Cardio-Toxicity during chemotherapy: feasibility of new diagnostic approaches

doi:10.4236/health.2010.24056

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Vol.2, No.4, 376-380 (2010) Health

doi:10.4236/health.2010.24056

Cardio-Toxicity during chemotherapy: feasibility of new

diagnostic approaches

Fable Zustovich1, Mario Trivellato2, Renato Ceravolo1, Davide Pastorelli1, Rosanna Canton2,

Lorena Buratin2, Monica Mion3, Martina Zaninotto3, Martina Mattiazzi1, Mario Plebani3,

Giuseppe Cartei1

1Oncologia Medica 1° piano, IOV – IRCCS, Padova, Italy; fable.zustovich@ioveneto.it

2Servizio di Cardiologia ULSS16 c/o IRA, Padova, Italy

3Dipartimento di Medicina di Laboratorio, Università – Azienda Ospedaliera, Padova, Italy

Received 25 October 2009; revised 28 November 2009; accepted 5 December 2009.

ABSTRACT

Chemotherapy induced cardio-toxicity is a well

known side effect of anticancer treatments,

moreover the 70% of all tumors involve patients

over 65 years-old, frequently with cardiac co-

morbidity. We evaluated the feasibility of the

application during chemotherapy administration

of some of the most recent diagnostic tech-

niques as 12-diagnostic leads telemetry, 7 days

EKG monitoring device (R-Test Evolution 3R),

blood level dosage of Brain Natriuretic Peptide

(BNP) and Ischemia Modified Albumin (IMA).

Some sub-clinical changes in the investigated

parameters were found in patients undergoing

chemotherapy, mostly containing fluorouracil,

as shown in the following paper. Far from sug-

gesting a widespread use of these methods

during chemotherapy administration, we think

that some more tools are needed to prevent

cardiac toxicity in high-risk patients and some

of what we studied may deserve further valua-

tion in chemotherapy clinical trials.

Keywords: Cardio-Toxicity Diagnostic

1. INTRODUCTION

The rising percentage of older subjects among cancer

patients has led oncologists to manage chemotherapy

administration often dealing with severe concomitant

diseases, mostly cardiovascular.

Chemotherapy induced cardio-toxicity is a well known

side effect of anticancer treatment. Among the most cardio-

toxic a gents there are anthr acyclines, 5-fluor ouracil, t a x a n e s

and Trastuzumab. These agents may cause left ventricu-

lar dysfunction as well as arrhyth mias and/or ST-T wave

changes [1].

The evaluation of the cardiac safety during cardio

toxic chemotherapy is usually based on standard EKG,

EKG Holter and mostly using echo-color doppler car-

diography. All these methods reveal cardiac damage

when macroscopic morphological alterations have been

reached, thus when damage is already present and often

irreversible.

New methods of investigation are needed in attempt to

detect a subclinical damage and to prevent the symptomatic

cardiac failure. We evaluated the feasibility of some new

techniques planning prospective preliminary studies

monitoring patients undergoing potentially cardio toxic

chemotherapy with 12-diagnostic leads EKG telemetry

(TDLT), 7 days EKG monitoring dev ice (R-Test Evolution

3R), blood level dosages of Brain Natriuretic Peptide

(BNP) and Ischemia Modified Albumin (IMA).

2. TWELVE-DIAGNOSTIC LEADS TE-

LEMETRY (TDLT)

The TDLT monitors continuously 12 diagnostic leads

electrocardiogram and gives a real time analysis with

events comparing with basal reference.

The telemetry monitor (Mortara Rangoni Europe) had

the following characteristics: acquisition data amplifier

with analogue digital converter (ADC) = 20 bit; sam-

pling sample channel (SSC) = 10000 Hz; low significant

bit (LSB) = 1.2 microVolt; band with 0.05-100 Hz; te-

lemetry transmission = 2.4 GHz. The system has high

accuracy for arrhythmias and ischemia. Comparison

among different time events and ST movements histo-

grams with automatic continuous bit by bit data storage

were also available. Patients were allowed to walk dur-

ing TDLT.

We firstly studied prospectively some aspects of car-

diac toxicity in patients during gemcitabine chemother-

apy infusion for non-small cell lung cancer (NSCLC) [2].

Seventeen patients were evaluated, 12 male and 5 female,

F. Zustovich et al. / Health 2 (2010) 376-380

377

median age was 63 years (range 37-84) and ECOG

(Eastern Cooperative Oncology Group) performance

status was 0 in 12 patients and 1 in 5. Gemcitabine was

administrated in a 30 minute iv. infusion in normal saline

solution at the median dose of 1000 mg/m2 (range 500 -

1200 according to age) on day 1, 8 and 15 every 28 days.

Patients were monitored during the chemotherapy ad-

ministration.

At basal condition a single patient had ventricular ec-

topic beats (VEB) arrhythmias and another one had ab-

normal ST and T waves. During the Gemcitabine ad-

ministration 13 patients had EKG changes as su-

pra-ventricular ectopic beats (SVEB), aberrance, VEB,

fusion beats, multiform VEB and couplet as 4A grading.

Two patients had minimal changes of ST as a sign of

ischemia. Four patients did not develop arrhythmias and

1 of them was already in therapy with propafenone.

These prelimin ary data offered the chance of a much

skillfull control on asymptomatic cardiovascular toxic-

ity during chemotherapy and induced us to further in-

vestigation. With the same technique, we studied pa-

tients with colo-rectal cancer during the infusion of

folate modulated 5-fluorouracil [3]. Cardiac toxicity

due to 5-fluorouracil infusion is well known [4] and

standard EKG is most used evaluation method of car-

diac ischemia and/or arrhythmia. We enrolled 6 patients

with age respectively of 61, 61, 66, 66, 71 and 75 years

old, 3 were males and 3 females. All patients had

ECOG (Eastern Cooperative Oncology Group) per-

formance status of 0. All patients were receiving post-

operative adjuvant chemotherapy treatment (5 patients

receiving 5-fluorouracil 365 mg/m2 iv and 50 mg/m2 iv

days 1 to 5 every 28 days; 1 patient receiving weekly

5-fluorouracil 600 mg/m2 iv and folinic acid 100 mg/m2

iv). Four patients had normal basal EKG and 2 had

right bundle block. Patients were monitored during and

after the entire chemotherapy treatment. The following

EKG changes were found: QT lengthening in 2 patients,

VEB in 2 patients (1 also with a triplet), SVEB in 2

patients. One patient had no EKG changes. Then 5 out

of 6 healthy patients had asymptomatic EKG changes

sometimes relevant during adjuvant fluoro-folate based

chemotherapy after colorectal cancer operation.

3. SEVEN DAYS EKG MONITORING

DEVICE (R-TEST EVOLUTION 3R)

Patients undergoing chemotherapy with 5-fluorouracil in

protracted infusion were studied over a period of 7 days

using a 7-days monitoring by R-Test Evolution 3R

(Novacor), able of a real time EKG acquisition and

processing [5]. This device stored only significant events

with an acquisition system favoring also the CM5 lead

for excellent results in arrhythmia detection and ST

shifts measurements.

We enrolled 12 patients. Median age was 65 (range:

51-81), 8 patients were males and 4 were females. Nine

patients had gastric cancer and 3 had colorectal cancer.

Three patients were chemo-treated in the adjuvant set-

ting and 9 for advanced disease. Median ECOG per-

formance status was 1 (range 0-2). Patients received

5-fluorouracil in protracted infusion at the daily dose of

200 mg/m2. Soon after the 5-fluorouracil in protracted

infusion beginning we started a 7 days monitoring by

R-Test Evolution 3R.

The following EKG changes were found: supra-

ventricular tachyarrhythmia ranging among 110 and

187 bpm in 7 patients; SVEB in 1; sinus tachycardia in 2

patients; VEB in 4 patients (1 monomorphyc, 1 poli-

morphyc, 1 couplets and 1 polimorphyc couplets); ST

changes among 1 and 3 mm depression in 4 patients and

T waves changes in 2 patients. No patient complained

cardiac symptoms except one, having an angina-like

pain with sinusal tachycardia (110 bpm) without ST/T

wave changes.

These data shows that the majority of these patients

treated with 5-fluorouracil in protracted infusion had

asymptomatic EKG changes, sometimes relevant.

4. BRAIN NATRIURETIC PEPTIDE (BNP)

BNP is widely known as a serum marker of clinical and

sub-clinical heart failure [6]. To evaluate a potential

chemotherapy cardio-toxicity we focused on BNP values

obtained before and after chemotherapy infusion [7,8].

BNP, Troponin I (TI), Myoglobin (MY) dosage and

EKG were performed be fore and 5 hours after the end of

the chemotherapy infusion. BNP was evaluated using the

ADVIA-Centaur BNP method (Bayer Diagnostics,

Tarrytown, NY ).

Twenty-five consecutive patients with different solid

tumors undergoing different chemotherapy treatments

(mostly 5-Fluorouracil and gemcitabine) were enrolled.

Nineteen were males and 6 females, mean age was 62

years (range: 48-75). All patients had a baseline cardiac

echo-color Doppler and cardiologic evaluation. Mean

ejection fraction was 57% (range 52-72%). No prior

pathological cardiac conditions were recognized.

See results in Table 1 and Figure 1. One patient with

BNP over 2000 ng/L had a chronic renal fail ure in dialyti c

treatment. A statistically significant difference (one-tail

Student t-test p = 0.02) was found between the pre and

post chemotherapy BNP mean values of patients with a

normal basal BNP (< 100 ng/L). No changes were seen in

the pre and post chemotherapy means of TI and MY.

These data suggest BNP as a possible early bio-

marker of sub-clinical cardiac damage. Future studies

will evaluate a possible correlation between the observed

BNP increases and the possible subsequent clinically

F. Zustovich et al. / Health 2 (2010) 376-380

378

Table 1. Results of BNP valuation before and after chemo-

therapy administration.

All

PTS

(n = 25)

PTS with

BNP < 100 ng/L

(n = 19)

PTS with

BNP < 90 ng/L

(n=18)

Pre-

CHT Post-

CHT Pre-

CHT Post-

CHT Pre-

CHT Post-

CHT

BNP

mean 180.8 203.2 40.4 44.6 38.142.6

BNP

range 8.6-

2556.0 13.2-

2992.0 8.6-

99.0 7.4-

86.0 8.6-

82.0 7.4-

84.0

t-test P = 0.112 P = 0.02 P = 0.006

1.0

10.0

100.0

1000.0

1357911 1315 17 19 2123 25

PTS

BNP

pre-CHT

post-CHT

Figure 1. Graphic representation of BNP results before and

after chemotherapy administration.

evident cardio-toxicity in patients undergoing chemo-

therapy.

5. ISCHEMIA MODIFIED ALBUMIN (IMA)

IMA is an emerging biomarker of cardiac ischemia [9].

Moreover, cromogranine A (CRA) and Brain Natriuretic

Peptide (BNP) are reported to be possible ischemia

markers too [10,11]. We have already put on evidence as

a protracted 5-fluorouracil infusion may induce asymp-

tomatic relevant EKG changes in cancer patients, while

5-fluorouracil’s cardiotoxicity, ischemical in particular,

is well known.

We analysed IMA, troponin I (cTnI), Myoglobine

(MYO), CRA and BNP in 6 colorectal advanced cancer

patients [8]. Five patients were males and 1 female; age was

respectively of 64, 71, 71, 62, 67 and 63 years old. Bio-

markers valuation was performed before and 5 hours after

5-fluorouracil 400 mg/m2 iv. Bolus infusion and a con-

comitant monitoring by TDLT (see previous paragraph).

See Table 2 for results. Patient n. 1 had a chronic re-

nal failure in dialytic treatment and his basal EKG

showed sinusal rhythm with left ventricular hypertrophy

and strain. In the overall analysis IMA and BNP means

showed a slight increase while cTnI, MYO and CRA

means did not show a significant trend. In particular, we

noted that IMA increased in 3 PTS out of 6. At the EKG

monitoring all the patients showed only few VEB only

during the 5-fluorouracil bolus infusion without any

other significant changes.

Table 2. Results of IMA, BNP, Troponine I (cTnI), Cromogranine A (CRA), Myoglobine (MYO) evaluation before and after

chemotherapy administration.

IMA (< 85 U/mL) cTnI (< 0.15 ug/L) MYO (< 70 ug/L) CRA (2-18 U/L) BNP (< 100 ng/L)

PT t0 t1 t0 t1 t0 t1 t0 t1 t0 t1

1 110 117 0.20 0.18 77 85 > 562 > 562 2556.21 2992.01

2 94 107 0.06 0.03 88 68 12 9.8 8.57 13.20

3 84 83 0.02 0.04 35 29 7.4 4.4 58.24 68.78

4 102 91 0.00 0.00 28 21 4.8 6.1 41 55

5 83 86 0.00 0.01 56 64 8.6 11.7 40 34

6 95 125 0.00 0.00 25 20 16.9 12.7 23 23

Mean 94.667 101.500 0.047 0.043 51.500 47.833 9.940 8.940 454.503 530.998

F. Zustovich et al. / Health 2 (2010) 376-380

379

Thus, chemotherapy administration could induce as-

ymptomatic cardiac ischemia potentially detectable by

the new biomarker IMA.

6. DISCUSSIONS

Preliminary data obtained with TDLT in gemcitabine

treated patients showed something of usually missed

about asymptomatic cardiac effects of chemotherapy.

Further evaluation in patients treated with bolus of

5-fluorouracil protracted infusion for gastrointestinal dis-

eases, confirmed and enforced this observation showing

sometimes relevant asymptomatic EKG changes. On the

other hand R-Test Evolution 3 R allowed us to monitor

patients undergoing treatment with 5-Fluorouracil in

continuous infusion as adjuvant chemotherapy after sur-

gery colorectal cancer. The high incidence of sub clinical

cardiac effects were confirmed as 5 out of 6 healthy pa-

tients had relevant EKG changes as QT lengthening,

VEB and SVEB .

This data are might be of great impact if we consider

that 5-fluorouracil is a milestone in the treatment of gas-

trointestinal tumors. In our clinical practice, the avail-

ability of these techniques, especially TDLT, might al-

low us to administer 5-fluorouracil based chemotherapy

also to cardiac high-risk patients, otherwise excluded

from a potentially curative treatment. This issue might

be of a great impact if we consider the high prevalence

of colorectal cancers (147500 new cases in the USA in

the 2003 [12]) and that the cancer-related overall sur-

vival benefit obtained by 5-fluorouracil based adjuvant

chemotherapy is 74% of patients alive at 5 years vs. 63%

treated with surgery alone [13].

Evaluation of BNP and IMA before and after chemo-

therapy administration revealed their potential role as

early bio-marker of sub-clinical cardiac damage. In par-

ticular BNP reveals a myocardic contractile failure [6].

Drugs as anthracyclines are well known as cardiotoxic,

especially for the contractile function of the myocar-

dium. Anthracyclines are largely used in the oncological

practice as the milestone in the adjuvant treatment of

operated breast cancer and in the curative treatment of

lymphomas. Broeyer et al. [14] showed as patients re-

ceiving anthracyclines based chemotherapy had a sig-

nificant BNP elevation in comparison to a control popu-

lation and suggested that what observed was the expres-

sion of the toxic effect on the myocardium. Late cardiac

toxicity of these drugs is a very important issues in this

long term cancers survivors. BNP, other biomarkers or

modern EKG techniques, could be predictive of late car-

diac toxicity and could help to define a high risk subset of

patients eligible for a prophylactic administration of

cardio protectors as dexrazoxane or to the administration

of alternative antiblasti c drugs as liposom ial doxorubicin.

Indeed, we hope that future studies will evaluate a

possible correlation between the observed BNP increases

and the subsequent late evidence of cardio-toxicity in

patients undergoing cardio toxic chemotherapy. This

approach will define the possible predictive role of these

bio-marker.

7. CONCLUSIONS

The potential availability of new methods able to dis-

cover the cardiac damage in an early stage is meaningful.

We think that some new tools are needed in cardiac tox-

icity prevention and some of what we tested deserve

further evaluation in chemotherapy clinical trials.

Moreover, basing on modern monitoring instruments,

cardiac high-risk patients maybe safely candidate to a

chemotherapy treatm e nt otherwi se unmanageable.

8. ACKNOWLEDGEMENTS

To Dr. Cla ud io B ano for his gr ea t hel p in val uat in g telemetry EKG data .

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