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Bone Marrow Transplantation (2000) 25, 185–189
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Cardiac conduction abnormalities in patients with breast cancer
undergoing high-dose chemotherapy and stem cell transplantation
M Ando1, T Yokozawa1,2, J Sawada3, Y Takaue1, K Togitani1, N Kawahigashi1, M Narabayashi1,
K Takeyama1,2, R Tanosaki1, S Mineishi1, Y Kobayashi1, T Watanabe1, I Adachi1 and K Tobinai1
1
Department of Medical Oncology, National Cancer Center Hospital; and 3Cardiovascular Institute, Tokyo, Japan
Summary:
Cardiac toxicities in 39 consecutive patients with breast
cancer receiving high-dose chemotherapy (HDC) with
stem cell transplantation were reviewed. All 39 patients
received various anthracycline-containing regimens in
adjuvant settings and/or for metastatic disease before
HDC. As a cytoreductive regimen, all received cyclophosphamide 2000 mg/m2 and thiotepa 200 mg/m2 for
3 consecutive days. No immediate fatal toxicities were
observed, but one patient developed chronic congestive
heart failure and two had transient left ventricular dysfunction. Pericardial effusion was observed in another
three patients. ST-T abnormalities during HDC were
observed in two patients and arrhythmias were
observed in nine, four of which occurred during stem
cell infusion (SCI). There were three atrial arrhythmias,
two ventricular arrhythmias, and four atrioventricular
(AV)-block episodes. Two patients developed advanced
and complete AV-block with an asystolic pause.
Notably, three patients experienced AV-block with
uncontrolled vomiting. No relationship was observed
between the cumulative dose of anthracycline and cardiac toxicities during HDC. These results suggest that
abnormalities in the conduction system during HDC
may be more frequent than previously reported. Vagal
reflex secondary to emesis may play an important role
in the development of AV-block. Bone Marrow Transplantation (2000) 25, 185–189.
Keywords: high-dose chemotherapy; cyclophosphamide;
advanced atrioventricular block; cardiac complications
Cyclophosphamide (CY) is widely used in stem cell transplantation for its antineoplastic and myeloablative effects.
In addition to well-known complications including a syndrome of inappropriate anti-diuretic hormone secretion and
hemorrhagic cystitis, cardiac toxicity occurs at a high dose,
and includes transient changes on electrocardiogram
(ECG), arrhythmias, pericardial effusion, myocarditis and
Correspondence: Dr K Tobinai, Department of Medical Oncology,
National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan
2
Present address: First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan
Received 31 March 1999; accepted 27 July 1999
congestive heart failure (CHF). Cardiac toxicity caused by
CY is often fatal.1–9 The incidence of acute CHF was 17%
to 28% in patients who received CY for bone marrow transplantation (BMT),2–5,7 and this correlated with the dose of
CY administered per day.6,7 Concerning arrhythmias
induced by CY, supraventricular and ventricular origins
were commonly observed.8,9 However, high-grade heart
block has rarely been reported.10,11
In this study, we retrospectively reviewed our experience
of cardiac toxicities induced by high-dose chemotherapy
(HDC) including CY in patients with breast cancer. Our
review of this well-known complication by continuous
monitoring revealed a rather higher incidence of abnormalities in the conduction system.
Patients and methods
Patients and pretransplant consolidation chemotherapy
We reviewed the medical records of 39 consecutive patients
with breast cancer who received HDC consisting of CY and
thiotepa (TEPA) with stem cell support between March 1990
and August 1998. The median age of the 39 patients at HDC
was 46 years (range 25 to 57 years). All patients were histologically diagnosed as having breast cancer and were registered in clinical trials conducted by the Japan Clinical
Oncology Group (JCOG); 26 patients to JCOG 9006
(ABMT-BC protocol) for recurrent or metastatic disease,
eight to JCOG 9208 (HDC-BC protocol) for operable breast
cancer with more than 10 nodes on adjuvant settings, and
five to a pilot regimen for recurrent or metastatic disease.
All of the patients had received anthracycline derivatives
and 33 received CY for adjuvant chemotherapy and/or
metastatic disease before HDC. Eighteen of the 26 patients
who were treated in the JCOG 9006 study had received
induction chemotherapy consisting of 4-epidoxorubicin
(Epi) 130 mg/m2 and CY 1000 mg/m2 i.v. on day 1, to be
repeated every 3 weeks for four to six cycles with granulocyte colony-stimulating factor (G-CSF).12 Eight of the 26
patients received induction chemotherapy consisting of CY
500 mg/m2, doxorubicin (DOX) 40 mg/m2 and 5-fluorouracil 500 mg/m2, i.v. on day 1, every 3 weeks (CAF
regimen) given for six to eight cycles. The eight patients
entered into the JCOG 9208 study received adjuvant
chemotherapy with the CAF regimen for a total of six
cycles. The remaining five patients received induction
chemotherapy for recurrent or metastatic disease with a
Cardiac complications of high-dose chemotherapy
M Ando et al
186
combination of DOX 50 mg/m2 and docetaxel 50 mg/m2,
i.v. on day 1, every 2 weeks for four cycles with G-CSF
support. Six patients received regional radiation therapy
before HDC. All of the regimens and transplant procedures
were approved by the Institutional Review Board at the
National Cancer Center in Japan. The cumulative dose
of Epi was converted to that of DOX by the following
formula: DOX doses = 1/2 × Epi dose.
Collection of stem cells, high-dose chemotherapy and
transplantation procedure
The source of stem cells was peripheral blood stem cells
(PBSC) in 11 patients, bone marrow in 10, and PBSC plus
bone marrow in 18 patients. PBSC were collected during the
induction phase of chemotherapy after mobilization with GCSF. Stem cells were cryopreserved with the traditional controlled-rate method for cryopreservation using a Cryo-Med
programmed freezer, model 701 (Mt Clemens, MI, USA)
or with the alternate uncontrolled-rate freezing method. All
patients received the same cytoreductive regimen including
CY 2000 mg/m2 and TEPA 200 mg/m2 for 3 days (days −5,
−4, −3). Each drug was given over a 3-h infusion. Stem cell
infusion (SCI) was given on day 0, which was defined as 3
days after the last day of chemotherapy. In patients who
received both blood and marrow cells, the graft was divided
over 2-day infusions. In this case, the first day of infusion
was defined as day 0. Stored stem cells were thawed in a
37°C water bath and reinfused through a central venous catheter at a rate of approximately 10 to 20 ml/min, without
washing, as previously described.13
was observed in 28 patients, and grade 3 was seen in 11.
The median duration of emesis was 10 days (range 5–16).
Grade 2 infection was seen in 32 patients.
Chronic toxicities other than cardiotoxicity were as follows: varicella-zoster virus infection developed 1 to 6
months after HDC (n = 9); auto-immuno hemolytic anemia
4 months after HDC (n = 1); hemorrhagic cystitis 4 months
after HDC (n = 1); myelodysplastic syndrome 17 months
after HDC (n = 1).
Cardiac complications
A total of 16 patients experienced various cardiac complications, as summarized in Table 1. No patient who had
received radiation therapy before HDC showed cardiac
complications. Nine patients developed episodes of arrhythmias (atrial arrhythmias (n = 3), ventricular arrhythmias (n
= 2), or atrioventricular (AV)-blocks (n = 4)). Four episodes
were observed during SCI. Other cardiac complications
were as follows; abnormalities in ST-T (n = 2), asymptomatic pericardial effusion (n = 3), transient decrease in left
ventricular ejection fraction (LVEF) to less than 50% (n =
2), and reversible CHF (n = 1).
In those who developed cardiac complications, the median
cumulative doses of anthracycline derivatives and CY
administered before HDC were 300 mg/m2 (range 240–650
mg/m2) and 4500 mg/m2 (range 0–18000 mg/m2), respectively, which were not significantly different from those in
patients without cardiac complications (290 mg/m2 (range
200–650 mg/m2) and 4500 mg/m2 (range 0–18000 mg/m2),
respectively). The patients who developed advanced and
complete AV-block are described below in detail.
Supportive therapy and monitoring
Vigorous hydration of 4000–4500 ml/body/day with mesna
was started at day −5 to enforce alkaline diuresis for 3 days.
Patients routinely received daily antiemetics (granisetron
and/or steroid) before the start of CY and metoclopramide
or haloperidol was administered repeatedly to those with
severe emesis. G-CSF support following SCI was used in
all patients. Transfusions of red cells and platelets were
administered as clinically indicated.
Routine cardiac evaluation including 12-lead ECG and
echocardiograms was done prior to and after HDC, and at
discharge. This was also repeated as indicated. All patients
underwent 24-h ECG monitoring from the initiation of the
cytoreductive regimen until 2 h after SCI. With the development of cardiac complications, this monitoring was
continued as indicated.
Results
There was no transplant-related mortality and the median
number of days to achieve an absolute granulocyte count
of 0.5 × 109/l and a platelet count of 50 × 109/l was 10
(range 8–17) and 14 (range 8–52), respectively. Major nonhematologic toxicities were emesis, diarrhea and mucositis.
Grade 2 nausea and vomiting according to the toxicity criteria of the JCOG,14 a modified and expanded version of
the National Cancer Institute Common Toxicity Criteria,
Bone Marrow Transplantation
Case 1
Case 1 developed second-degree AV-block with a 2:1 conduction rate immediately following the infusion of TEPA
on day −5, with no associated episodes of nausea, vomiting
or loss of consciousness. An advanced AV-block with a 9s asystolic pause was observed 3 h after the first episode
(Figure 1). Since an onsite evaluation with a 12-lead ECG
and chest X-ray disclosed no abnormalities, the chemotherapeutic regimen was continued as scheduled. However, a
second episode of AV-block with a 7-s asystolic pause
occurred during the infusion of CY on day −4 and lasted
for 7 days despite treatment with isoproterenol (0.005
mg/kg/min). Nonetheless, the scheduled regimen was completed and thawed graft was infused on days 0 and 1, with
no immediate adverse events. She then recovered completely and an echocardiogram on the 10th day disclosed
normal regional wall motion. Repeated 24-h Holter ECG
monitoring performed 2 and 4 weeks after SCT showed no
abnormalities. She remained free of cardiac complications
for 20 months, at which point she died of metastatic
breast cancer.
Case 2
Case 2 developed severe nausea at the start of TEPA on
day −5, and was found to have second-degree AV-block,
which persisted intermittently until day −1, when advanced
Cardiac complications of high-dose chemotherapy
M Ando et al
Table 1
Case
187
Cardiac complications associated with high-dose chemotherapy of cyclophosphamide and thiotepa
Agea
Induction chemotherapy
Cumulative doseb
DOX
(mg/m2)
CY
(mg/m2)
1
36
CAF × 6 cycles
240
3000
2
46
DOX/DTX × 4 cycles
200
0
3
4
5
6
51
33
48
46
240
240
260
300
3500
3000
4000
4500
7
8
9
10
11
12
13
14
15
16
36
57
48
40
47
52
46
47
50
32
CAF × 7 cycles
CAF × 6 cycles
Epi/CY × 4 cycles
CAF × 1 cycle,
Epi/CY × 4 cycles
CAF × 6 cycles
CAF × 6 cycles
CAF × 6 cycles
DOX/CY × 18 cycles
Epi/CY × 6 cycles
Epi/CY × 6 cycles
Epi/CY × 5 cycles
DOX/DTX × 4 cycles
DOX/DTX × 4 cycles
Epi/CY × 5 cycles
240
240
340
650
630
390
445
440
440
325
3000
3000
3000
18000
9400
6000
7000
3000
3000
9000
Cardiac complications
During high-dose
chemotherapy
(the day of onset)
During
SCI
II advanced AV-block
(day − 5–2)
II advanced and complete
AV-block (day −5–4)
II SA-block (day −1)
EF ↓ (6 mo)
negative-T (day −4)
ST depression (day −3)
SVPC (day − 4)
VPC (day − 5)
VPC (day −4–2)
II AV-block (day − 5)
PAT (day −3)
Post transplantation
(duration between the onset
and SCI)
EF ↓ (5 mo)
CHF (9 mo)
SVPC
VPC
II Av-block (day −3–1)
pericardial effusion (1 mo)
pericardial effusion (1 mo)
pericardial effusion (1 mo)
AV-block = atrioventricular block; CAF, cyclophosphamide/doxorubicin/5-fluorouracil; DOX = doxorubicin; DTX = docetaxel; Epi = 4-epidoxorubicin;
PAT = paroxysmal atrial tachycardia; SA-block = sinoatrial block; SCI = stem cell infusion; SVPC = supraventricular premature contraction; VPC =
ventricular premature contraction.
All patients received CY, 2000 mg/m2/day and Thiotepa, 200 mg/m2/day for each of 3 days (day −5, −4, −3) and SCI was done on day 0.
a
Age at the treatment of SCI.
b
The cumulative dose which patients received before high-dose chemotherapy.
Anthracyclines converted into DOX as follows (mg/m2); epirubicin/2.
/S 19:22 RR:11
ST;D.O
STOLE 25mm/s
KOHDEN
K25231
Figure 1 ECG monitoring recorded on day −5 showing advanced atrioventricular (AV)-block with a 9-s asystolic pause.
and complete AV-block with an 11-s asystolic pause
developed with a transient loss of consciousness (Figure 2a
and b). There was no evidence of heart failure and no
change in the ST-T wave was observed in a 12-lead ECG.
After continuous infusion of isoproterenol (0.005
mg/kg/min), she had not experienced complete block, but
second-degree AV-block with emesis had been observed
intermittently. SCI was given on day 0 with no exacerbation of the AV-block. On day 3, she experienced transient
sinus tachycardia. Therefore, infusion of isoproterenol was
stopped immediately. Second-degree AV-block then
developed following uncontrolled vomiting, which gradually decreased in frequency. Echocardiogram taken on the
14th day disclosed normal regional wall motion. However,
in an electrophysiologic study performed 1 month later, AV
nodal re-entrant tachycardia (AVNRT) was induced by
electrical pacing. Administration of adenosine triphosphate
(ATP) terminated tachycardia and repetitive complete AVblock was observed. After catheter ablation, AVNRT was
no longer induced by pacing. 24-h Holter ECG monitoring
performed 1 and 4 months after SCT showed no abnormalities. She was free of palpitation and loss of consciousness
at 8 months after HDC.
Discussion
Anthracycline is one of the most active agents for the treatment of breast cancer,15 while its adverse effects include
cumulative cardiotoxicities.16,17 In our study, most patients
had received previous chemotherapy with anthracyclines
and CY, while there were no significant differences in
cumulative doses of anthracycline derivatives and CY
administered before HDC between patients with or without
cardiotoxicity. Three patients in our series had asymptomatic pericardial effusions and two of them received induction therapy including doxorubicin and docetaxel. Fluid
retention characteristic of docetaxel is manifested in the
Bone Marrow Transplantation
Cardiac complications of high-dose chemotherapy
M Ando et al
188
Figure 2 (a) ECG monitoring on day −1 showing first-degree and advanced AV-block. The PR interval was prolonged to 0.32 s. An advanced AVblock with escape beats followed first-degree block. (b) The event shown in (a) progressed to complete AV-block with an 11-s asystolic pause associated
with AV junctional beats and a loss of consciousness, which was induced by vomiting.
form of peripheral edema, while the occurrence of pleural
effusion or pericardial effusion is less common.18 One of
the two patients with pericardial effusion which developed
after HDC had had mild peripheral edema after induction
therapy, although no pericardial effusion was detected
before HDC. Thus, this may suggest that fluid retention was
further enhanced by high-dose CY or vigorous hydration
during HDC.
Continuous and routine monitoring of arrhythmias following HDC and SCI is rarely recommended, possibly
because of the undefined cost/benefit ratio and the difficulty
of managing patients with myelosuppression after HDC. It
has been reported that the frequencies of atrial and ventricular arrhythmias in patients during HDC using high-dose CY
were 7.9%8 and 10%,9 respectively. Sinus bradycardia,
which commonly lasted for a few hours, was frequently
observed during or after the transfusion of cryopreserved
stem cells. Additionally, heart block after SCI caused by
dimethylsulfoxide (DMSO) has been well described.19–21 In
one study, four of the 41 patients showed high-grade heart
Bone Marrow Transplantation
block, and two of these developed third-degree block after
SCI which lasted for 12 to 24 h.19
Nevertheless, there have been rare reports of high-grade
heart block after SCI. One reported case experienced
advanced heart block after high-dose CY and etoposide,10
while in the other complete heart block was induced by CY
and TEPA.11 These blocks developed a few days after the
beginning of HDC, although they were transient in nature.
Both patients had a transient loss of consciousness and
required pacemaker implantation for treatment.
There are many factors which could potentially lead to
arrhythmias in HDC. Damage to the myocardium and/or
conduction system induced by chemotherapeutic agents is
an important etiological mechanism. Additionally, the concomitant presence of vagal reflex induced by emesis, volume overload by hydration, electrolyte abnormalities, infections and anti-emetic drugs may contribute to the
development of this complication. In our cases with highgrade AV-block (cases 1 and 2), they experienced their first
episode of second-degree AV-block a few hours after start-
Cardiac complications of high-dose chemotherapy
M Ando et al
ing HDC. Particularly, case 2 showed AV-block along with
intense and uncontrolled nausea and vomiting during HDC,
which lasted beyond 7 days. Hence, we emphasize that
vagal stimulation induced by emesis enhances reversible
damage to the conduction system induced by HDC. Therefore, we believe that efforts to prevent emesis and continuous monitoring of ECG should become important parts of
the transplant procedure.
We speculated that a possible etiology of heart block is
physical damage to the conduction system secondary to
microangiopathy or transient spasms caused by CY-induced
injury of the capillary endothelium.3,22 In case 2, repetitive
complete AV-block was induced by ATP in an electrophysiologic study performed after HDC. This finding suggested
the presence of damage in the atrioventricular conduction
system, although no abnormalities were documented by
Holter ECG monitoring after HDC. Vagal stimulation
might enhance any reversible damage of the conduction
system induced by HDC, which could develop into
advanced and complete AV-block. To our knowledge, such
a complication has not been reported with TEPA. The incidences of severe arrhythmias are not so frequent in the previous reports and the outcome in patients treated with highdose chemotherapy appears satisfactory without continuous
ECG-monitoring during HDC.
In conclusion, 16 of 39 patients with breast cancer
developed cardiac toxicities when treated with HDC including CY and TEPA. Although no fatalities occurred, four
patients showed a transient AV-block and two of them
developed advanced and complete block. In three cases, the
heart block appeared to be triggered and exaggerated by
intense emesis. More effective prevention of emesis during
HDC and SCI is warranted.
5
6
7
8
9
10
11
12
13
14
15
Acknowledgements
16
We thank Akio Kohno, Takuya Fukushima, MD, and the nursing
staff of the National Cancer Center Hospital for their excellent
care of patients undergoing HDC. This work was supported in
part by Grants-in-Aid for Cancer Research (2S-1, 5S-1, and
8S-1) from the Ministry of Health and Welfare of Japan.
17
18
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