseline and 6 months of follow-up were 
also predictive of subsequent declines in EF.  Notably, only longitudinal strain indices were 
significant predictors of subsequent cardiac toxicity in this study.67 
 
To date, most investigations into the role of echocardiographic myocardial strain in detecting 
subclinical anthracycline-induced cardiac toxicity have focused on systolic measures.  However, 
Stoodley et al recently observed changes in diastolic function in breast cancer patients 
immediately after completing 4-6 cycles of anthracycline-based chemotherapy.  Furthermore, 
they identified reduced baseline systolic strain as a predictor of reduced diastolic strain rate after 
chemotherapy.68 
 
Together, these findings suggest significant clinical utility for echocardiographic myocardial 
strain analysis in the prediction of subsequent cardiac outcomes in breast cancer patients treated 


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with cardiotoxic therapy.  Ultimately, risk stratification based on strain could offer the potential 
to identify individuals for whom enhanced cardiac monitoring or prevention interventions could 
be directed.  Indeed, early data suggests that interventions can improve strain in both patients 
with cardiovascular disease and in breast cancer patients.  For example, Blondheim et al 
performed echocardiography 2 hours prior to and 2 hours after the administration of heart failure 
medications to a group of 21 patients with ischemic cardiomyopathy.  They identified an 
improvement in segmental strain in initially dysfunctional segments, but no change in global 
strain measurements.69  In a study with longer follow-up, Leong et al performed 
echocardiography at baseline and after 4-7 months of treatment in newly diagnosed patients with 
idiopathic dilated cardiomyopathy.  GLS improved between baseline and follow-up assessments 
(baseline mean -12% compared to follow-up mean -16%).70 
 
To our knowledge, only three studies to date have reported on whether interventions can improve 
strain in cancer patients at risk for chemotherapy-induced cardiac toxicity.  Negishi et al 
presented non-randomized, retrospective data regarding GLS at baseline and follow-up in 159 
women receiving anthracyclines, trastuzumab or anthracyclines followed by trastuzumab.  Of the 
159 patients, 52 experienced a decline in GLS > 11%.  Beta-blocker therapy was administered to 
24 of the women with a decline in GLS > 11% while 28 women who experienced similar 
declines in GLS did not receive beta-blocker therapy.  Subsequent assessment of GLS revealed 
greater improvement in the women treated with beta-blocker therapy.71  El-Shitany et al reported 
a prospective randomized trial in 50 leukemia patients, half of whom were pre-treated with 
carvedilol prior to anthracycline-based chemotherapy and half of whom received anthracycline-
based chemotherapy alone.  Post-treatment peak GLS was noted to be improved compared to 
baseline in the group which received carvedilol.72  Cadeddu et al performed a study in 49 
patients receiving epirubicin for a variety of solid tumors who were randomized to telmisartan or 
placebo.  Epirubicin was noted to impair strain rate peak, but it subsequently normalized in only 
the telmisartan arm, with the effect noted to persist until follow-up assessment after 18 
months.73,74 
 
Although these data are promising, it should be noted that prospective randomized data 
indicating that strain can be improved in breast cancer patients with chemotherapy-related 
cardiac toxicity are currently limited.  More importantly, it is not yet known whether 
interventions to improve strain can attenuate the expected subsequent decline in EF predicted by 
an abnormal strain and whether this would ultimately lead to superior clinical cardiac outcomes. 
 
In addition, it should be noted that the use of myocardial strain as a clinical measure is still in 
development and several issues remain to be clarified before widespread clinical use.  For 
example, the optimal measure of strain (longitudinal strain, radial strain, circumferential strain or 
strain rate) is not yet known, although the largest body of data to date supports the use of GLS.  
In addition, the cut-off values to define normal and abnormal strain require further clarification 
as different investigators have used different definitions, although a recent meta-analysis 
suggested a normal range of -15.9% to -22.1% for GLS.75  Potential differences in normal values 
for strain between men and women have also not yet been clarified.  Furthermore, the potential 
impact of the echocardiographic technique used to obtain the images required to calculate strain, 
the frame rate of the machine used and the impact of the type of software used for the calculation 
of strain are also not well defined.  Reproducibility of strain assessments and measurement error 


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also remain a potential concern.  Finally, at this time, availability of software to calculate strain 
and echocardiography technicians trained to obtain the images required for strain analysis are 
limited.53,67,75,76 
 
Despite these limitations, the data described above suggest that echocardiographic myocardial 
strain is a promising new tool which can predict subsequent decline in EF and, potentially predict 
inferior cardiac outcomes in cancer patients undergoing therapies which may be cardiotoxic.  
Thus, it may be able to detect anthracycline-induced cardiac toxicity at an earlier stage at which 
it may be reversible.    Johns Hopkins has extensive experience to date in measuring 
echocardiographic myocardial strain, making it an ideal site for further study of this new 
echocardiographic tool.  In our lab, the intra-observer reproducibility coefficient of variation for 
GLS measurements is 5% and the inter-observer reproducibility coefficient of variation for GLS 
measurements is 9%.   
3.3 
Cardioprotective Interventions to Prevent Anthracycline-Induced Cardiac Toxicity 
3.3.1 Agents Previously Evaluated for Cardioprotection 
To date, multiple agents have been studied as potential interventions to prevent anthracycline-
induced cardiac toxicity, although only dexrazaxone has been approved by the United States 
Food and Drug Administration (FDA) for this purpose.  Evidence suggests that earlier 
intervention with standard heart failure medications in patients affected with anthracycline-
induced heart failure is associated with greater cardiac recovery, thus the notion of intervention 
prior to the development of cardiac toxicity is appealing.23 
 
In 2011, a Cochrane review evaluated randomized controlled trials of N-acetylcysteine, 
coenzyme Q10, L-carnitine, carvedilol, phenethylamines, amifostine, dexrazaxone and the 
combination of Vitamin E, Vitamin C and N-acetylcysteine for the prevention of anthracycline-
induced cardiotoxicity.  Unfortunately, this review found no benefit for any of these agents other 
than dexrazaxone in the prevention of cardiac toxicity.  As part of the Cochrane review, a meta-
analysis of 8 randomized controlled trials evaluating dexrazaxone in 1,561 patients receiving 
anthracycline therapy was performed.  This revealed an 82% reduction in the risk of heart failure 
with dexrazaxone.  Of note, while there exists some concern about the possibility of reduced 
efficacy of chemotherapy with concurrent administration of dexrazaxone, no reduction in 
response rate was noted in this meta-analysis.77  Consideration of dexrazaxone use is currently 
recommended for patients who have received at least 300 mg/m2 of doxorubicin and who plan to 
continue to be treated with anthracycline therapy.78 
 
Recently, attention has turned to evaluation of drugs used for the treatment of heart disease, such 
as beta-blockers, ACE inhibitors or angiotensin II receptor blockers (ARBs), as potential 
preventive agents for anthracycline-induced cardiac toxicity.  For example, Kalay et al 
performed a small randomized trial evaluating carvedilol in patients planning to receive 
anthracycline chemotherapy in which they found that carvedilol prevented a decline in EF.79  A 
similar study utilizing nebivolol for cardiac protection in anthracycline-treated patients also 
revealed higher follow-up EF in the patients who received the beta-blocker compared to 
controls.80  Seicean et al reported a retrospective study revealing that breast cancer patients 
treated with anthracyclines and trastuzumab who were on beta-blockers continuously throughout 


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their cancer treatments had lower risk of subsequent diagnoses of new heart failure than those 
who did not take continuous beta-blockers.81  Using a different approach, Cardinale et al selected 
patients expected to be at high risk for chemotherapy-induced cardiac toxicity based on elevated 
cardiac troponin-I levels immediately after high-dose chemotherapy and randomized these 
patients to treatment with an ACE inhibitor or none.  This study revealed a lower rate of decline 
in EF among the patients treated with the ACE inhibitor.82  Similarly, Bosch et al demonstrated 
less reduction in EF and lower risk of death and heart failure with the administration of enalapril 
and carvedilol to patients with acute leukemia and other malignant hematologic diseases being 
treated with stem cell transplant.83  In another study, Nakamae et al demonstrated that valsartan, 
prevented increases in left ventricular end diastolic diameter, QTc interval on electrocardiogram 
(EKG) and QTc dispersion on EKG in lymphoma patients treated concurrently with an 
anthracycline-based chemotherapy regimen.84  Ongoing studies such as the Multidisciplinary 
Approach to Novel Therapies in Cardiology Oncology Research (MANTICORE), Prevention of 
Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) and Sun Coast 
University of South Florida (SCUSF) 0806 (clinicaltrials.gov identifier NCT01009918) trials 
aim to further assess the role of ACE inhibitors, ARBs and beta-blockers in the prevention of 
cardiac toxicity induced by oncologic therapies.85,86 
3.3.2 Statins as Cardioprotective Agents 
While typically used for the management of hyperlipidemia and coronary artery disease, several 
lines of evidence suggest that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase 
inhibitors (“statins”) may be effective for prevention of anthracycline-induced cardiac toxicity.   
Simvastatin has been shown to attenuate mitochondrial dysfunction in rat cardiomyocyte cell 
cultures exposed to oxidant stress.87  This potential mechanism of action is particularly 
promising given that recent evidence suggests that doxorubicin-induced cardiac toxicity is 
mediated by mitochondrial dysfunction.  Mice treated with both statins and doxorubicin 
demonstrate less short term cardiac toxicity as measured by troponin release and hemodynamic 
measurements compared to mice treated with doxorubicin alone.88,89  Furthermore, concurrent 
treatment of rats with rosuvastatin and doxorubicin compared to doxorubicin alone and to 
doxorubicin plus carvedilol resulted in less cardiac damage, suggesting statin therapy may be 
more beneficial than beta-blocker therapy in the prevention of anthracycline-induced cardiac 
toxicity.90 
 
To date, there is only minimal clinical data evaluating the ability of statin therapy to prevent 
cardiac toxicity in patients receiving anthracyclines.  A retrospective study of 67 breast cancer 
patients on uninterrupted statin therapy during anthracycline chemotherapy for breast cancer and 
during a follow-up period of 2.55 +/- 1.68 years compared to 134 propensity-matched controls 
not on uninterrupted statin therapy during chemotherapy and the follow-up period revealed a 
70% reduction in incident heart failure requiring hospitalization after initiation of anthracycline 
treatment in the statin group (6% versus 17.2%).  Notably, the presence of cardiovascular risk 
factors was associated with higher risk for heart failure in this study.91,92  Acar et al performed a 
small study randomizing 40 patients receiving anthracycline chemotherapy to atorvastatin 40 mg 
oral daily starting prior to chemotherapy and continuing for 6 months or to no intervention.  
Echocardiography was performed at baseline and 6 months later.  Mean EF was noted to drop in 
the control group but not in the atorvastatin group.93  A randomized pilot trial evaluating 3 
months of rosuvastatin for cardiac protection in breast cancer patients receiving anthracycline, 


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cyclophosphamide, paclitaxel and trastuzumab therapy is currently ongoing with a primary 
endpoint of adherence to rosuvastatin therapy (clinicaltrials.gov identifier NCT01051401). 
 
While published data regarding statins as cardioprotective agents in chemotherapy patients is 
limited at this time, there is no data to suggest safety concerns for the combination of 
anthracyclines and statins.  Indeed, many patients take both drugs concurrently in the clinical 
setting.  Furthermore, cell line data has suggested that statins may potentiate the anti-tumor 
effects of anthracyclines.88  However, a small phase II study evaluating pravastatin therapy plus 
anthracycline-based chemotherapy (epirubicin, cisplatin, capecitabine) in gastric cancer revealed 
no significant anti-cancer benefit from the addition of the statin.  Notably, there was no 
additional toxicity observed from co-administration of the statin and the anthracycline-based 
chemotherapy in this trial.94 
 
Dr. Theodore Abraham’s Translational Cardiovascular Ultrasound Research Laboratory at Johns 
Hopkins has further explored the potential benefit of statins for the prevention of anthracycline-
induced cardiac toxicity.  Baseline echocardiography in rats treated with doxorubicin alone and 
in rats treated with doxorubicin plus atorvastatin was performed.  Follow-up echocardiography 7 
weeks later provided in vivo morphologic and functional evidence of the benefit of atorvastatin.  
The rats treated with doxorubicin alone displayed ventricular dilatation and impaired function 
compared to baseline.  In contrast, the rats treated concurrently with atorvastatin did not 


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demonstrate significant ventricular dilatation and the decrease in ventricular function was 
blunted (Figure A) (unpublished data).  
 
 
 
Further work in Dr. Abraham’s lab using transverse, coronal and sagittal views on annexin 
imaging to perform in vivo quantification of apoptosis in the heart demonstrated that atorvastatin 
therapy can diminish apoptosis induced by doxorubicin therapy. The extent of apoptosis was 
compared in control rats, rats treated with doxorubicin and rats treated with doxorubicin plus 
atorvastatin (Figure B).  No apoptosis was observed in the control rats (upper panel).  Less 
Figure A:
Echocardiography:  Rats treated with doxorubicin for 7 weeks develop 
substantial ventricular dilatation (B) compared to baseline (A) and reduction in 
function. In contrast, rats treated with doxorubicin but also pre-treated with 
statin do not develop significant heart dilatation and the decrease in function is 
blunted (C and D). 


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apoptosis was observed in the rats who received doxorubicin and atorvastatin (lower panel) than 
the rats who received doxorubicin alone (middle panel) (unpublished data). 
 
 
 
Gross pathologic analysis was also performed on hearts from rats treated with doxorubicin alone 
and those who received concurrent atorvastatin therapy in Dr. Abraham’s lab (Figure C).  This 
confirmed the imaging findings with greater dilatation observed in the hearts from the rats who 
received doxorubicin alone (lower panel) than those who received doxorubicin plus statin 
therapy (upper panel) (unpublished data). 
 
 
Finally, ultrastructural evidence supporting the use of statins to attenuate cardiac toxicity induced 
by anthracyclines was observed in Dr. Abraham’s lab by the use of electron microscopy.  
Mitochondrial density and structure in cardiomyocytes from control rats, rats treated with 
Figure B: 
Figure C: 
Gross pathology:  Hearts from doxorubicin treated animals who 
also received statin therapy (upper panel) were less dilated than 
those not treated with statin (lower panel).  Thus these data 
corroborated the morphologic data from echocardiography.


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doxorubicin alone and rats treated with doxorubicin plus atorvastatin were analyzed by electron 
microscopy (Figure D).  Control rats showed normal mitochondrial density and structure (left 
panel).  In contrast, substantial mitochondrial damage was observed in rats treated with 
doxorubicin alone (middle panel).  Less evidence of mitochondrial damage was observed in the 
rats treated with both doxorubicin and atorvastatin (right panel) consistent with the hypothesis 
that doxorubicin-induced cardiotoxicity is mediated by mitochondrial dysfunction and that statin 
therapy can block this effect (unpublished data). 
 
 
 
At this time, much is unknown regarding the potential use of statins for the prevention of 
anthracycline-induced cardiac toxicity.  For example, since most investigators have waited a few 
months to perform cardiac evaluation after anthracycline exposure (either with or without 
statins), it is not known if the potential cardioprotective effect of statins is mediated by 
prevention of cardiac damage or by repair of cardiac damage induced by anthracyclines.  In 
addition, it is not known whether one statin may be more a more effective cardioprotective agent 
against anthracycline-induced cardiac toxicity than another.  Indeed, this is a potentially relevant 
question as evaluation of statins for other potential uses in cancer patients has revealed benefits 
may be limited to the lipophilic class.95    
 
In addition, the optimal dose, duration and timing of administration of statin therapy for 
cardioprotection in patients receiving anthracyclines is currently not unknown.  However, key 
characteristics of an optimal statin for use as a cardioprotective agent during anthracycline-based 
chemotherapy include ease of dosing and minimal interactions with chemotherapy.   
 
For this study, we have selected simvastatin which is dosed once daily.  For the purpose of this 
trial, we have selected a moderate dose of 40 mg daily.  Like doxorubicin and paclitaxel, 
simvastatin is a substrate of the cytochrome P450 3A4 (CYP3A4) enzyme, but it does not 
significantly inhibit or induce CYP3A4, making clinically significant interactions between 
simvastatin and the commonly used chemotherapy regimen of AC followed by paclitaxel for 
early stage breast cancer unlikely.97  We have selected a 6 month course of simvastatin starting 
concurrently with anthracycline therapy based on the previous small trial of Acar et al which 
evaluated a similar duration of statin therapy for cardioprotection.93  After discussion with Dr. 
Abraham we have decided that administering the first dose of simvastatin the day of cycle 1 AC 
Figure D: 


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closely approximates the previous small trial of Acar et al while permitting patients to enroll 
with fewer delays from time of consent to time of first AC therapy. 
3.3.3 Other Potential Benefits of Statins in Breast Cancer Patients 
 
In addition to potentially preventing cardiac toxicity associated with anthracycline therapy, 
statins have been shown to have in vitro anti-tumor effects.98  To this end, the ability of statins to 
help prevent breast cancer incidence and to help reduce the risk of breast cancer recurrence has 
been evaluated.  With regard to chemoprevention, data to support statins has not been 
consistently promising, although there may be a class effect, with the potential chemoprevention 
benefit limited to the lipophilic statins, such as simvastatin.96  On the other hand, a reduction in 
the risk of breast cancer recurrence with statin use has been more consistently observed, again 
with the benefit primarily linked to the lipophilic statins.  Kwan et al first evaluated post-
diagnosis use of statins in 1,945 breast cancer survivors enrolled in the prospective Life After 
Cancer Epidemiology cohort.  They identified a 33% lower risk of recurrence among women 
who started statin therapy after breast cancer diagnosis compared to those who did not start statin 
therapy, although this finding was not statistically significant.  Most patients who received 
statins in this study were treated with lipophilic statins.99  This finding was confirmed in a 
nationwide, population-based prospective cohort study of 18,769 Danish women with early stage 
breast cancer.  Risk of recurrence was reduced among the women who had been prescribed 
statins, with the benefit limited to prescription of lipophilic statins (10 year adjusted hazard ratio 
0.73, 95% confidence interval 0.60-0.89).95  More recently, population-based data from the entire 
Danish population has demonstrated a reduction in cancer-related mortality among patients who 
used statins prior to diagnosis (hazard ratio 0.85, 95% confidence interval 0.83-0.87).  When 
these results were examined separately by tumor type, the findings were essentially unchanged 
(hazard ratio for death from breast cancer among breast cancer patients who used statins 
compared to those who did not use statins 0.88, 95% confidence interval 0.80-0.99).100  Finally, 
data from the German MARIEplus population-based prospective cohort of breast cancer patients 
demonstrates a trend towards reduced risk of breast cancer recurrence and breast cancer-specific 
mortality among statin users with early stage breast cancer compared to non-users (hazard ratio 
for recurrence 0.83, 95% confidence interval 0.54-1.24; hazard ratio for breast cancer-specific 
mortality 0.89, 95% confidence interval 0.52-1.49), although these findings were not statistically 
signficant.101  At this time, there have been no reported randomized trials evaluating the use of 
statins for the reduction of breast cancer recurrence and the available data remains observational 
in nature.   
3.4 
Study Rationale and Design 
This is a prospective, randomized study evaluating the effects of AC chemotherapy concurrent 
with statin therapy versus AC chemotherapy alone on change in strain parameters over time in 
women with early stage breast cancer.  We plan to randomize women undergoing neo-adjuvant 
or adjuvant anthracycline-based chemotherapy for breast cancer in a 1:1 ratio to receive 
chemotherapy plus simvastatin or chemotherapy alone.  We will evaluate patients who do and do 
not receive simvastatin for evidence of cardiac toxicity by using the echocardiographic 
myocardial strain, echocardiographic EF and by assessment for symptoms of heart failure.  Our 
hypothesis is that simvastatin will minimize reduction in myocardial strain.  This will serve as a 
surrogate endpoint for symptomatic cardiac toxicity.  Since the bulk of the data regarding 


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myocardial strain as a tool for evaluating cardiac toxicity from cancer therapy suggests that GLS 
is the strongest measure, we will use that as our primary measure.  However, we will also 
measure velocity-based GLS rate and we will evaluate other measures of systolic and diastolic 
strain in an exploratory manner in addition to routine measurements of left ventricular diastolic 
function and filling pressures.  We will also explore the capacity of strain and changes in strain 
to predict subsequent cardiac endpoints including reduction in EF and development of 
symptomatic heart failure if these endpoints occur in our study population. 
 
To our knowledge, this will be the first prospective study to provide information about 
echocardiographic strain in breast cancer patients treated with anthracyclines who receive statin 
therapy.  In addition, since prior studies evaluating strain in breast cancer patients have included 
small sample sizes, our study population, although also small, will add significantly to the 
available data describing serial changes in strain in breast cancer patients treated with 
anthracycline therapy.  Furthermore, unlike prior studies evaluating strain in breast cancer 
patients which typically utilized echocardiography with strain analysis at baseline and after 
anthracycline treatment, we will also obtain an echocardiogram with strain analysis early during 
the course of anthracycline chemotherapy to detect any early impact of chemotherapy and 
simvastatin on myocardial strain.  Comparison of this echocardiogram to subsequent 
echocardiograms in the patients who do and do not receive simvastatin could potentially shed 
light on whether simvastatin can prevent cardiac toxicity or whether it can repair cardiac toxicity 
after anthracycline exposure.    
 
This study is not intended or powered to detect a specific difference in strain between those who 
do and do not receive statin therapy, but it will be able to find a minimal detectable difference 
with sufficient power (Section 13.3).  The data collected will help plan future studies to establish 
a clinically important difference in strain between breast cancer patients who do and do not 
receive statin therapy and to assess the protective effect of statin on AC-induced cardiac toxicity 
with long-term follow-up. 
 
 


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4. Hypothesis 
We hypothesize that simvastatin will provide cardiac protection, as evidenced by minimizing 
reduction in myocardial strain, during (neo)adjuvant anthracycline-based chemotherapy for early 
stage breast cancer. 
 
5. Objectives 
5.1 
Primary Objective 
To compare the absolute change in echocardiographic GLS from baseline to 2-3 weeks after 
completion of 4 cycles of (neo)adjuvant anthracycline-based chemotherapy in early stage breast 
cancer patients who do and do not receive concurrent simvastatin therapy 
5.2 
Secondary Objectives 
5.2.1 To compare the relative change in echocardiographic GLS from baseline to 2-3 weeks 
after completion of 4 cycles of (neo)adjuvant anthracycline-based chemotherapy in early 
stage breast cancer patients who do and do not receive concurrent simvastatin therapy 
5.2.2 To compare the absolute and relative changes in echocardiographic GLS rate from 
baseline to 1-3 weeks after completion of 4 cycles of (neo)adjuvant anthracycline-based 
chemotherapy in early stage breast cancer patients who do and do not receive concurrent 
simvastatin therapy. 
5.2.3 To describe echocardiographic GLS and GLS strain rate and change in these parameters 
at multiple time points from baseline to 52 weeks in breast cancer patients treated with 
(neo)adjuvant anthracycline-based chemotherapy who do and do not receive 24 weeks of 
concurrent simvastatin therapy. 
5.2.4 To evaluate the feasibility of concurrent administration of simvastatin therapy with 
(neo)adjuvant anthracycline-based chemotherapy in early stage breast cancer patients. 
5.2.5 To assess the feasibility of performing serial echocardiographic myocardial strain 
assessments in early stage breast cancer patients undergoing (neo)adjuvant anthracycline-
based chemotherapy. 
5.2.6 To evaluate the safety and tolerability of concurrent administration of simvastatin with 
(neo)adjuvant anthracycline-based chemotherapy in early stage breast cancer patients. 
5.2.7 To describe the recurrence free survival (RFS) in early stage breast cancer patients 
treated with anthracycline-based chemotherapy with and without concurrent simvastatin. 
5.3 
Exploratory Objectives 
5.3.1 To describe the relationships between early measurements of echocardiographic GLS and 
GLS rate and of change in these parameters with subsequent measurements of EF and 
subsequent development of symptomatic heart failure in early stage breast cancer patients 


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treated with (neo)adjuvant anthracycline-based chemotherapy who do and do not receive 
24 weeks of concurrent simvastatin therapy. 
5.3.2 To explore risk factors that may predict early change in GLS in breast cancer patients 
treated with neo(adjuvant) anthracycline-based chemotherapy who do and do not receive 
24 weeks of concurrent simvastatin therapy 
 
5.3.3 To describe additional echocardiographic strain parameters besides GLS and GLS rate, 
including right ventricular strain, in addition to routine assessment of left ventricular diastolic 
function and filling pressures, at multiple time points from baseline to 52 weeks in breast cancer 
patients treated with (neo)adjuvant anthracycline based chemotherapy who do and do not receive 
24 weeks of concurrent simvastatin therapy.      
 


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6. Patient Population 
6.1 
Inclusion Criteria 
The following individuals are eligible for participation in this study: 
6.1.1 Female Sex 
Note:  Patients may be pre-menopausal or post-menopausal 
6.1.2 Age 18 years or older 
6.1.3 Histologically confirmed invasive breast carcinoma, stage I-III (see Appendix A for 
staging) 
Note:  Estrogen Receptor (ER), Progesterone Receptor (PR) and HER2 status must be 
known.  In newly diagnosed patients planning neoadjuvant treatment, a formal 
assessment of axillary lymph nodes is not required. 
6.1.4 Planning to initiate adjuvant or neoadjuvant AC chemotherapy (doxorubicin 60 mg/m2 
and cyclophosphamide 600 mg/m2 every 2-3 weeks x 4 cycles). 
Note:   
- Participants may be planning to receive additional adjuvant therapy after the completion 
of AC chemotherapy.   
- Receipt of all standard chemotherapy and/or targeted therapy regimens  after AC that 
deemed clinically appropriate by the treating physician are permitted.   For example, 
patients may receive taxanes or carboplatin/paclitaxel.  Her2 positive patients may 
receive trastuzumab with or without pertuzumab.      
- HER2 positive patients must be planning to initiate trastuzumab therapy after AC 
chemotherapy. 
6.1.5 Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (see Appendix B) 
6.1.6 Normal organ function and marrow function as defined below:   
 Absolute neutrophil count (ANC) ≥ 1000/mm3 
 Platelet count ≥ 100,000/mm3 
 Total bilirubin less than or equal to the upper limit of normal 
 Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5  
times the upper limit of normal 
 Creatinine ≤1.5 times the upper limit of normal 
 Creatine kinase (CK) ≤2.5 times the upper limit of normal 
6.1.7 Left ventricular ejection fraction (LVEF) as assessed by baseline echocardiogram at or 
above the lower limit of normal 
6.1.8 Women of childbearing potential must agree to use adequate contraception (non-
hormonal or barrier method of birth control or abstinence) prior to study entry and for the 


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duration of participation. Should a woman become pregnant or suspect she is pregnant 
while participating in the study, she should inform her treating physician immediately. 
6.1.9 Ability to understand the study regimen and the willingness to sign a written informed 
consent document 
6.1.10 Negative pregnancy test (women of childbearing potential only) 
6.2 
Exclusion Criteria 
The following individuals are not eligible for participation in this study: 
6.2.1 Prior anthracycline therapy 
6.2.2 Currently pregnant or lactating  
6.2.3 Currently receiving investigational agents 
6.2.4 Known active liver disease (cirrhosis, chronic viral hepatitis, autoimmune liver disease or 
other known clinically significant active liver disease) 
6.2.5 Known myopathy or history of rhabdomyolysis 
6.2.6 Uncontrolled hypothyroidism 
6.2.7 History of allergic reaction or intolerance to statin treatment 
6.2.8 Currently receiving statin therapy or have received any statin therapy within the last 3 
months 
6.2.9 Known history of ischemic cardiac disease (including angina requiring anti-anginal 
medications, myocardial infarction, coronary artery disease documented on cardiac 
catheterization or ischemia documented on stress test), congestive heart failure, clinically 


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significant arrhythmia or conduction system abnormalities, clinically significant valvular 
disease, clinically significant pericardial effusion or EF below the lower limit of normal 
6.2.10 Uncontrolled inter-current illness including, but not limited to, ongoing or active serious 
infection, other active cardiac disease or psychiatric illness/social situations which would 
limit compliance with study requirements 
6.2.11 Inability to swallow tablets or use of a feeding tube 
6.2.12 Gastrointestinal disease, surgery or malabsorption that could potentially impact the 
absorption of the study drug 
6.2.13 Daily consumption of alcohol exceeding 3 standard drinks a day (defined as 10 grams of 
alcohol, which is equivalent to 285 mL of beer, 530 mL of light beer, 100 mL of wine or 
30 mL of liquor) 
6.2.14 Women currently taking drugs which are strong inhibitors or inducers of CYP3A4 are not 
eligible.  These may be found at the Indiana University Clinical Pharmacology website at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
6.2.15 Women taking drugs associated with a substantial risk of myopathy when co-
administered with simvastatin are not eligible.  These drugs are listed in the simvastatin 
package insert (available at: 
http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf).  
6.2.16 Women taking medications for which interaction with simvastatin may result in increased 
levels of simvastatin are not eligible.  Such drugs are listed in the simvastatin package 
insert (available at: 
http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf).   
6.2.17 Any medical condition which, in the opinion of the investigator, puts the patient at risk of 
potentially serious complications while on study treatment 
6.3 
Inclusion of Women and Minorities 
This study is open to individuals of all races and ethnic groups.  There is no bias towards age or 
race in the clinical trial outlined.  This trial is open to accrual of women only because breast 
cancer is rare in men and because normal values for myocardial strain may differ between men 
and women.53 
 
 
 


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7. Study Design and Treatment Plan 
7.1 
Recruitment 
Patients will be recruited through the breast cancer medical oncology clinics that are part of the 
Johns Hopkins Medical Institutions.  Only patients willing to come to the East Baltimore Campus 
of Johns Hopkins Hospital for echocardiograms will be eligible to participate. 
7.2 
Determination of Eligibility 
Subjects will be registered with the study coordinator once an informed consent form is signed.  
The study coordinator will assign a study number – the study number is a sequential number 
beginning with “001”.  Subjects will not begin protocol-specified treatment until eligibility is 
confirmed and randomization takes place. 
 
Subjects who sign a consent form, but do not initiate protocol treatment for any reason [i.e., 
subjects who are screen failures, those who do not initiate the planned course of AC 
chemotherapy or those who do not initiate simvastatin (if randomized to receive it)] will be 
replaced.   
7.3 
Study Drug and Management of Toxicities 
7.3.1 Treatment Assignment and Randomization 
This is a non-blinded, non-placebo controlled, randomized, prospective study.  Eligible patients 
will be randomized in a 1:1 ratio to receive either simvastatin with AC chemotherapy or AC 
chemotherapy alone. Randomization will occur after registration and prior to the planned first 
cycle of chemotherapy.  All participants and providers will know the arm to which they are 
randomized. A master list of randomization assignments will be made by the protocol 
biostatistician and will be delivered to the Research Pharmacy at Johns Hopkins and to other key 
personnel, as identified.  Upon successful registration of a subject, randomization will occur by 
the appropriate study staff using the participant’s study number and initials to the correct group.   
7.3.2 Control Group:  AC Chemotherapy alone  
Patients not randomized to simvastatin will participate in all aspects of the study with the 
exception of simvastatin administration and completion of the study drug diary (Appendix C).  
All other assessments (e.g., study visits, toxicity assessments, questionnaires, laboratory studies 
and echocardiograms) will be performed according to the same schedule as that which is used for 
the intervention group. 
7.3.3 Intervention Group:  AC chemotherapy with concurrent Simvastatin  
7.3.3.1 Simvastatin Administration 
For those participants randomized to receive study drug, simvastatin will be administered on an 
outpatient basis orally at a dose of 40 mg once daily.  Treatment will start on the evening of the 
first dose of AC and will continue for a total of 24 weeks.  No pre-medications are required.  


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Patients will be instructed to take simvastatin at approximately the same time each evening.  
Missed doses will not be made up.   
 
Patients will be asked to record administration of each dose of the study drug in the study drug 
diary (Appendix C).  Study staff will fill in the calendar in the diary to reflect the appropriate 
dates for which the patient should be taking simvastatin prior to giving the calendar to the patient 
to complete.  This calendar will be compared with the drug accountability records (number of 
returned pills, if any) in order to assess compliance.   
 
No other investigational agents should be administered concurrently.  Any questions about 
concurrent enrollment in other clinical trials should be discussed with the Protocol Chair in 
advance. 
7.3.3.2 Safety Assessments and Dose Modifications 
If possible, symptoms should be managed symptomatically.  In case of toxicity, appropriate 
medical treatment should be used (including anti-emetics for nausea/vomiting, anti-diarrheals for 
diarrhea, etc.). 
 
If statin treatment is interrupted due to an adverse event, treatment can be resumed as soon as 
possible if the adverse event is deemed unrelated to the study drug. If the drug is stopped, due 
to the hospitalization of the patient, the principal investigator should be contacted to confirm if it 
is safe to resume the drug. The maximum allowable interruption is 4 weeks for the duration of 
time that the patient is on study. 
7.3.3.2.1 Hepatotoxicity 
Simvastatin can cause rare hepatotoxicity characterized by elevations in transaminases (ALT and 
AST).  In clinical trials of simvastatin, persistent increases in transaminases were observed in 
approximately 1% of patients.  Literature indicates that this is likely an idiosyncratic event which 
is often not clinically significant and there is controversy about the need for routine monitoring 
of transaminases when simvastatin is used in the clinical setting.  However, guidelines suggest 
assessment of transaminases at baseline, 12 weeks after initiation of statin therapy, whenever the 
dose is changed and yearly thereafter.102  Given that chemotherapy can also cause hepatotoxicity, 
transaminases will be monitored carefully in this study.  The schedule for monitoring 
transaminases in this study is more frequent than that recommended for statin therapy alone due 
to the potential impact of chemotherapy on the liver.   
 
Liver function panels will be assessed at baseline.  In addition, liver function panels are 
recommended immediately prior to the second, third and fourth cycles of AC.  Liver function 
panels will also be performed 1-3 weeks after the fourth cycle of AC and monthly during any 
additional treatment period after AC.  The liver assessment performed 1-3 weeks after the fourth 


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cycle of AC will coincide approximately with the recommended standard of care assessment for 
hepatotoxicity 12 weeks after initiation of statin therapy.   
 
In case of abnormalities in ALT or AST, dose adjustments of simvastatin (for patients in the 
intervention group only) and repeat assessments of transaminases (for patients in both the 
intervention and control groups) will be made as follows: 
 
 


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AST and/or ALT 
level 
Guidelines for Dose Adjustment (for patients randomized to receive 
simvastatin) and for Repeat Assessment of AST and ALT (for all 
patients) 
≤ 1.5 times ULN 
Continue current dose of simvastatin.  Re-assess AST and ALT according to 
study calendar 
> 1.5 times ULN 
 and  
< 3 times ULN 
Continue current dose of simvastatin.  Re-assess AST and ALT in 4 weeks 
(+/- 3 days) or according to study calendar (whichever occurs first).  
≥3 times ULN 
Hold simvastatin and re-assess AST and ALT in 4 weeks (+/- 3 days) or 
according to study calendar (whichever occurs first).  Evaluation for other 
causes of abnormal AST and ALT such as viral hepatitis, autoimmune 
hepatitis alcohol, other medications or biliary disorders may be performed at 
the discretion of the investigator.   
 
 
If AST and/or ALT remain ≥3 times ULN when re-assessed, 
simvastatin will be permanently discontinued.  If possible, patient 
will stay on study for clinical assessments and echocardiography but 
will no longer receive study drug.  AST and ALT will be monitored 
every 4 weeks (+/- 3 days) or according to the study calendar 
(whichever occurs first) until AST and ALT are < the ULN or until 
the investigator determines no further improvement can be expected. 
 
If AST and ALT become < 3 times ULN when re-assessed, the 
investigator thinks it is safe to re-challenge with simvastatin, and < 
24 weeks have passed since simvastatin was initiated, the study drug 
may be restarted at 20 mg oral daily with repeat assessment of AST 
and ALT in 4 weeks (+/- 3 days) or according to the study calendar 
(whichever occurs first).  If repeat AST and/or ALT are again > 3 
times ULN after simvastatin is re-started at the lower dose, the drug 
will be permanently discontinued.  If possible, the patient will stay 
on study for clinical assessments and echocardiography but will no 
longer receive study. If AST and ALT are < 3 times ULN on the 
lower dose, simvastatin will be continued at 20 mg oral daily and 
AST and ALT will be monitored every 4 weeks (+/- 3 days) or 
according to the study calendar (whichever occurs first) until AST 
and ALT are < ULN or until the investigator determines no further 
improvement can be expected. 
7.3.3.2.2 Skeletal Muscle Toxicity 
Simvastatin can cause myopathy which manifests as muscle pain, tenderness or weakness.   In 
some cases CK is elevated and, rarely, rhabdomyolysis can occur.  The risk of skeletal muscle 
toxicity is dose related.  103  There are no guidelines regarding screening for skeletal muscle 
toxicity or managing skeletal muscle toxicity for patients receiving simvastatin therapy.   


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Predisposing factors for skeletal muscle toxicity in patients taking simvastatin include older age, 
female gender, renal impairment and uncontrolled hypothyroidism.   
 
In this trial, CK will be assessed at baseline and only patients with CK less than or equal to 2.5 
times the ULN will be able to participate.  Repeat CK will be assessed within 72 hours of patient 
report of grade 2 or higher myalgia or investigator suspicion of skeletal muscle toxicity.   
 
If skeletal muscle toxicity occurs, dose adjustments of simvastatin (for patients in the 
intervention group only), repeat assessments of skeletal muscle symptoms and repeat 


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assessments of CK (for patients in both the intervention group and the control group) will be 
made as follows: 
 
Skeletal Muscle 
Toxicity 
Guidelines for Dose Adjustment (for patients randomized to receive 
simvastatin) and for Repeat Assessment of Skeletal Muscle Toxicity (for 
all patients) 
Grade 1 myalgia and 
CK ≤10 X ULN (if 
CK checked) 
or 
CK ≤10 X ULN (if 
checked) and no 
myalgia 
or 
Grade 2 myalgia and 
CK ≤10 X ULN 
Continue current dose of simvastatin.  Pain control at the discretion of the 
investigator.  Repeat assessment for muscle toxicity symptoms as per study 
calendar.   Repeat CK (if has been checked) in 4 weeks (+/- 7 days) with 
management as per this table. 
Grade 3 myalgia with 
any level of CK 
or  
Grade 2 myalgia with 
CK > 10 X ULN  
or  
Grade 1 myalgia with 
CK > 10 X ULN (if 
CK checked) 
or 
CK > 10 X ULN (if 
checked) and no 
myalgia 
Hold Simvastatin.  Pain control at the discretion of the investigator.  Re-assess 
skeletal muscle toxicity symptoms and CK in 2 weeks (+/- 3 days) or per 
study calendar (whichever occurs first) 
 
If repeat assessment for skeletal muscle toxicity reveals grade 3 
myalgia and/or CK remains > ULN, permanently discontinue 
simvastatin.  If possible, patient will stay on study for clinical 
assessments and echocardiography but will no longer receive study 
drug. 
 
If repeat assessment for skeletal muscle toxicity reveals  ≤ grade 2 
myalgia and CK becomes normal, may restart simvastatin at 20 mg 
oral daily if the investigator thinks it is safe and if < 24 weeks have 
passed since simvastatin was initiated.  If simvastatin is restarted at 
the lower dose, the patient will be assessed for muscle toxicity 
symptoms and CK at the next study visit and managed according to 
this table.  If grade 3 myalgia and/or CK > 10 X ULN occurs again, 
permanently discontinue simvastatin.  If possible, patient will stay on 
study for clinical assessments and echocardiography but will no 
longer receive study drug. 
Clinical evidence of 
rhabdomyolysis 
Permanently discontinue simvastatin.  Clinical management of 
rhabdomyolysis at the discretion of the investigator.  If possible, patient will 
stay on study for clinical assessments and echocardiography but will no longer 
receive study drug. 
 
Rhabdomyolysis with renal failure occurs more commonly with administration of statin therapy 
in certain high-risk situations.  If the following clinical scenarios occur for patients randomized 


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to simvastatin, the study drug will be discontinued until resolution of the problem at the 
discretion of the investigator: 
 
 Severe infection 
 Hypotension 
 Major surgery (not including planned breast surgeries or axillary lymph node 
evaluations) 
 Trauma 
 Uncontrolled seizures 
 Severe metabolic abnormalities 
 Severe endocrine abnormalities 
 Severe electrolyte abnormalities 
 
If any of the above clinical scenarios resolve, simvastatin may be re-started at the same dose as 
prior at the discretion of the investigator.  Such patients would continue to participate in clinical 
assessments and echocardiography for the study. 
 
The risk for skeletal muscle toxicity associated with simvastatin is higher with co-administration 
with certain other medications.  Drugs which must be avoided during participation in this study 
are described below (Section 7.3.4.2). 
7.3.3.2.3 Cardiac Toxicity 
Simvastatin is not expected to cause cardiac toxicity.  To the contrary, this study aims to use 
simvastatin to protect against chemotherapy-induced cardiac toxicity with myocardial strain as a 
surrogate endpoint for cardiac toxicity.  However, since the primary endpoint of this study is 
GLS instead of clinically apparent cardiac toxicity, guidelines for assessment and management 
of clinically apparent cardiac toxicity, should it occur, are provided here. 
 
Participants will be assessed for clinical signs of cardiac toxicity by investigator evaluation at the 
time of study visits and by echocardiographic evaluation of EF and wall motion abnormalities.  
During study visits, investigators will assess for symptoms of heart failure including exertional 
dyspnea, lower extremity swelling, paroxysmal nocturnal dyspnea, and orthopnea.  If present, 
investigators will attribute whether these symptoms are due to heart failure or to other causes.  
Physical examination to detect signs of heart failure such as a S3 heart sound, jugular venous 
distention, peripheral edema, hepatomegaly and pulmonary crackles will be performed at the 
investigators’ discretion.  Investigators will record New York Heart Association (NYHA) 
functional classification (Appendix D) for participants thought to have cardiac disease at each 
visit.  In addition echocardiographic myocardial strain will be assessed according to the study 
schedule, but results of strain analysis will not be available to investigators or participants during 
study participation. 
 
Clinical management of cardiac toxicities will be at the discretion of the investigator, although 
cardiology consultation is encouraged.  Decisions regarding cessation of chemotherapy, delay in 
chemotherapy and/or reduction in dose of chemotherapy in the face of cardiac toxicities will be 
at the discretion of the investigator.  Patients may continue to participate in this study in the face 
of cardiac toxicity if it is thought to be safe by the investigator.  The decision of whether to 


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discontinue simvastatin will be at the discretion of the investigator.  In cases in which 
simvastatin is discontinued, patients may stay on study for clinical assessments and 
echocardiography but will no longer receive study drug. 
7.3.3.3 Other Toxicity 
Management of toxicities other than hepatic, skeletal muscle and cardiac toxicity that the 
investigator attributes to simvastatin (for the intervention group only) is described in the table 
below: 
 
Toxicity Grade 
Guidelines for dose adjustment (for patients randomized to receive 
simvastatin only)  
Grade 1 or 2 
Continue simvastatin if investigator thinks it is safe.  Management of toxicity at 
discretion of investigator.  Re-assess toxicity at frequency at the discretion of the 
investigator 
Grade 3 or 4 
Hold simvastatin if investigator thinks toxicity is attributable to simvastatin.  Re-
assess toxicity at frequency determined by investigator.  If toxicity resolves to ≤ 
grade 2 and investigator deems it to be safe, may restart simvastatin at 20 mg oral 
daily.  If any grade 3 or 4 toxicity occurs again, discontinue simvastatin 
permanently.  If possible, patient will stay on study for clinical assessments and 
echocardiography but will no longer receive study drug. 
7.3.3.4 Special Considerations 
 For toxicities which are considered by the treating investigator unlikely to develop into 
serious or life–threatening events (e.g. alopecia, altered taste etc.), simvastatin treatment 
may be continued at the same dose without reduction or interruption. 
 The treating investigator may reduce a subject’s simvastatin dose for a toxicity of any 
grade/duration where s/he believes it to be in the best interests of the subject. 
 Any consideration to modify the above dose modification guidelines should be discussed 
with the Principal Investigator for approval or disapproval in advance. 
7.3.4 Concomitant Therapy 
7.3.4.1 Cancer-Directed Therapies and Supportive Care 
All patients will receive chemotherapy (with or without trastuzumab) as per usual clinical care.  
AC may be administered every 2 weeks or every 3 weeks.  If administered, taxane therapy may 
be given weekly, every 2 weeks or every 3 weeks.  Either paclitaxel or docetaxel may be used.  If 
administered, trastuzumab may be given weekly or every 3 weeks or a combination of these 
dosing schedules.  Any other chemotherapy regimens will be administered as directed at the 
discretion of the treating physician. Administration of anti-emetics, growth factors, 
chemotherapy pre-medications and any other supportive medications will be at the discretion of 
the investigator.  Any necessary dose modifications and delays in chemotherapy or trastuzumab 
will also be at the discretion of the investigator.  Since study assessments are timed in relation to 
chemotherapy administration, the study assessment schedule during the period of AC 
administration will be adjusted appropriately if chemotherapy is delayed.  Details regarding 
adjustment of the study assessment schedule in the event that AC chemotherapy is discontinued 
before the planned 4 cycles are completed are provided in the study calendar (section 8.0).  For 
patients receiving neoadjuvant AC chemotherapy, surgery will be performed when deemed 


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appropriate by the clinical team.  Every attempt will be made to perform study assessments on 
time in patients undergoing surgery during the course of the study, but if unable to do so, the 
missed assessments will be performed as soon as possible post-operatively.  After completion of 
AC, patients will continue to receive appropriate therapy such as additional chemotherapy, 
HER2 targeted therapy, and/or radiation therapy as clinically indicated at the discretion of the 
investigator. 
7.3.4.2 Prohibited Concomitant Medications 
Drugs which are strong inhibitors or inducers of CYP3A4 should be avoided during study 
participation.  A list of CYP3A4 inhibitors and inducers can be found at the Indiana University 
Clinical Pharmacology website at http://medicine.iupui.edu/clinpharm/ddis/main-table/.  All 
medications study participants are taking should be cross-referenced with the medications listed 
in this online table.  
 
In addition, certain drugs are associated with a higher risk of myopathy if co-administered with 
statins and simvastatin can increase levels of certain other drugs.  Such drugs are listed in the 
simvastatin package insert (available at: 
http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf).  If possible, use of these 
drugs should be avoided during study participation.   
 
In addition, study participants should not consume > 8 ounces of grapefruit juice or carbonated 
grapefruit beverages daily. 
 
Co-administration of ACE inhibitors, ARBs and beta-blockers is allowed.  Administration of 
these medications will be tracked as part of review of concomitant medications. 
   
All concomitant medications will be recorded by study staff at each study visit.   
7.4 
Study Assessments 
7.4.1 Medical Records  
Charts will be reviewed and information regarding tumor characteristics (e.g., stage, hormone 
receptor status, HER2 status, grade, surgery performed or planned, radiation plans, endocrine 
therapy plans) and relevant cardiovascular medical history will be entered into a case report form 
at baseline.  Medical records related to cardiovascular medical history will be reviewed if 
appropriate.  Medical records will be reviewed every 6 months from randomization for 5 years to 
assess for recurrence (defined as in-breast recurrence, distant metastases, new contralateral 
primary breast cancer, and death from breast cancer). 
7.4.2 Echocardiogram 
Two-dimensional echocardiography will be at Johns Hopkins Hospital.  The standard clinical 
echocardiography protocol will be followed.  Assessment of EF and myocardial strain will be 
performed.  Myocardial strain analysis will be performed using FDA approved software.  Results 
of clinical assessment of EF will be provided to the investigators to share with patients.  Results 
of the clinical assessment of EF from the study echocardiograms will be available in the 
electronic medical record.  For baseline study echocardiograms, every effort will be made to 


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have results of EF available in the electronic medical record within 3 business days.  For 
subsequent study echocardiograms, every effort will be made to have results of EF available in 
the electronic medical record within 10 business days.  Myocardial strain results will not be 
available in the electronic medical record and will not be shared with the treating investigators or 
patients.   
 
For patients who continue to receive trastuzumab after completion of AC, every effort will be 
made to time the study echocardiogram due after the fourth dose of AC such that it can serve as 
the pre-trastuzumab assessment of EF.   
 
If a clinically concerning abnormality is detected on echocardiogram performed for the study, the 
treating physician will be notified.  Management of such abnormalities will be at the discretion 
of the treating physician and may include termination of therapy. 
7.4.3 Participant Questionnaire 
Participants will complete a baseline questionnaire describing risk factors for heart disease 
(Appendix E).  This questionnaire has been modified from a questionnaire used for multiple 
other trials in the Johns Hopkins Breast Cancer Program. 
7.5 
Duration of Study Participation 
All patients who initiate AC therapy while on this study and who complete at least one 
echocardiogram after initiating AC will be included in the analysis in an intent-to-treat fashion.  
The total duration of study participation is approximately 52 weeks (from first cycle of AC and 
initiation of study drug until end of study assessments 52 weeks after first dose of AC).  While 
the duration of study participation is only 52 weeks, all patients will be followed by chart review 
for 5 years after randomization to identify breast cancer recurrence. 
 
Duration of individual subject treatment will depend on individual tolerance.  Should a patient 
decide to withdraw, all efforts will be made to complete and report the observations as 
thoroughly as possible.  If a patient discontinues AC prior to completing 4 cycles, assessments 
due after AC #4 will be performed after the last cycle administered whenever possible.  Further 
assessments will then be performed according to the study calendar.  If a patient discontinues 
simvastatin, all efforts will be made to keep the patient on the study for clinical assessments and 


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echocardiography but study drug will no longer be administered.  Reason(s) for discontinuation 
should be recorded in the medical record.  Reasons for premature withdrawal may include: 
 
 Disease progression 
 Unacceptable adverse events 
 Inter-current illness that prevents further administration of treatment or would affect 
assessment of clinical status to a significant degree 
 Non-compliance with protocol or treatment 
 Subject becomes pregnant 
 Subject refuses to continue treatment 
 Subject is lost to follow-up 
7.6 
Additional Information 
Participants will be offered parking stickers in appreciation of time at each study-specific 
echocardiogram with strain analysis procedure.  Participants will also be asked to agree to 
optional future contact for possible participation in other clinical trials.  
 
Follow-up of participants will continue for 5 years after randomization for ongoing collection of 
information pertaining to breast cancer treatment and outcomes, and changes in medical history, 
such as development of cardiovascular disease.  
 
 
 


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8. Study Calendar 
 
Parameter 
Baseline1 
 AC 
During AC2 
(within 3 days prior to 
each cycle) 
Post-AC Period3 
End of 
Treatment4
Day1 
Pre-  
AC #2
Pre-  
AC #3
Pre-  
AC #4
1-3 weeks 
post last AC
(±3 days)3a 
Additional 
treatment 
period3b 
24 weeks 
after AC #1
(±14 days)3c
CLINICAL EVALUATIONS: 
History and 
Physical5 
X 
 
X 
X 
X 
X 
X 
X 
X 
ECOG PS6 
X 
 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Vitals signs7 
X 
 
X 
X 
X 
X 
X 
X 
X 
Waist and hip  
circumference 
X 
 
 
 
 
 
 
 
 
NYHA Functional 
Classification8 
X 
 
X 
X 
X 
X 
X 
X 
X 
LABORATORY/IMAGING EVALUATIONS: 
Echocardiogram,  
strain analysis9 
X 
 
X 
 
 
X 
 
X 
X 
Hematology and  
Chemistry panel10 
X 
 
 
 
 
 
 
 
 
Creatine Kinase 
X 
 
 
 
 
 
 
 
 
Hepatic/Liver 
Function Panel 
(LFTs)11 
 
 
X 
X 
X 
X 
X 
 
 
Pregnancy Test 12 
X 
 
 
 
 
 
 
 
 
STUDY ASSESSMENTS/TREATMENT ADMINISTRATION: 
Participant 
questionnaire13 
X 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
   X .................................................................................. X 
 
Symptoms/ 
Adverse Events14 
X 
   X ........................................................................................................ X 
Randomization15 
X 
 
 
 
 
 
 
 
 
Simvastatin16 
 
   X .................................................................................. X 
 
Follow-Up17 
 
 
 
 
 
 
 
 
X 
 
Note:  Additional tests may be performed at the discretion of the treating investigator as clinically 
indicated. 
 
 


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8.0   Study Calendar (continued) 
 
1. Baseline assessments should be performed ≤21 days prior to randomization, as noted.  
2. Pre-cycle assessments to be performed ≤3 days prior to each planned cycle.  If a cycle of AC is delayed, 
LFTs should be repeated if delay is >7 days; repeat of other assessments is not required.   
3. This period refers to the time after the last cycle of AC and until the End of Treatment assessments:  
a. Post-last dose of AC: assessments due after the last dose of AC administered and prior to start of any 
additional treatment; preferred window for study echocardiogram is 1-3 weeks after last dose (±3 
days), no window applies to other assessments.   
b. This refers to patients who receive chemotherapy with or without trastuzumab.  These patients should 
have assessments  about every 4 weeks during the period of post-AC chemo.   
c. 24 weeks after AC #1:  assessments are required in all patients regardless of dose holds/delays.   
4. End of study assessments to be performed 52 weeks after AC #1 (+/- 14 days), regardless of delays.   
5. History will include documentation of specific symptoms of heart failure and muscle disease, including 
exertional dyspnea, lower extremity swelling and/or edema, paroxysmal nocturnal dyspnea, orthopnea and 
muscle pain - if cardiac symptoms are present, investigators will attribute whether due to heart failure or 
another cause.  If clinically indicated, physical examination will include evaluation for signs of heart 
failure such as presence of a S3 heart sound, jugular venous distention, peripheral edema, hepatomegaly 
and pulmonary crackles. 
6. ECOG Performance Status (Appendix B). 
7. Vital signs include weight, heart rate, respiratory rate, and blood pressure. 
8. NYHA Classification to be determined only if cardiac disease is thought to be present (Appendix D). 
9. Echocardiogram will include assessment of EF and myocardial strain.  Note:  Baseline test should be done 
after majority of eligibility testing is complete and prior to randomization.   
10. Complete blood count (CBC) with differential and comprehensive chemistry panel, including 
measurement of sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, total bilirubin, 
calcium, total protein, albumin, AST, ALT, and alkaline phosphatase.  In follow-up, these assessments 
should be done as per standard of care/provider discretion. 
11. LFTs include AST, ALT, total bilirubin, alkaline phosphatase, and albumin.  (Note:  Assessments done as 
part of a comprehensive chemistry panel may be used.)  In cases of sample hemolysis, at least the total 
bilirubin and either the AST or ALT must be reported – if results ≤ ULN, no tests need to be repeated.  If 
the total bilirubin is > ULN and either the AST or ALT are > 1.5 X ULN, LFTs should be repeated to 
monitor simvastatin toxicity, but treatment may proceed without waiting for results; any actions or dose 
modifications for simvastatin should be addressed when repeat results are received. LFTs are required at 
baseline and are included in the chemistry panel at that time LFTs are recommended but not required prior 
to each AC cycle and at least monthly in the additional treatment period. For patients with normal LFTs, 
no additional LFTs are required after the completion of chemotherapy. For patients who had abnormalities 
in LFTs during chemotherapy, LFTs must be followed until they resolve to a grade 1 or less.  
12. Pregnancy test (blood or urine), for women of childbearing potential only. 
13. Participant questionnaire at baseline only (Appendix E).   
14. Symptoms and adverse events that will be tracked and reported include those related to simvastatin 
(treatment arm only, last assessment due 30 days after last dose of simvastatin), and to cardiac disease, 
muscle disease, liver disease (both arms). The collection of toxicities related to chemotherapy and other 


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breast cancer therapy administration  is not required.  Symptoms of uncertain etiology will be collected 
and adjudicated by the Principal Investigator.   
15. Randomization to occur after eligibility confirmation; allow time for simvastatin supply to be prepared and 
provided to the participant for dosing to start on day of AC #1.. 
16. For patients randomized to receive it:  Simvastatin 40 mg oral daily starts on day of  AC #1 and continues 
daily x 24 weeks unless held due to toxicity or at the discretion of the investigator.  Participants will 
complete a pill diary for simvastatin administration (Appendix C). 
17. Follow-up for changes in disease status, recurrence, and cardiovascular health will continue for up to 5 
years from randomization. 
 
NOTE: The schedule should be followed as closely as is realistically possible; however, the schedule may be 
modified due to problems such as scheduling delays or conflicts (e.g., clinic closure, poor weather conditions, 
vacations, etc.) with the guidance of the Protocol Chair/designee, as appropriate, and will not be reportable as a 
deviation unless the endpoints of the study are affected. 
9. Pharmaceutical Information 
Pharmaceutical information described below is derived from the simvastatin package insert, 
available at http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf. 
9.1 
Simvastatin Product Identification  
 Mode of action: Simvastatin is a pro-drug which is hydrolyzed to its β-hydroxyacid form, 
which is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. 
This enzyme is responsible for catalyzing the conversion of HMG-CoA to mevalonate, a 
precursor of sterols, including cholesterol.  This is a rate-limiting step in cholesterol 
biosynthesis.    
 Other names in the United States:  Zocor 
 Classification:  Statin 
 Molecular formula: butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-
[2-(tetarhydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenylester, [1S-1α,3 
α,7β,8 β (2S*, 4S*)-8a β]] 
 Empirical formula:  C25H38O5 
 Molecular weight: 418.57 
 Structural formula: 
 
9.2 
Simvastatin Pharmacokinetics 
Simvastatin is orally absorbed.  It undergoes extensive hepatic first-pass metabolism.  Both 
simvastatin and its β-hydroxyacid metabolite are highly bound to plasma proteins.  Metabolism 


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is via the cytochrome P450 enzyme system (CYP 3A4 substrate).  Plasma half-life is 3 hours.  
Simvastatin is primarily excreted in feces. 
9.3 
Contraindications to Simvastatin Therapy 
Simvastatin is contraindicated in women who are pregnant, women who may become pregnant 
or nursing women.   Simvastatin is contraindicated in patients with acute liver disease and in 
patients taking strong CYP 3A4 inhibitors, gemfibrozil, cyclosporine or danazol. 
9.4 
Drug Interactions with Simvastatin 
Concomitant administration of simvastatin and strong CYP3A4 inhibitors such as itraconazole, 
ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, human 
immunodeficiency virus (HIV) protease inhibitors, boceprevir, telaprevir, nefazodone, 
gemfibrozil, cyclosporine and danazol is associated with increased risk of skeletal muscle 
toxicity.  In addition, simvastatin doses must be limited in patients also taking amiodarone, 
amlodipine, verapamil, diltiazem, ranolazine and dronedarone due to increased risk of skeletal 
muscle toxicity with higher doses of simvastatin.  Grapefruit juice should be avoided in patients 
taking simvastatin due to increased risk of skeletal muscle toxicity.  Caution should be used with 
co-prescription of fibrates or niacin and simvastatin due to increased risk of skeletal muscle 
toxicity.  Simvastatin can enhance anti-coagulant effects of coumadin, thus frequent monitoring 
is recommended for patients on coumadin and simvastatin.  Co-administration of colchicine and 
simvastatin has also been associated with increased risk of rhabdomyolysis.  Simvastatin may 
increase plasma concentrations of digoxin. 
9.5 
Reported Simvastatin Toxicities 
The primary side effects of concern for the statins include elevated transaminases and myopathy.  
Elevated transaminases occur in up to 0.7% of patients, are dose-dependent and typically occur 
within the first 3 months of therapy.  Monitoring of hepatic transaminases is recommended.  
Statin-associated myopathy ranges from mild aches to more severe myopathy causing pain and 
immobility associated with elevations in creatine kinase (CK) and, rarely, in rhabdomyolysis.  
The reported incidence of statin-associated myopathy is 0.1-0.2%.97 
 
Increases in fasting serum glucose levels and in hemoglobin A1c have also been observed in 
patients taking simvastatin.  Other common side effects of simvastatin  reported in the pre-
marketing clinical trials experience included gastrointestinal disorders, myalgias, arthralgias, 
headache, upper respiratory infection, rash and asthenia.  The post-marketing experience for 
simvastatin also identified several other possible toxicities including cognitive impairment, 
hypersensitivity syndrome, skin changes, dizziness, paresthesias, peripheral neuropathy, 


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depression, interstitial lung disease, pancreatitis, pruritis, alopecia, vomiting, anemia and erectile 
dysfunction in addition to the known risks of hepatotoxicity and skeletal muscle toxicity. 
9.6 
Simvastatin Monitoring Parameters                           
Simvastatin levels are not monitored.   
9.7 
Storage and Stability of Simvastatin 
Simvastatin is stored at room temperature. 
9.8 
Simvastatin Preparation and Administration 
Simvastatin is available in 5 mg, 10 mg, 20 mg, 40 mg and 80 mg tablets.  It is administered 
orally.   Simvastatin 20 mg tablets will be used for this study.   
9.9 
Simvastatin Availability 
Simvastatin is an FDA approved drug.  Simvastatin will be provided to study participants 
randomized to the simvastatin arm.  The drug will be purchased for use in this study. 
9.10 Accountability for Study Drug 
The Investigational Drug Service of the Sidney Kimmel Comprehensive Cancer Center at Johns 
Hopkins will keep records of study drug receipts and dispensation as per standard practice.  
Documentation of study drug destruction will be maintained in the research study binder. 
 
 


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10. Adverse Events 
10.1 General 
This study will use the descriptions and grading scales found in the revised NCI CTCAE Version 
4 for adverse event reporting that can be found at http://ctep.cancer.gov/reporting/ctc.html. 
 
Information about adverse events, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be 
collected, recorded, and followed as appropriate. Adverse events will be collected from the time 
of consent, throughout the study and until the completion of all end-of-study assessments (52 
weeks +/- 14 days after the first cycle of AC).   
 
Specific symptoms of cardiac, liver, and muscle disease, such as exertional dyspnea, lower 
extremity swelling and/or edema, paroxysmal nocturnal dyspnea, orthopnea and muscle pain will 
be captured; collection of toxicity related to chemotherapy administration  is not required.  
Elevations of AST, ALT and CK will be closely monitored and tabulated in all participants; 
these will be reported as adverse events if felt to be possibly related to simvastatin.  Changes in 
EF or the development of other concerning findings on echocardiograms will also be closely 
monitored and reported in the study data in the presence or absence of symptoms; these will also 
be reported as adverse events. 
 
Subjects who have an ongoing adverse event related to the study procedures and/or simvastatin 
may continue to be periodically contacted by a member of the study staff until the event is 
resolved or determined to be irreversible by the investigator. 
10.2 Definitions 
10.2.1 Adverse event (AE)   
Any undesirable sign, symptom or medical condition occurring after starting study participation 
even if the event is not considered to be related to the study.  An undesirable medical condition 


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can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram). 
  
Medical conditions/diseases present before starting study treatment are only considered adverse 
events if they worsen after starting study treatment.  Adverse events occurring before starting 
study treatment but after signing the informed consent form will be recorded.   
10.2.2 Serious adverse event or reaction   
A serious adverse event (SAE) is an undesirable sign, symptom or medical condition which: 
 
 is fatal or life-threatening; 
 requires or prolongs hospitalization; 
 results in persistent or significant disability/incapacity; 
 constitutes a congenital anomaly or a birth defect; 
 is medically significant, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
 
Events not considered to be SAEs are hospitalizations for the: 
 
 routine treatment or monitoring of a pre-existing condition, not associated 
with any deterioration in condition, or for elective procedures (for example, 
venous access placement);  
 treatment, which was elective or pre-planned, and/or for a pre-existing 
condition that did not worsen – including hospitalizations for pre-planned 
breast and/or axillary surgeries for patients who receive chemotherapy in the 
neoadjuvant setting; 
 treatment on an emergency, outpatient basis for an event not fulfilling any of 
the definitions of serious given above and not resulting in hospital admission. 
 
Specific exclusions for events not considered to be reportable SAEs as part of a 
routine/expedited report on this study include the following: 
 
 events for participants on the intervention/simvastatin arm believed to be definitely 
unrelated to statin treatment  
 expected toxicities related to chemotherapy administration (eg, febrile neutropenia of a 
participant receiving AC or subsequent chemotherapy); 
 any event meeting SAE criteria for any participant on the non-intervention/control arm of 
the study.  
 
NOTE:  The exception to this is the death of a participant within the study 
intervention/observation period; deaths should be reported per IRB requirements regardless 
of attribution and regardless of whether the participant is in the control or statin arm. 
 
The definition of serious adverse event (experience) also includes important medical event.  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life 


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threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  These should also 
usually be considered serious.  Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
10.2.3 Expectedness 
 Unexpected adverse event:  An adverse event, which varies in nature, intensity or 
frequency from information on the package insert or safety reports.  Any adverse event 
that is not included in the informed consent is considered “unexpected”. 
 
 Expected (known) adverse event:  An adverse event, which has been reported.  An 
adverse event is considered “expected”, only if it is included in the informed consent 
document as a risk. 
 
 
10.3 Relationship 
The relationship of all adverse events and serious adverse events to study medication will be 
assessed by an investigator and assigned as follows: 
 
 Definitely:  An adverse event which has a timely relationship to the administration of the 
investigational drug/agent, follows a known pattern of response, and for which no 
alternative cause is present.  
 
 Probably:  An adverse event which has a timely relationship to the administration of the 
investigational drug/agent, follows a known pattern of response, but for which a potential 
alternative cause may be present.  
 
 Possibly:  An adverse event which has a timely relationship to the administration of the 
investigational drug/agent, follows no known pattern of response, but a potential 
alternative cause does not exist. 
 
 Unlikely:  An adverse event which does not have a timely relationship to the 
administration of the investigational drug/agent, follows no known pattern of response, 
does not reappear or worsen after re-administration of the investigational drug/agent (if 
applicable), and for which there is evidence that it is related to a cause other than the 
investigational drug/agent. 
 
 Unrelated:  An adverse event for which there is evidence that it is definitely related to a 
cause other than the investigational drug/agent.  In general, there is no timely relationship 


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to the administration of the investigational drug/agent, or if there is a timely relationship, 
the event does not follow a known pattern of response, and there is an alternative cause.  
10.4 Reporting Procedures 
10.4.1 General 
All reportable adverse events as described above will be captured on the appropriate study-
specific case report forms (CRFs).  In addition, all events meeting the definition of serious 
adverse events above, regardless of causality to study drug, will be reported promptly to the 
Principal Investigator and/or the Study Coordinator. 
10.4.2 Institutional Review Board 
All adverse events and serious adverse events will be reported to the institutional review board 
(IRB) per current institutional standards.  If an adverse event requires modification of the study 
protocol and informed consent, these modifications will be provided to the IRB with the report of 
the adverse event or as soon as possible thereafter. 
10.4.3 Food and Drug Administration (FDA) 
The clinical trial outlined uses an FDA-approved medication and has been determined to be 
IND-exempt.  Any unexpected adverse events believed to be definitely, probably, or possibly 
related to the medication (s) will be reported to the Food and Drug Administration via 
MedWatch (using the online form available at 
https://www.accessdata.fda.gov/scripts/medwatch/; by telephone 1-800-FDA-1088; or by fax 1-
800-FDA-0178 using form available at http://www.fda.gov/medwatch/report/hcp.htm). 
 
 
 
 


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11. Data and Safety Monitoring  
11.1 Data Management 
All information will be collected on study-specific case report forms (CRFs) by study staff.  
These data will be reviewed for completeness and accuracy by the Principal Investigator as well 
as the Sidney Kimmel Comprehensive Cancer Center Clinical Research Office. 
11.2 Meetings 
Scheduled meetings will take place as needed and will include the protocol principal 
investigators, study coordinator(s), data manager(s), sub-investigators (as appropriate), 
collaborators (as appropriate), and biostatisticians (as appropriate) involved with the conduct of 
the protocol.  During these meetings, matters related to the following will be discussed:  safety of 
protocol participants, validity and integrity of the data, enrollment rate relative to expectation, 
characteristics of participants, retention of participants, adherence to protocol (potential or real 
protocol violations), data completeness, and progress of data for objectives. 
11.3 Monitoring 
This is a DSMP Level I study under the SKCCC Data Safety Monitoring Plan (12/6/2012).  The 
Clinical Research Office QA Group will perform an audit at the end of the first year and then 
periodically depending on the rate of accrual and prior audit results.  All trial monitoring and 
reporting will be reviewed annually by the SKCCC Safety Monitoring Committee. 
 
 


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12. Administrative Procedures  
12.1 Protocol Amendments 
Any changes to the protocol will be made in the form of an amendment and must be approved by 
the IRB before implementation. Any modifications made to the protocol or informed consent 
document according to local requirements or any other reason may also require approval from 
sponsoring agencies.  
12.2 Informed Consent 
An investigator will explain to each subject the nature of the study, its purpose, procedures 
involved, expected duration, potential risks and benefits. Each subject will be informed that 
participation in the study is voluntary and that she may withdraw from the study at any time, and 
that withdrawal of consent will not affect her subsequent medical treatment. This informed 
consent will be given by means of a standard written statement and will be submitted for IRB 
approval prior to use. No patient will enter the study before her informed consent has been 
obtained. In accordance with the Health Insurance Portability and Accountability Act (HIPAA), 
the written informed consent document (or a separate document to be given in conjunction with 
the consent document) will include a subject authorization to release medical information to the 
study sponsor and supporting agencies and/or allow these bodies, a regulatory authority, or 
Institutional Review Board access to subjects’ medical information that includes all hospital 
records relevant to the study, including subjects’ medical history. 
12.3 Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as 
described in: 
 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations). 
3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 
1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice that it conforms to. 
12.4 Regulatory Authorities 
12.4.1 Institutional Review Board 
Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per the current institutional standards.. 
12.4.2 Food and Drug Administration (FDA) 
This trial does not involve an Investigational New Drug (IND) application and no reporting is 
required with regards to the clinical trial outlined at this time.  
 
 


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13. Statistical Considerations 
13.1 Study Design  
This is a prospective, randomized, open-label, non-placebo controlled study evaluating change in 
myocardial strain with anthracycline (AC) chemotherapy plus simvastatin (investigational arm) 
or chemotherapy alone (control arm) in women with early stage breast cancer. Patients will be 
randomized 1:1 to the investigational arm or the control arm. 
 
A number of recent studies suggest anthracyclines may reduce myocardial strain, a sign of 
cardiac toxicity which can be detected prior to decline in EF.  Data suggests that simvastatin may 
attenuate the risk of anthracycline-related cardiac toxicity.   The primary goal of this study is to 
assess change in global longitudinal strain (GLS) from baseline to 1-3weeks after completion of 
4 cycles of chemotherapy in early stage breast cancer patients receiving AC with and without 
concurrent simvastatin. We hypothesize that simvastatin may have a cardio-protective effect by 
minimizing reduction in myocardial strain during treatment with anthracycline-based 
chemotherapy.  
 
The study will accrue 90 patients, 45 in each arm. Safety of concurrent administration of statin 
and AC chemotherapy will be monitored continuously. The design includes interim monitoring 
for futility, i.e., we will suspend enrollment for re-evaluation if there is high probability that 
more than 30% of patients receiving statin therapy experience >5% absolute decline in GLS for 
the first two consecutive visits post therapy. 
 
This study is not intended or powered to detect a specific difference in GLS declines between 
arms, but it will be able to find a minimal detectable difference with sufficient power (Section 
13.3). Results will be used in designing future definitive studies assessing the clinically 


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important difference in strain between patients who do and do not receive statin therapy as well 
as the protective effect of statin on AC-induced cardiotoxicity with long-term follow-up.  
13.2 Endpoints 
13.2.1 Primary Endpoint 
The primary endpoint is the difference in mean absolute change in GLS from baseline until 1-3 
weeks after the completion of AC chemotherapy between patients who do and do not receive 
concurrent simvastatin therapy. 
13.2.2 Secondary Endpoints 
Secondary endpoints include the difference in the relative change, measured as percent change in 
GLS from baseline until 1-3weeks after completion of AC chemotherapy between patients who 
do and do not receive concurrent simvastatin therapy. 
 
Additionally, we will measure the differences in the absolute and relative change in velocity-
based GLS rate from baseline until 1-3weeks after the completion of AC chemotherapy between 
arms. 
 
Changes in GLS and GLS strain rate will also be evaluated over multiple time points from 
baseline to 52 weeks in both arms. 
 
Feasibility of administering simvastatin during AC chemotherapy will be assessed by the 
proportion of doses which are documented as missed by patients randomized to receive 
simvastatin based on pill diaries. 
 
Feasibility of using myocardial strain as a measure of cardiac toxicity in breast cancer patients 
receiving AC will be assessed by the proportion of patients who complete all five study-
mandated echocardiograms and by the overall proportion of missing echocardiograms. 
 
Safety and tolerability of concurrent administration of simvastatin with AC chemotherapy will be 
evaluated according to the NCI CTCAE version 4. 
 
Finally, RFS will be assessed by review of medical records every six months for 5 years after 
randomization. 
13.2.3 Exploratory Endpoints  
Exploratory endpoints will include correlations between early measurements (defined as 
measurements taken at baseline and prior to AC#2) of GLS and GLS rate with subsequent 
measurements of EF and subsequent development of symptomatic heart failure, risk factors that 
may predict early change in GLS in addition to changes in other echocardiographic parameters 
(e.g.,right ventricular strain, left ventricular diastolic function and filling pressures) over time.     
13.3 Sample Size and Accrual Rate 
 
Following the intent-to-treat approach, we will include all randomized patients in the primary 
efficacy analysis. We plan to have 80 patients, 40 in each arm, for the primary analysis.  


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Previous studies showed that breast cancer patients receiving chemotherapy alone have an 
average of 1-5% absolute decline in strain post-therapy, which is associated with subsequent 
development of cardiotoxicity.  Other published studies collectively suggest that the standard 
deviation of baseline GLS ranges from 1.5% to 3%.  Based on these results, we estimated that 
the standard deviation of changes across patients from baseline to follow-up approximately 
ranged from 2% to 4%. The changes in GLS in the statin and control arms will be compared 
using a two-sample t-test. The table below (table 1) shows the minimal detectable difference for 
a range of assumed standard deviations with 80% power and a one-sided type I error of 0.05. If 
the actual difference between arms is larger than we expect, we will be able to detect it with 
greater statistical power. 
 
To account for approximately 10% attrition, a total of 90 patients will be enrolled and 
randomized, 45 in each arm of the study. With an accrual goal of approximately 3 patients per 
month and total duration of study participation of approximately 52 weeks, the data collection 
for the primary endpoint should be complete in about 3.5 years; follow-up for disease recurrence 
will continue for at least 5 years after enrollment of each subject. 
 
 


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Table 1: Detectable difference assuming equal variances in a two-sample t test with 80% 
Power and one-sided alpha of 0.05 (n=80) 
Mean Absolute Change  
(Pre-Post) in GLS  
Standard 
Deviation of 
Change  
Detectable Difference 
between Arms, 
 GLS (%) 
Chemo Alone  
Statin + Chemo 
1% 
-0.11% 
2.0% 
1.11% 
-0.39% 
2.5% 
1.39% 
-0.66% 
3.0% 
1.66% 
-0.96% 
3.5% 
1.96% 
-1.21% 
4.0% 
2.21% 
3% 
1.89% 
2.0% 
1.11% 
1.61% 
2.5% 
1.39% 
1.34% 
3.0% 
1.66% 
1.06% 
3.5% 
1.96% 
0.76% 
4.0% 
2.24% 
5% 
3.89% 
2.0% 
1.11% 
3.61% 
2.5% 
1.39% 
3.34% 
3.0% 
1.66% 
3.04% 
3.5% 
1.96% 
2.79% 
4.0% 
2.21% 
 
13.4 Stratification factors 
None.  
13.5 Analysis Plan 
13.5.1 Analysis of the Primary Endpoint 
For the echocardiography, digital data will be direct image output. GLS will be obtained 
automatically and expressed as a percentage. Absolute change in GLS from baseline to 1-3weeks 
after completion of AC chemotherapy will be calculated in each arm. The descriptive statistics 
(mean, standard deviation, median, and range) along with the 95% confidence intervals will be 
estimated. GLS may be transformed if necessary to achieve normality. If so, estimates of means 
and confidence intervals of the transformed outcome will be back-transformed so that parameter 
estimates and confidence intervals are interpretable. A two-sample t-test will be used to 
determine if the detected changes from baseline are significantly different between arms.  
Missing data at post-baseline, if at all, will be handled using a mixed-effects regression model 
that includes all randomized subjects, assuming missing completely at random. Additionally, we 
will perform a sensitivity analysis following the as-treated approach (also referred to as a 


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‘complete cases’ approach) including only patients that have a baseline GLS value and at least 
one post-AC GLS value, particularly at 1-3weeks after completion of 4 cycles of AC. 
13.5.2 Analyses of the Secondary Endpoints 
Percent changes in GLS from baseline to 2-3 weeks after completion of AC chemotherapy will 
be calculated as (baseline – follow-up)*100% / baseline. Analyses of the percent change will be 
performed in a similar fashion as described above.   
 
Changes in velocity-based GLS rate from baseline to 1-3 weeks after completion of AC 
chemotherapy will be summarized in each arm and compared between arms as described above. 
Echocardiography will be performed prior to the first dose of AC (baseline), prior to the second 
dose of AC, 1-3 weeks after 4 cycles of AC, 24 weeks after the first dose of AC and 52 weeks 
after the first dose of AC. A mixed-effects model will be used to assess changes in GLS and GLS 
strain rate over time, which accounts for correlation among measures from the same subject and 
meanwhile provides a flexible structure at the presence of missing data (assuming missing at 
random). Within patient changes over time will be described via such model. Difference in strain 
parameters between arms will be evaluated with the adjustment for whether or not trastuzumab is 
received as a time-dependent covariate and other potential confounders.  
 
Feasibility of administering simvastatin during AC chemotherapy will be assessed by the 
proportion of doses which are documented as missed by patients randomized to receive 
simvastatin based on pill diaries. These analyses will be descriptive only. 
 
Feasibility of using myocardial strain as a measure of cardiac toxicity in breast cancer patients 
receiving AC will be assessed by the proportion of patients who complete all five study-
mandated echocardiograms and by the overall proportion of missing echocardiograms. These 
analyses will be descriptive only. 
 
Safety and tolerability of concurrent administration of simvastatin with AC chemotherapy will be 
described using summary statistics with frequencies and percentages. All subjects receiving at 
least one dose of the study drug(s) will be included in the safety analysis. 
 
RFS will be calculated as the time from randomization until the time of the first documentation 
of breast cancer recurrence at any site (in-breast recurrence, new contralateral primary recurrence 
or distant metastases) or death due to breast cancer, whichever occurs first. Subjects who do not 
recur but die of other unrelated cause will be censored at the time of death. Subjects who remain 
alive with no disease recurrence will be censored at the date of their last chart review. RFS 
probabilities will be estimated in each arm (chemotherapy + simvastatin versus chemotherapy 
alone) separately using the Kaplan-Meier method. Effect of statin treatment on RFS will be 
explored through the use of the Cox proportional hazards model. 
13.5.3 Analyses of the Exploratory Endpoints 
Changes in EF over time will be described. All time points will be combined in a mixed-effects 
model that includes change in EF as the outcome and change in GLS (and GLS rate), time point 
and their interaction as covariates, while accounting for the correlation of measurements from the 
same patient. Mean strain parameters along with EF measurements over time will be visually co-


Anthracycline-Related Cardiac Toxicity 
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Page 57 
displayed using a scatterplot. We will also consider change in EF as a binary outcome by 
classifying patients into those who have a clinically significant drop in EF at 1-year follow-up, 
i.e., an absolute decrease of ≥ 10% from baseline to < 50%, and those who do not. We will 
utilize a logistic regression with generalized estimating equations (GEE) method to assess the 
independent effect of early change in strain in predicting EF decline and simultaneously account 
for important sources of variation including baseline measurement, age, stage, cardiac risk 
factors, receipt of hormonal therapy, receipt of radiation, type of surgery, schedule of AC (q 2 
week vs. q 3 week), receipt of other medications which may impact  cardiac function (such as 
ACE inhibitors, ARBs or beta blockers), receipt of taxanes, receipt of HER2 targeted therapy, 
laterality of cancer and other potentially relevant breast cancer factors. We will also examine 
whether treatment arm modifies the association between change in strain parameters and EF 
decline (i.e., interaction). Association of early change in strain with subsequent heart failure 
within 1-year follow-up will be explored in a similar fashion. Heart failure will be classified as 
symptomatic or asymptomatic, where symptomatic heart failure will be considered to be grade 2 
or higher according to the NCI CTCAE v. 4.0 and/or NYHA functional classification class II or 
higher. Considering only less than a handful of patients will experience a clinically significant 
drop in EF or symptomatic heart failure within the study follow-up, these analysis will be largely 
descriptive and hypothesis generating in nature; however, they will provide valuable data for 
future studies. 
 
We will use a linear regression model to explore risk factors collected through questionnaires 
(including but not limited to hypertension, diabetes, obesity, and smoking history) that may 
predict early change in GLS. 
 
We will describe additional echocardiographic strain parameters besides GLS and GLS rate, 
including right ventricular strain, in addition to routine assessment of left ventricular diastolic 
function and filling pressures, at multiple time points from baseline to 52 weeks in this patient 
population treated with (neo)adjuvant anthracycline based chemotherapy with and without 
concurrent simvastatin therapy.   
 
13.6 Early Stopping 
13.6.1 Early Stopping Guidelines for Safety 
The most likely toxicity associated with simvastatin that we expect to encounter in this study is 
hepatotoxicity, although only approximately 1% of patients on statin drugs experience persistent 
transaminitis.  We will monitor transaminases regularly while patients are on chemotherapy and 
statin therapy in this trial.  In order to avoid potentially concerning hepatotoxicity related to our 
intervention, we plan to suspend enrollment for a safety assessment if we are 65% certain that 
the risk of ≥ grade 3 elevation in AST and/or ALT exceeds 5%.  The prior for the stopping rule is 
beta (0.1, 9.9), representing our prior guess at the risk of liver function toxicities is 1% on 
average and there is 90% certainty that this proportion is between 0.006% and 3.8%.   The 
following tables (table 2 and table 3) show the stopping rules and associated operating 
characteristics based on 5000 simulations. 
 
Table 2: Early Stopping Rules for Safety 


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Suspend enrollment if 
2 
3 
4 
Out of total number of patients 
2-17 
18-34 
35-45 
 
Table 3:  Operating Characteristics 
True risk of AE 
Probability declare 
treatment unsafe 
Average  
sample size 
0.01 
1.5% 
44.6 
0.05 
34.4% 
35.9 
0.10 
78.2% 
23.4 
0.15 
95.6% 
14.8 
13.6.2 Early Stopping Guidelines for Futility 
Preliminary data are not yet available to estimate the effect that adding statin therapy to AC 
chemotherapy will have on change in myocardial strain over time in this patient population, 
neither to what extent the protective effect, if any, will be associated with a clinical benefit. As a 
result, we do not plan to stop early based on lacking statistically significant difference in GLS 
decline between arms, but rather will consider halting enrollment for re-evaluation if we are 90% 
certain that more than 30% of patients in the statin arm experience >5% absolute decline in GLS 
for the first two consecutive visits. This interim look will not occur until 15 patients have entered 
the statin arm and received treatment, and thereafter every 10 patients. The prior distribution for 
the decision rule is a beta (0.1, 9.9), representing our prior guess that it is almost unlikely we will 
see patients receiving statin therapy having experienced >5% absolute decline in GLS for two 
consecutive visits. Enrollment will be suspended if this occurs in 11 out of 15, 15 out of 25, 18 
out of 35, and 21 out of 45 patients. Given this stopping rule, we will have 45% chance to stop if 
the corresponding true risk is 50% and 87% chance to stop the study if the true risk reaches 60%. 


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blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with 
cyclophosphamide, doxorubicin, vincristine, and prednisolone. Cancer 2005;104:2492-8. 
85. 
Pituskin E, Haykowsky M, Mackey JR, et al. Rationale and design of the 
Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research Trial 
(MANTICORE 101--Breast): a randomized, placebo-controlled trial to determine if conventional 


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Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
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heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling 
among patients with HER2+ early breast cancer using cardiac MRI. BMC Cancer 2011;11:318. 
86. 
Heck SL, Gulati G, Ree AH, et al. Rationale and design of the prevention of cardiac 
dysfunction during an Adjuvant Breast Cancer Therapy (PRADA) Trial. Cardiology 
2012;123:240-7. 
87. 
Jones SP, Teshima Y, Akao M, Marban E. Simvastatin attenuates oxidant-induced 
mitochondrial dysfunction in cardiac myocytes. Circ Res 2003;93:697-9. 
88. 
Feleszko W, Mlynarczuk I, Balkowiec-Iskra EZ, et al. Lovastatin potentiates antitumor 
activity and attenuates cardiotoxicity of doxorubicin in three tumor models in mice. Clin Cancer 
Res 2000;6:2044-52. 
89. 
Riad A, Bien S, Westermann D, et al. Pretreatment with statin attenuates the 
cardiotoxicity of Doxorubicin in mice. Cancer Res 2009;69:695-9. 
90. 
Kim YH, Park SM, Kim M, et al. Cardioprotective effects of rosuvastatin and carvedilol 
on delayed cardiotoxicity of doxorubicin in rats. Toxicol Mech Methods 2012;22:488-98. 
91. 
Seicean S, Seicean A, Plana JC, Budd GT, Marwick TH. Effect of statin therapy on the 
risk for incident heart failure in patients with breast cancer receiving anthracycline 
chemotherapy: an observational clinical cohort study. J Am Coll Cardiol 2012;60:2384-90. 
92. 
Lenihan DJ. Statins in preparation for chemotherapy: "do these medications help your 
fitness for battle?". J Am Coll Cardiol 2012;60:2391-2. 
93. 
Acar Z, Kale A, Turgut M, et al. Efficiency of atorvastatin in the protection of 
anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2011;58:988-9. 
94. 
Konings IR, van der Gaast A, van der Wijk LJ, de Jongh FE, Eskens FA, Sleijfer S. The 
addition of pravastatin to chemotherapy in advanced gastric carcinoma: a randomised phase II 
trial. Eur J Cancer 2010;46:3200-4. 
95. 
Ahern TP, Pedersen L, Tarp M, et al. Statin prescriptions and breast cancer recurrence 
risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst 2011;103:1461-8. 
96. 
Prowell TM, Stearns V, Trock B. Lipophilic statins merit additional study for breast 
cancer chemoprevention. J Clin Oncol 2006;24:2128-9; author reply 9. 
97. 
Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics 
and drug interactions. Circulation 2004;109:III50-7. 
98. 
Jakobisiak M, Golab J. Potential antitumor effects of statins (Review). Int J Oncol 
2003;23:1055-69. 
99. 
Kwan ML, Habel LA, Flick ED, Quesenberry CP, Caan B. Post-diagnosis statin use and 
breast cancer recurrence in a prospective cohort study of early stage breast cancer survivors. 
Breast Cancer Res Treat 2008;109:573-9. 
100. 
Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related 
mortality. N Engl J Med 2012;367:1792-802. 
101. 
Nickels S, Vrieling A, Seibold P, et al. Mortality and recurrence risk in relation to the use 
of lipid-lowering drugs in a prospective breast cancer patient cohort. PLoS One 2013;8:e75088. 
102. 
Calderon RM, Cubeddu LX, Goldberg RB, Schiff ER. Statins in the treatment of 
dyslipidemia in the presence of elevated liver aminotransferase levels: a therapeutic dilemma. 
Mayo Clin Proc 2010;85:349-56. 
103. 
Alberton M, Wu P, Druyts E, Briel M, Mills EJ. Adverse events associated with 
individual statin treatments for cardiovascular disease: an indirect comparison meta-analysis. 
QJM 2012;105:145-57. 
 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 66 
APPENDICES 
 
A 
American Joint Committee on Cancer Staging 
B 
Performance Status Criteria 
C 
Study Drug Diary 
D 
NYHA Functional Classification 
E 
Participant Questionnaire 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
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APPENDIX A:  American Joint Committee on Cancer Staging  
 
T – Primary Tumor 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
Tis (DCIS) 
Ductal carcinoma in situ 
Tis (LCIS) 
Lobular carcinoma in situ 
Tis (Paget) 
Paget’s disease of the nipple with no tumor 
  Note:  Paget’s disease associated with a tumor is classified according to the size of the tumor. 
T1 
Tumor ≤ 2 cm in greatest dimension 
T1mic 
Microinvasion ≤ 0.1 cm in greatest dimension 
T1a 
Tumor > 0.1 cm but not > 0.5 cm in greatest dimension 
T1b 
Tumor > 0.5 cm but not > 1 cm in greatest dimension 
T1c 
Tumor > 1 cm but not > 2 cm in greatest dimension 
T2 
Tumor > 2 cm but not > 5 cm in greatest dimension 
T3 
Tumor > 5 cm in greatest dimension 
T4 
Tumor of any size with direct extension to 
(a) chest wall or 
(b) skin, only as described below 
T4a 
Extension to chest wall, not including pectoralis muscle 
T4b 
Edema (including peau d’orange” or ulceration of the skin of the breast, or satellite skin nodules 
confined to the same breast 
T4c 
Both T4a and T4b 
T4d 
Inflammatory carcinoma 
 
 
N – Regional lymph nodes 
NX 
Regional lymph nodes cannot be assessed (e.g., previously removed) 
N0 
No regional lymph node metastasis 
N1 
Metastasis in movable ipsilateral axillary lymph node(s) 
N2 
Metastases in ipsilateral axillary lymph nodes fixed or matted, or in clinically apparent ipsilateral 
internal mammary nodes in the absence of clinically evident axillary lymph node metastasis 
N2a 
Metastasis in ipsilateral axillary lymph nodes fixed to one another (matted) or to other structures 
N2b 
Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of 
clinically evident axillary lymph node metastasis 
N3 
Metastasis in ipsilateral infraclavicular lymph node(s), or in clinically apparent ipsilateral internal 
mammary lymph node(s) and in the presence of clinically evident axillary lymph node metastasis; 
or metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or internal 
mammary lymph node involvement 
N3a 
Metastasis in ipsilateral infraclavicular lymph node(s) and axillary lymph node(s) 
N3b 
Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) 
N3c 
Metastasis in ipsilateral supraclavicular lymph node(s) 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 68 
APPENDIX A (CONTINUED):  American Joint Committee on Cancer Staging  
 
 
PN – Regional lymph nodes 
pNX 
Regional lymph nodes cannot be assessed  (e.g., previously removed or not removed for 
pathologic study) 
pN0 
No regional lymph node metastasis histologically, no additional examination for isolated tumor 
cells 
pN0(i-) 
No regional lymph node metastasis histologically, negative IHC 
pN0(i+) 
No regional lymph node metastasis histologically, positive IHC, no IHC cluster > 0.2 mm 
pN0(mol-) 
No regional lymph node metastasis histologically, negative molecular findings (RT-PCR) 
pN0(mol+) 
No regional lymph node metastasis histologically, positive molecular findings (RT-PCR) 
pN1mi 
Micrometastasis (> 0.2 mm, none > 2.0 mm) 
pN1 
Metastasis in one to three axillary lymph nodes and/or in internal mammary nodes with 
microscopic disease detected by sentinel lymph node dissection but not clinically apparent 
pN1a 
Metastasis in one to three axillary lymph nodes 
pN1b 
Metastasis in internal mammary nodes with microscopic disease detected by sentinel lymph node 
dissection but not clinically apparent 
pN1c 
Metastasis in one to three axillary lymph nodes and in internal mammary lymph nodes with 
microscopic disease detected by sentinel lymph node dissection but not clinically apparent 
pN2 
Metastasis in four to nine axillary lymph nodes, or in clinically apparent internal mammary lymph 
nodes in the absence of axillary lymph node metastasis 
pN2a 
Metastasis in four to nine axillary lymph nodes (at least one tumor deposit > 2.0 mm) 
pN2b 
Metastasis in clinically apparent internal mammary lymph nodes in the absence of axillary lymph 
node metastasis 
pN3 
Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically 
apparent ipsilateral internal mammary lymph nodes in the presence of one or more positive 
axillary lymph nodes; or in more than three axillary lymph nodes with clinically negative 
microscopic metastasis in internal mammary lymph nodes; or in ipsilateral supraclavicular lymph 
nodes 
pN3a 
Metastasis in 10 or more axillary lymph nodes (at least one tumor deposit > 2.0 mm), or 
metastasis to the infraclavicular lymph nodes 
pN3b 
Metastasis in clinically apparent ipsilateral internal mammary lymph nodes in the presence of one 
or more positive axillary lymph nodes; or in more than three axillary lymph nodes and in internal 
mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but 
not clinically apparent 
pN3c 
Metastasis in ipsilateral supraclavicular lymph nodes 
 
 
M – Distant metastasis 
MX 
Distant metastasis cannot be assessed 
M0 
No distant metastasis 
M1 
Distant metastasis 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 69 
APPENDIX A (CONTINUED):  American Joint Committee on Cancer Staging  
 
 
Stage Grouping 
T 
N 
M 
0 
Tis 
N0 
M0 
I 
T1 
N0 
M0 
IIA 
T0 
N1 
M0 
T1 
N1 
M0 
T2 
N0 
M0 
IIB 
T2 
N1 
M0 
T3 
N0 
M0 
IIIA 
T0 
N2 
M0 
T1 
N2 
M0 
T2 
N2 
M0 
T3 
N1 
M0 
T3 
N2 
M0 
IIIB 
T4 
N0 
M0 
T4 
N1 
M0 
T4 
N2 
M0 
IIIC 
Any T 
N3 
M0 
IV 
Any T 
Any N 
M1 
 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 70 
APPENDIX B:  Performance Status Criteria 
 Score 
Definition 
Karnofsky Equivalent 
0 
Asymptomatic 
100 
1 
Symptomatic, fully ambulatory 
80 – 90 
2 
Symptomatic, in bed less than 50% of day 
60 – 70 
3 
Symptomatic, in bed more than 50% of day,  
but not bedridden 
40 – 50 
4 
Bedridden 
20 – 30 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 71 
APPENDIX C:  Study Drug Diary  
 
Subject:   
 
 
 
 
 
 
Study Drug Diary – Simvastatin 
Please complete this diary by signing your initials for each day that you take your simvastatin. 
Two pills of 20 mg simvastatin should be taken by mouth. Please take simvastatin at approximately 
the same time each evening. Missed doses will not be made up. 
 
Please be sure to bring this diary with you to your next doctor’s visit. 
 
Month/Year:  ______________________  
Month/Year:  ______________________ 
Sun Mon Tues Wed Thurs Fri 
Sat 
 
Sun Mon
Tues
Wed Thurs Fri 
Sat 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Month/Year:  ______________________  
Month/Year:  ______________________ 
Sun Mon Tues Wed Thurs Fri 
Sat 
 
Sun Mon
Tues
Wed Thurs Fri 
Sat 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Completed by: 
 
 
 
 
 
 
Date:    
 
 
 
 
Initials of Participant 
 
  
Reviewed by:  
 
 
 
 
 
 
Date:    
 
 
 
 
Initials of Study Staff  


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 72 
APPENDIX D:  NYHA Functional Classification 
 
Class 
Description 
Class I 
Patients with cardiac disease but without resulting limitation of physical activity.  
Ordinary physical activity does not cause undue fatigue, palpitations, dyspnea or 
anginal pain. 
Class II 
Patients with cardiac disease resulting in slight limitation of physical activity.  
They are comfortable at rest.  Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitation of physical activity.  
They are comfortable at rest.  Less than ordinary activity causes fatigue, 
palpitation, dyspnea or anginal pain. 
Class IV Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort.  Symptoms of heart failure the anginal syndrome may be 
present even at rest.  If any physical activity is undertaken, discomfort increases. 
 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 73 
APPENDIX E:  Participant Questionnaire 
 
 
 
 
 
 
Detection and Prevention of Anthracycline-Related Cardiac 
Toxicity with Concurrent Simvastatin 
 
Baseline Subject Questionnaire 
 
 
 
Subject Study #: 
 
Date: 
 
 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 74 
 
Menstrual History  
1. How old were you when you had your first menstrual period?  _______ 
2. Have you had a menstrual period in the past 12 months?   
O No – What was your age or the month and year of your last menstrual period?  
 
 
 
 
Age: _______     or       _____ /_____  
 
 
 
  
 
 
   Month 
Year 
O Yes – What was the start date of your last 3 menstrual periods?  
  
1) _____ /_____ /_____   2) _____ /_____ /_____ 3) _____ /_____ /_____ 
 
 
Month 
 Day  
 Year  
Month 
Day  
  Year 
 Month      Day  
 Year 
3. Have you had any of the following gynecological surgeries?  
O Removal of ovaries - O One  or  O Both 
Age: _______ 
O Hysterectomy (removal of uterus) 
Age: _______ 
O None   
 
 
Medical History 
1. Have you ever been diagnosed with any of the following medical conditions (check all that 
apply)? 
O Heart failure 
O Heart attack or angina 
O Irregular heart beat 
O Problems with a heart valve 
O Other heart problems  
O High blood pressure 
O Kidney failure 
 
O Thyroid disease 
   
O Diabetes 
   
O Stroke or transient ischemic attack 
    
O Connective tissue disease  (such as Lupus, Rheumatoid arthritis) 
O Liver disease 
O Blood clot(s) 
O High cholesterol 
O Other medical problems:______________________________ 
O I have never had any of the above conditions or others. 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 75 
 
2. If you have been diagnosed with high blood pressure, have you ever been 
prescribed medicines to lower your blood pressure (select one answer)? 
 
O  I have not been diagnosed with high blood pressure 
O  I have been diagnosed with high blood pressure but have never been 
prescribed medicines to lower my blood pressure 
O  I have been diagnosed with high blood pressure and have been prescribed 
medicines to lower my blood pressure  
 
 
Family History of Cardiovascular Disease  
Please describe your family history of cardiovascular disease (check all that apply). 
 
Family member:  Mother 
Cardiovascular problems 
Status 
Age at 
diagnosis  
 
Heart attack or angina O Yes 
O No 
O Unknown 
____ 
 
High blood pressure O Yes 
O No 
O Unknown 
____ 
 
Heart failure O Yes 
O No 
O Unknown 
____ 
 
Irregular heart beat O Yes 
O No 
O Unknown 
____ 
 
Problem with heart valve O Yes 
O No 
O Unknown 
____ 
 
Stroke O Yes 
O No 
O Unknown 
____ 
 
Diabetes O Yes 
O No 
O Unknown 
____ 
 
High cholesterol O Yes 
O No 
O Unknown 
____ 
 
Other cardiovascular problem O Yes 
O No 
O Unknown 
____ 
 
  
 
 
 
 
Family member:  Father 
Cardiovascular problems 
Status 
Age at 
diagnosis  
 
Heart attack or angina O Yes 
O No 
O Unknown 
____ 
 
High blood pressure O Yes 
O No 
O Unknown 
____ 
 
Heart failure O Yes 
O No 
O Unknown 
____ 
 
Irregular heart beat O Yes 
O No 
O Unknown 
____ 
 
Problem with heart valve O Yes 
O No 
O Unknown 
____ 
 
Stroke O Yes 
O No 
O Unknown 
____ 
 
Diabetes O Yes 
O No 
O Unknown 
____ 
 
High cholesterol O Yes 
O No 
O Unknown 
____ 
 
Other cardiovascular problem O Yes 
O No 
O Unknown 
____ 
 
  
 
 
 
 
 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 76 
Family History of Cardiovascular Disease (continued) 
Family member:  Sister(s)                    O I do not have any sisters 
Cardiovascular problems 
Status 
Age at 
diagnosis  
If yes, how many 
affected?
Heart attack or angina O Yes 
O No 
O Unknown 
____ 
____ 
High blood pressure O Yes 
O No 
O Unknown 
____ 
____ 
Heart failure O Yes 
O No 
O Unknown 
____ 
____ 
Irregular heart beat O Yes 
O No 
O Unknown 
____ 
____ 
Problem with heart valve O Yes 
O No 
O Unknown 
____ 
____ 
Stroke O Yes 
O No 
O Unknown 
____ 
____ 
Diabetes O Yes 
O No 
O Unknown 
____ 
____ 
High cholesterol O Yes 
O No 
O Unknown 
____ 
____ 
Other cardiovascular problem O Yes 
O No 
O Unknown 
____ 
____ 
  
 
 
 
 
Family member:  Brother(s)                    O I do not have any brothers 
Cardiovascular problems 
Status 
Age at 
diagnosis  
If yes, how many 
affected?
Heart attack or angina O Yes 
O No 
O Unknown 
____ 
____ 
High blood pressure O Yes 
O No 
O Unknown 
____ 
____ 
Heart failure O Yes 
O No 
O Unknown 
____ 
____ 
Irregular heart beat O Yes 
O No 
O Unknown 
____ 
____ 
Problem with heart valve O Yes 
O No 
O Unknown 
____ 
____ 
Stroke O Yes 
O No 
O Unknown 
____ 
____ 
Diabetes O Yes 
O No 
O Unknown 
____ 
____ 
High cholesterol O Yes 
O No 
O Unknown 
____ 
____ 
Other cardiovascular problem O Yes 
O No 
O Unknown 
____ 
____ 
  
 
 
 
 
Family member:  Daughter(s)                    O I do not have any daughters 
Cardiovascular problems 
Status 
Age at 
diagnosis  
If yes, how many 
affected?
Heart attack or angina O Yes 
O No 
O Unknown 
____ 
____ 
High blood pressure O Yes 
O No 
O Unknown 
____ 
____ 
Heart failure O Yes 
O No 
O Unknown 
____ 
____ 
Irregular heart beat O Yes 
O No 
O Unknown 
____ 
____ 
Problem with heart valve O Yes 
O No 
O Unknown 
____ 
____ 
Stroke O Yes 
O No 
O Unknown 
____ 
____ 
Diabetes O Yes 
O No 
O Unknown 
____ 
____ 
High cholesterol O Yes 
O No 
O Unknown 
____ 
____ 
Other cardiovascular problem O Yes 
O No 
O Unknown 
____ 
____ 
  
 
 
 
 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 77 
Family History of Cardiovascular Disease (continued) 
 
Family member:  Sons(s)                    O I do not have any sons 
Cardiovascular problems 
Status 
Age at 
diagnosis  
If yes, how many 
affected?
Heart attack or angina O Yes 
O No 
O Unknown 
____ 
____ 
High blood pressure O Yes 
O No 
O Unknown 
____ 
____ 
Heart failure O Yes 
O No 
O Unknown 
____ 
____ 
Irregular heart beat O Yes 
O No 
O Unknown 
____ 
____ 
Problem with heart valve O Yes 
O No 
O Unknown 
____ 
____ 
Stroke O Yes 
O No 
O Unknown 
____ 
____ 
Diabetes O Yes 
O No 
O Unknown 
____ 
____ 
High cholesterol O Yes 
O No 
O Unknown 
____ 
____ 
Other cardiovascular problem O Yes 
O No 
O Unknown 
____ 
____ 
  
 
 
 
 
Family member:  Grandmother (mother’s side) 
Cardiovascular problems 
Status 
Age at 
diagnosis  
 
Heart attack or angina O Yes 
O No 
O Unknown 
____ 
 
High blood pressure O Yes 
O No 
O Unknown 
____ 
 
Heart failure O Yes 
O No 
O Unknown 
____ 
 
Irregular heart beat O Yes 
O No 
O Unknown 
____ 
 
Problem with heart valve O Yes 
O No 
O Unknown 
____ 
 
Stroke O Yes 
O No 
O Unknown 
____ 
 
Diabetes O Yes 
O No 
O Unknown 
____ 
 
High cholesterol O Yes 
O No 
O Unknown 
____ 
 
Other cardiovascular problem O Yes 
O No 
O Unknown 
____ 
 
  
 
 
 
 
Family member:  Grandmother (father’s side) 
Cardiovascular problems 
Status 
Age at 
diagnosis  
 
Heart attack or angina O Yes 
O No 
O Unknown 
____ 
 
High blood pressure O Yes 
O No 
O Unknown 
____ 
 
Heart failure O Yes 
O No 
O Unknown 
____ 
 
Irregular heart beat O Yes 
O No 
O Unknown 
____ 
 
Problem with heart valve O Yes 
O No 
O Unknown 
____ 
 
Stroke O Yes 
O No 
O Unknown 
____ 
 
Diabetes O Yes 
O No 
O Unknown 
____ 
 
High cholesterol O Yes 
O No 
O Unknown 
____ 
 
Other cardiovascular problem O Yes 
O No 
O Unknown 
____ 
 
  
 
 
 
 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 78 
Family History of Cardiovascular Disease (continued) 
Family member:  Grandfather (mother’s side) 
Cardiovascular problems 
Status 
Age at 
diagnosis  
 
Heart attack or angina O Yes 
O No 
O Unknown 
____ 
 
High blood pressure O Yes 
O No 
O Unknown 
____ 
 
Heart failure O Yes 
O No 
O Unknown 
____ 
 
Irregular heart beat O Yes 
O No 
O Unknown 
____ 
 
Problem with heart valve O Yes 
O No 
O Unknown 
____ 
 
Stroke O Yes 
O No 
O Unknown 
____ 
 
Diabetes O Yes 
O No 
O Unknown 
____ 
 
High cholesterol O Yes 
O No 
O Unknown 
____ 
 
Other cardiovascular problem O Yes 
O No 
O Unknown 
____ 
 
  
 
 
 
 
Family member:  Grandfather (father’s side) 
Cardiovascular problems 
Status 
Age at 
diagnosis  
 
Heart attack or angina O Yes 
O No 
O Unknown 
____ 
 
High blood pressure O Yes 
O No 
O Unknown 
____ 
 
Heart failure O Yes 
O No 
O Unknown 
____ 
 
Irregular heart beat O Yes 
O No 
O Unknown 
____ 
 
Problem with heart valve O Yes 
O No 
O Unknown 
____ 
 
Stroke O Yes 
O No 
O Unknown 
____ 
 
Diabetes O Yes 
O No 
O Unknown 
____ 
 
High cholesterol O Yes 
O No 
O Unknown 
____ 
 
Other cardiovascular problem O Yes 
O No 
O Unknown 
____ 
 
 
 
 
 
 
 
Family member:  Aunt(s) (mother’s side)                    O I do not have any maternal aunts 
Cardiovascular problems 
Status 
Age at 
diagnosis  
If yes, how many 
affected?
Heart attack or angina O Yes 
O No 
O Unknown 
____ 
____ 
High blood pressure O Yes 
O No 
O Unknown 
____ 
____ 
Heart failure O Yes 
O No 
O Unknown 
____ 
____ 
Irregular heart beat O Yes 
O No 
O Unknown 
____ 
____ 
Problem with heart valve O Yes 
O No 
O Unknown 
____ 
____ 
Stroke O Yes 
O No 
O Unknown 
____ 
____ 
Diabetes O Yes 
O No 
O Unknown 
____ 
____ 
High cholesterol O Yes 
O No 
O Unknown 
____ 
____ 
Other cardiovascular problem O Yes 
O No 
O Unknown 
____ 
____ 
  
 
 
 
 
 
 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 79 
Family History of Cardiovascular Disease (continued) 
Family member:  Aunt(s) (father’s side)                    O I do not have any paternal aunts 
Cardiovascular problems 
Status 
Age at 
diagnosis  
If yes, how many 
affected?
Heart attack or angina O Yes 
O No 
O Unknown 
____ 
____ 
High blood pressure O Yes 
O No 
O Unknown 
____ 
____ 
Heart failure O Yes 
O No 
O Unknown 
____ 
____ 
Irregular heart beat O Yes 
O No 
O Unknown 
____ 
____ 
Problem with heart valve O Yes 
O No 
O Unknown 
____ 
____ 
Stroke O Yes 
O No 
O Unknown 
____ 
____ 
Diabetes O Yes 
O No 
O Unknown 
____ 
____ 
High cholesterol O Yes 
O No 
O Unknown 
____ 
____ 
Other cardiovascular problem O Yes 
O No 
O Unknown 
____ 
____ 
  
 
 
 
 
Family member:  Uncle(s) (mother’s side)                    O I do not have any maternal uncles 
Cardiovascular problems 
Status 
Age at 
diagnosis  
If yes, how many 
affected?
Heart attack or angina O Yes 
O No 
O Unknown 
____ 
____ 
High blood pressure O Yes 
O No 
O Unknown 
____ 
____ 
Heart failure O Yes 
O No 
O Unknown 
____ 
____ 
Irregular heart beat O Yes 
O No 
O Unknown 
____ 
____ 
Problem with heart valve O Yes 
O No 
O Unknown 
____ 
____ 
Stroke O Yes 
O No 
O Unknown 
____ 
____ 
Diabetes O Yes 
O No 
O Unknown 
____ 
____ 
High cholesterol O Yes 
O No 
O Unknown 
____ 
____ 
Other cardiovascular problem O Yes 
O No 
O Unknown 
____ 
____ 
  
 
 
 
 
 
Family member:  Uncle(s) (father’s side)                    O I do not have any paternal uncles 
Cardiovascular problems 
Status 
Age at 
diagnosis  
If yes, how many 
affected?
Heart attack or angina O Yes 
O No 
O Unknown 
____ 
____ 
High blood pressure O Yes 
O No 
O Unknown 
____ 
____ 
Heart failure O Yes 
O No 
O Unknown 
____ 
____ 
Irregular heart beat O Yes 
O No 
O Unknown 
____ 
____ 
Problem with heart valve O Yes 
O No 
O Unknown 
____ 
____ 
Stroke O Yes 
O No 
O Unknown 
____ 
____ 
Diabetes O Yes 
O No 
O Unknown 
____ 
____ 
High cholesterol O Yes 
O No 
O Unknown 
____ 
____ 
Other cardiovascular problem O Yes 
O No 
O Unknown 
____ 
____ 
  
 
 
 
 
 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 80 
Smoking, Drugs and Alcohol History 
 
1. Have you ever smoked? 
O No -  Skip to # 4. 
O Yes - Age when you first smoked:  _______ 
2. Do you currently smoke? 
O No - Age when you last smoked:  _______ 
O Yes 
3. If you are a current or former smoker, indicate for each age about how many cigarettes you 
smoked per day?  
 
Age 
Less than 1 per day  
or experimented only 
1 – 4 
5 – 14 
15 – 24 
25 – 34 
35 – 44 
45+ 
Age <15 
O 
O 
O 
O 
O 
O 
O 
Age 15-19 
O 
O 
O 
O 
O 
O 
O 
Age 20-29 
O 
O 
O 
O 
O 
O 
O 
Age 30-39 
O 
O 
O 
O 
O 
O 
O 
Age 40-49 
O 
O 
O 
O 
O 
O 
O 
Age 50-59 
O 
O 
O 
O 
O 
O 
O 
Age 60-69 
O 
O 
O 
O 
O 
O 
O 
Age 70-79 
O 
O 
O 
O 
O 
O 
O 
Age 80+ 
O 
O 
O 
O 
O 
O 
O 
 
4. Have you lived or worked in a place, or been in other places, where people around you 
smoked? 
 
 
No 
Yes 
If yes… 
for about how 
many years? 
are you currently in 
this place? 
Home  
O 
O 
_______ 
No O   Yes O 
Work 
O 
O 
_______ 
No O   Yes O 
Other places  O 
O 
_______ 
No O   Yes O 
 
If you answered “yes” to other places above, please specify the other place(s) below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Anthracycline-Related Cardiac Toxicity 
Protocol Chair:  Karen Smith, M.D., M.P.H. 
 
 
 
 
 
 
 
Version: November 21, 2016 (Amendment #9)   
Page 81 
5. During the past year how many alcoholic beverages did you have? 
 
Beverage 
Never or 
less than 
1 per 
month 
1-3 
per 
month 
1  
per 
week
2-4 
per 
week
5-6 
per 
week
1 
per 
day 
2-3 
per 
day 
4-5 
per 
day 
Beer  
(1 glass, 
bottle, can) 
O 
O 
O 
O 
O 
O 
O 
O 
Red wine  
(4 oz. glass) 
O 
O 
O 
O 
O 
O 
O 
O 
White wine  
(4 oz. glass) 
O 
O 
O 
O 
O 
O 
O 
O 
Liquor 
(1shot ) 
O 
O 
O 
O 
O 
O 
O 
O 
Other 
O 
O 
O 
O 
O 
O 
O 
O 
 
 
Physical Activity  
 
1. How many hours per week do you spend doing physical activity (walking, running, lap 
swimming, bicycling, and other sports)? 
________ hours 
 
2. How many hours per week do you spend sitting at work or at home using a computer, 
watching TV/VCR/DVD, or reading?  
 ________ hours