Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 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 References 19 1 Buckner CD, Randolph RA, Fefer A et al. High-dose cyclophosphamide therapy for malignant disease: toxicity tumor response and the effects of stirred autologous marrow. Cancer 1972; 29: 357–365. 2 Appelbaum FR, Straychen JA, Graw RG et al. Acute lethal carditis caused by high-dose combination chemotherapy. A unique clinical and pathological entity. Lancet 1976; 1: 58–62. 3 Gottdiener JS, Appelbaum FR, Ferrans VJ et al. Cardiotoxicity associated with high-dose cyclophosphamide therapy. Arch Intern Med 1981; 141: 758–763. 4 Steinherz LJ, Steinherz PG, Mangiacasale D et al. Cardiac 20 21 22 changes with cyclophosphamide. Med Ped Oncol 1986; 9: 417–422. Allen A. The cardiotoxicity of chemotherapeutic drugs. Semin Oncol 1995; 19: 529–542. Goldberg MA, Antin JH, Guinan EC et al. Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor. Blood 1986; 68: 1114–1118. Braverman AC, Antin JH, Plappert MT et al. Cyclophosphamide cardiotoxicity in bone marrow transplantation: a prospective evaluation of new dosing regimens. J Clin Oncol 1991; 9: 1215–1223. Cazin B, Gorin NC, Laporte JP et al. Cardiac complications after bone marrow transplantation: a report on a series of 63 consecutive transplantations. Cancer 1986; 57: 2061–2069. Kupari M, Volin L, Suokas A et al. Cardiac involvement in bone marrow transplantation: electrocardiographic changes, arrhythmias, heart failure and autopsy findings. Bone Marrow Transplant 1990; 5: 91–98. Sculier JP, Coune A, Klastersky J. Transient heart block an unreported toxicity of high dose chemotherapy with cyclophosphamide and etoposide. Acta Clin Belg 1985; 40: 112–114. Ramireddy K, Kane KM, Adhar GC. Acquired episodic complete heart block after high-dose chemotherapy with cyclophosphamide and thiotepa. Am Heart J 1994; 127: 701–704. Takashima S, Saeki T, Adachi I et al. A phase II study of high-dose epirubicin (EPI) plus cyclophosphamide (CPA) with G-CSF for breast cancer patients with visceral metastases or hormone-independent tumors: a trial of the Japan Clinical Oncology Group. Jpn J Clin Oncol 1997; 27: 325–330. Kohno A, Takeyama K, Narabayashi M et al. Low-dose granulocyte colony-stimulating factor enables the efficient collection of peripheral blood stem cells after disease-oriented, conventional-dose chemotherapy for breast cancer, malignant lymphoma and germ cell tumor. Bone Marrow Transplant 1995; 15: 49–54. Tobinai K, Kohno A, Shimada Y et al. Toxicity grading criteria of the Japanese Clinical Oncology Group. Jpn J Clin Oncol 1993; 23: 250–257. Hortobagyi GN. Drug therapy: treatment of breast cancer. New Engl J Med 1998; 339: 974–984. Taylor AL, Applefeld MM, Wiernik PH et al. Acute anthracycline cardiotoxicity: comparative morphologic study of three analogues. Cancer 1984; 53: 1660–1666. Von Hoff DD, Layard MW, Basa P et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979; 91: 710–719. Semb KA, Aamdal S, Oian P. Capillary protein leak syndrome appears to explain fluid retention in cancer patients who receive docetaxel treatment. J Clin Oncol 1998; 16: 3426– 3432. Davis JM, Rowly SD, Braine HG et al. Clinical toxicity of cryopreserved bone marrow graft infusion. Blood 1990; 75: 781–786. Styler MJ, Topolsky DL, Crilley PA et al. Transient highgrade block following autologous bone marrow infusion. Bone Marrow Transplant 1992; 10: 435–438. Keung YK, Lau S, Elkayam U et al. Cardiac arrhythmia after infusion of cryopreserved stem cells. Bone Marrow Transplant 1994; 14: 363–372. Hopkins HA, Betsill WL, Hobson AS et al. Cyclophosphamide-induced cardiomyopathy in the rat. Cancer Treat Rep 1982; 66: 1521–1527. 189 Bone Marrow Transplantation