Bone Marrow Transplantation (2000) 25, 185–189  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt 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

1Department of Medical Oncology, National Cancer Center Hospital; and 3Cardiovascular Institute, Tokyo, Japan

Summary: congestive failure (CHF). Cardiac toxicity caused by CY is often fatal.1–9 The incidence of acute CHF was 17% Cardiac toxicities in 39 consecutive patients with breast to 28% in patients who received CY for bone marrow trans- cancer receiving high-dose chemotherapy (HDC) with plantation (BMT),2–5,7 and this correlated with the dose of stem cell transplantation were reviewed. All 39 patients CY administered per day.6,7 Concerning received various anthracycline-containing regimens in induced by CY, supraventricular and ventricular origins adjuvant settings and/or for metastatic disease before were commonly observed.8,9 However, high-grade heart HDC. As a cytoreductive regimen, all received cyclo- block has rarely been reported.10,11 phosphamide 2000 mg/m2 and thiotepa 200 mg/m2 for In this study, we retrospectively reviewed our experience 3 consecutive days. No immediate fatal toxicities were of cardiac toxicities induced by high-dose chemotherapy observed, but one patient developed chronic congestive (HDC) including CY in patients with breast cancer. Our and two had transient left ventricular dys- review of this well-known complication by continuous function. was observed in another monitoring revealed a rather higher incidence of abnormali- three patients. ST-T abnormalities during HDC were ties in the conduction system. observed in two patients and arrhythmias were observed in nine, four of which occurred during stem cell infusion (SCI). There were three atrial arrhythmias, Patients and methods two ventricular arrhythmias, and four atrioventricular (AV)-block episodes. Two patients developed advanced Patients and pretransplant consolidation chemotherapy and complete AV-block with an asystolic pause. Notably, three patients experienced AV-block with We reviewed the medical records of 39 consecutive patients uncontrolled vomiting. No relationship was observed with breast cancer who received HDC consisting of CY and between the cumulative dose of anthracycline and car- thiotepa (TEPA) with stem cell support between March 1990 diac toxicities during HDC. These results suggest that and August 1998. The median age of the 39 patients at HDC abnormalities in the conduction system during HDC was 46 years (range 25 to 57 years). All patients were histo- may be more frequent than previously reported. Vagal logically diagnosed as having breast cancer and were regis- reflex secondary to emesis may play an important role tered in clinical trials conducted by the Japan Clinical in the development of AV-block. Bone Marrow Trans- Oncology Group (JCOG); 26 patients to JCOG 9006 plantation (2000) 25, 185–189. (ABMT-BC protocol) for recurrent or metastatic disease, Keywords: high-dose chemotherapy; cyclophosphamide; eight to JCOG 9208 (HDC-BC protocol) for operable breast advanced ; cardiac complications 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 Cyclophosphamide (CY) is widely used in stem cell trans- metastatic disease before HDC. Eighteen of the 26 patients plantation for its antineoplastic and myeloablative effects. who were treated in the JCOG 9006 study had received In addition to well-known complications including a syn- induction chemotherapy consisting of 4-epidoxorubicin drome of inappropriate anti-diuretic hormone secretion and (Epi) 130 mg/m2 and CY 1000 mg/m2 i.v. on day 1, to be hemorrhagic cystitis, cardiac toxicity occurs at a high dose, repeated every 3 weeks for four to six cycles with granulo- and includes transient changes on electrocardiogram cyte colony-stimulating factor (G-CSF).12 Eight of the 26 (ECG), arrhythmias, pericardial effusion, and patients received induction chemotherapy consisting of CY 500 mg/m2, doxorubicin (DOX) 40 mg/m2 and 5-fluorour- acil 500 mg/m2, i.v. on day 1, every 3 weeks (CAF Correspondence: Dr K Tobinai, Department of Medical Oncology, regimen) given for six to eight cycles. The eight patients National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104- entered into the JCOG 9208 study received adjuvant 0045, Japan 2Present address: First Department of Internal Medicine, Nagoya Univer- chemotherapy with the CAF regimen for a total of six sity School of Medicine, Nagoya, Japan cycles. The remaining five patients received induction Received 31 March 1999; accepted 27 July 1999 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, was observed in 28 patients, and grade 3 was seen in 11. i.v. on day 1, every 2 weeks for four cycles with G-CSF The median duration of emesis was 10 days (range 5–16). support. Six patients received regional radiation therapy Grade 2 infection was seen in 32 patients. before HDC. All of the regimens and transplant procedures Chronic toxicities other than cardiotoxicity were as fol- were approved by the Institutional Review Board at the lows: varicella-zoster virus infection developed 1 to 6 National Cancer Center in Japan. The cumulative dose months after HDC (n = 9); auto-immuno hemolytic anemia of Epi was converted to that of DOX by the following 4 months after HDC (n = 1); hemorrhagic cystitis 4 months formula: DOX doses = 1/2 × Epi dose. after HDC (n = 1); myelodysplastic syndrome 17 months after HDC (n = 1). Collection of stem cells, high-dose chemotherapy and transplantation procedure Cardiac complications The source of stem cells was peripheral blood stem cells A total of 16 patients experienced various cardiac compli- (PBSC) in 11 patients, bone marrow in 10, and PBSC plus cations, as summarized in Table 1. No patient who had bone marrow in 18 patients. PBSC were collected during the received radiation therapy before HDC showed cardiac induction phase of chemotherapy after mobilization with G- complications. Nine patients developed episodes of arrhyth- CSF. Stem cells were cryopreserved with the traditional con- mias (atrial arrhythmias (n = 3), ventricular arrhythmias (n trolled-rate method for cryopreservation using a Cryo-Med = 2), or atrioventricular (AV)-blocks (n = 4)). Four episodes programmed freezer, model 701 (Mt Clemens, MI, USA) were observed during SCI. Other cardiac complications or with the alternate uncontrolled-rate freezing method. All were as follows; abnormalities in ST-T (n = 2), asymptom- patients received the same cytoreductive regimen including atic pericardial effusion (n = 3), transient decrease in left CY 2000 mg/m2 and TEPA 200 mg/m2 for 3 days (days −5, ventricular ejection fraction (LVEF) to less than 50% (n = −4, −3). Each drug was given over a 3-h infusion. Stem cell 2), and reversible CHF (n = 1). infusion (SCI) was given on day 0, which was defined as 3 In those who developed cardiac complications, the median days after the last day of chemotherapy. In patients who cumulative doses of anthracycline derivatives and CY received both blood and marrow cells, the graft was divided administered before HDC were 300 mg/m2 (range 240–650 over 2-day infusions. In this case, the first day of infusion mg/m2) and 4500 mg/m2 (range 0–18000 mg/m2), respect- was defined as day 0. Stored stem cells were thawed in a ively, which were not significantly different from those in 37°C water bath and reinfused through a central venous cath- patients without cardiac complications (290 mg/m2 (range eter at a rate of approximately 10 to 20 ml/min, without 200–650 mg/m2) and 4500 mg/m2 (range 0–18000 mg/m2), washing, as previously described.13 respectively). The patients who developed advanced and complete AV-block are described below in detail. Supportive therapy and monitoring Case 1 Vigorous hydration of 4000–4500 ml/body/day with mesna was started at day −5 to enforce alkaline diuresis for 3 days. Case 1 developed second-degree AV-block with a 2:1 con- Patients routinely received daily antiemetics (granisetron duction rate immediately following the infusion of TEPA and/or steroid) before the start of CY and metoclopramide on day −5, with no associated episodes of nausea, vomiting or haloperidol was administered repeatedly to those with or loss of consciousness. An advanced AV-block with a 9- severe emesis. G-CSF support following SCI was used in s asystolic pause was observed 3 h after the first episode all patients. Transfusions of red cells and platelets were (Figure 1). Since an onsite evaluation with a 12-lead ECG administered as clinically indicated. and chest X-ray disclosed no abnormalities, the chemother- Routine cardiac evaluation including 12-lead ECG and apeutic regimen was continued as scheduled. However, a echocardiograms was done prior to and after HDC, and at second episode of AV-block with a 7-s asystolic pause discharge. This was also repeated as indicated. All patients occurred during the infusion of CY on day −4 and lasted underwent 24-h ECG monitoring from the initiation of the for 7 days despite treatment with isoproterenol (0.005 cytoreductive regimen until 2 h after SCI. With the devel- mg/kg/min). Nonetheless, the scheduled regimen was com- opment of cardiac complications, this monitoring was pleted and thawed graft was infused on days 0 and 1, with continued as indicated. no immediate adverse events. She then recovered com- pletely and an echocardiogram on the 10th day disclosed normal regional wall motion. Repeated 24-h Holter ECG Results monitoring performed 2 and 4 weeks after SCT showed no abnormalities. She remained free of cardiac complications There was no transplant-related mortality and the median for 20 months, at which point she died of metastatic number of days to achieve an absolute granulocyte count breast cancer. 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 non- Case 2 hematologic toxicities were emesis, diarrhea and mucositis. Grade 2 nausea and vomiting according to the toxicity cri- Case 2 developed severe nausea at the start of TEPA on teria of the JCOG,14 a modified and expanded version of day −5, and was found to have second-degree AV-block, the National Cancer Institute Common Toxicity Criteria, which persisted intermittently until day −1, when advanced

Bone Marrow Transplantation Cardiac complications of high-dose chemotherapy M Ando et al 187 Table 1 Cardiac complications associated with high-dose chemotherapy of cyclophosphamide and thiotepa

Case Agea Induction chemotherapy Cumulative doseb Cardiac complications

DOX CY During high-dose During Post transplantation (mg/m2) (mg/m2) chemotherapy SCI (duration between the onset (the day of onset) and SCI)

1 36 CAF × 6 cycles 240 3000 II advanced AV-block (day − 5–2) 2 46 DOX/DTX × 4 cycles 200 0 II advanced and complete AV-block (day −5–4) 3 51 CAF × 7 cycles 240 3500 II SA-block (day −1) 4 33 CAF × 6 cycles 240 3000 EF ↓ (6 mo) 5 48 Epi/CY × 4 cycles 260 4000 negative-T (day −4) 6 46 CAF × 1 cycle, 300 4500 EF ↓ (5 mo) Epi/CY × 4 cycles 7 36 CAF × 6 cycles 240 3000 ST depression (day −3) CHF (9 mo) 8 57 CAF × 6 cycles 240 3000 SVPC (day − 4) SVPC 9 48 CAF × 6 cycles 340 3000 VPC (day − 5) 10 40 DOX/CY × 18 cycles 650 18000 VPC (day −4–2) 11 47 Epi/CY × 6 cycles 630 9400 II AV-block (day − 5) 12 52 Epi/CY × 6 cycles 390 6000 PAT (day −3) 13 46 Epi/CY × 5 cycles 445 7000 VPC 14 47 DOX/DTX × 4 cycles 440 3000 pericardial effusion (1 mo) 15 50 DOX/DTX × 4 cycles 440 3000 II Av-block (day −3–1) pericardial effusion (1 mo) 16 32 Epi/CY × 5 cycles 325 9000 pericardial effusion (1 mo)

AV-block = atrioventricular block; CAF, cyclophosphamide/doxorubicin/5-fluorouracil; DOX = doxorubicin; DTX = docetaxel; Epi = 4-epidoxorubicin; PAT = paroxysmal atrial ; 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. aAge at the treatment of SCI. bThe 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 no longer induced by pacing. 24-h Holter ECG monitoring developed with a transient loss of consciousness (Figure 2a performed 1 and 4 months after SCT showed no abnormali- and b). There was no evidence of heart failure and no ties. She was free of palpitation and loss of consciousness change in the ST-T wave was observed in a 12-lead ECG. at 8 months after HDC. 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 Discussion intermittently. SCI was given on day 0 with no exacer- bation of the AV-block. On day 3, she experienced transient Anthracycline is one of the most active agents for the treat- . Therefore, infusion of isoproterenol was ment of breast cancer,15 while its adverse effects include stopped immediately. Second-degree AV-block then cumulative cardiotoxicities.16,17 In our study, most patients developed following uncontrolled vomiting, which gradu- had received previous chemotherapy with anthracyclines ally decreased in frequency. Echocardiogram taken on the and CY, while there were no significant differences in 14th day disclosed normal regional wall motion. However, cumulative doses of anthracycline derivatives and CY in an electrophysiologic study performed 1 month later, AV administered before HDC between patients with or without nodal re-entrant tachycardia (AVNRT) was induced by cardiotoxicity. Three patients in our series had asympto- electrical pacing. Administration of adenosine triphosphate matic pericardial effusions and two of them received induc- (ATP) terminated tachycardia and repetitive complete AV- tion therapy including doxorubicin and docetaxel. Fluid block was observed. After catheter ablation, AVNRT was 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 AV- block 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 block, and two of these developed third-degree block after effusion or pericardial effusion is less common.18 One of SCI which lasted for 12 to 24 h.19 the two patients with pericardial effusion which developed Nevertheless, there have been rare reports of high-grade after HDC had had mild peripheral edema after induction after SCI. One reported case experienced therapy, although no pericardial effusion was detected advanced heart block after high-dose CY and etoposide,10 before HDC. Thus, this may suggest that fluid retention was while in the other complete heart block was induced by CY further enhanced by high-dose CY or vigorous hydration and TEPA.11 These blocks developed a few days after the during HDC. beginning of HDC, although they were transient in nature. Continuous and routine monitoring of arrhythmias fol- Both patients had a transient loss of consciousness and lowing HDC and SCI is rarely recommended, possibly required pacemaker implantation for treatment. because of the undefined cost/benefit ratio and the difficulty There are many factors which could potentially lead to of managing patients with myelosuppression after HDC. It arrhythmias in HDC. Damage to the myocardium and/or has been reported that the frequencies of atrial and ventricu- conduction system induced by chemotherapeutic agents is lar arrhythmias in patients during HDC using high-dose CY an important etiological mechanism. Additionally, the con- were 7.9%8 and 10%,9 respectively. Sinus , comitant presence of vagal reflex induced by emesis, vol- which commonly lasted for a few hours, was frequently ume overload by hydration, electrolyte abnormalities, infec- observed during or after the transfusion of cryopreserved tions and anti-emetic drugs may contribute to the stem cells. Additionally, heart block after SCI caused by development of this complication. In our cases with high- dimethylsulfoxide (DMSO) has been well described.19–21 In grade AV-block (cases 1 and 2), they experienced their first one study, four of the 41 patients showed high-grade heart episode of second-degree AV-block a few hours after start-

Bone Marrow Transplantation Cardiac complications of high-dose chemotherapy M Ando et al 189 ing HDC. Particularly, case 2 showed AV-block along with changes with cyclophosphamide. Med Ped Oncol 1986; 9: intense and uncontrolled nausea and vomiting during HDC, 417–422. which lasted beyond 7 days. Hence, we emphasize that 5 Allen A. The cardiotoxicity of chemotherapeutic drugs. Semin vagal stimulation induced by emesis enhances reversible Oncol 1995; 19: 529–542. damage to the conduction system induced by HDC. There- 6 Goldberg MA, Antin JH, Guinan EC et al. Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor. Blood fore, we believe that efforts to prevent emesis and continu- 1986; 68: 1114–1118. ous monitoring of ECG should become important parts of 7 Braverman AC, Antin JH, Plappert MT et al. Cyclophospham- the transplant procedure. ide cardiotoxicity in bone marrow transplantation: a prospec- We speculated that a possible etiology of heart block is tive evaluation of new dosing regimens. J Clin Oncol 1991; physical damage to the conduction system secondary to 9: 1215–1223. microangiopathy or transient spasms caused by CY-induced 8 Cazin B, Gorin NC, Laporte JP et al. Cardiac complications injury of the capillary endothelium.3,22 In case 2, repetitive after bone marrow transplantation: a report on a series of 63 complete AV-block was induced by ATP in an electrophy- consecutive transplantations. Cancer 1986; 57: 2061–2069. siologic study performed after HDC. This finding suggested 9 Kupari M, Volin L, Suokas A et al. Cardiac involvement in the presence of damage in the atrioventricular conduction bone marrow transplantation: electrocardiographic changes, arrhythmias, heart failure and autopsy findings. Bone Marrow system, although no abnormalities were documented by Transplant 1990; 5: 91–98. Holter ECG monitoring after HDC. Vagal stimulation 10 Sculier JP, Coune A, Klastersky J. Transient heart block an might enhance any reversible damage of the conduction unreported toxicity of high dose chemotherapy with cyclopho- system induced by HDC, which could develop into sphamide and etoposide. Acta Clin Belg 1985; 40: 112–114. advanced and complete AV-block. To our knowledge, such 11 Ramireddy K, Kane KM, Adhar GC. Acquired episodic com- a complication has not been reported with TEPA. The inci- plete heart block after high-dose chemotherapy with cyclopho- dences of severe arrhythmias are not so frequent in the pre- sphamide and thiotepa. Am Heart J 1994; 127: 701–704. vious reports and the outcome in patients treated with high- 12 Takashima S, Saeki T, Adachi I et al. A phase II study of dose chemotherapy appears satisfactory without continuous high-dose epirubicin (EPI) plus cyclophosphamide (CPA) ECG-monitoring during HDC. with G-CSF for breast cancer patients with visceral metastases or hormone-independent tumors: a trial of the Japan Clinical In conclusion, 16 of 39 patients with breast cancer Oncology Group. Jpn J Clin Oncol 1997; 27: 325–330. developed cardiac toxicities when treated with HDC includ- 13 Kohno A, Takeyama K, Narabayashi M et al. Low-dose gra- ing CY and TEPA. Although no fatalities occurred, four nulocyte colony-stimulating factor enables the efficient collec- patients showed a transient AV-block and two of them tion of peripheral blood stem cells after disease-oriented, con- developed advanced and complete block. In three cases, the ventional-dose chemotherapy for breast cancer, malignant heart block appeared to be triggered and exaggerated by lymphoma and germ cell tumor. Bone Marrow Transplant intense emesis. 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