Vol.2, No.4, 376-380 (2010) Health
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
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.
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
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
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).
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
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
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-
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.
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.
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
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Table 1. Results of BNP valuation before and after chemo-
therapy administration.
(n = 25)
PTS with
BNP < 100 ng/L
(n = 19)
PTS with
BNP < 90 ng/L
CHT Post-
CHT Pre-
CHT Post-
CHT Pre-
CHT Post-
mean 180.8 203.2 40.4 44.6 38.142.6
range 8.6-
2556.0 13.2-
2992.0 8.6-
99.0 7.4-
86.0 8.6-
82.0 7.4-
t-test P = 0.112 P = 0.02 P = 0.006
1357911 1315 17 19 2123 25
Figure 1. Graphic representation of BNP results before and
after chemotherapy administration.
evident cardio-toxicity in patients undergoing chemo-
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
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Thus, chemotherapy administration could induce as-
ymptomatic cardiac ischemia potentially detectable by
the new biomarker IMA.
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
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.
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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