Introduction of high-dose (HD) chemotherapy followed by hematopoietic stem cell (HSC) transplantation has improved the clinical outcome for selected groups of patients with chemosensitive tumors, such as non–Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, leukemias, breast cancer and germ cell tumors.1,2 Moreover, HD melphalan and HD cyclophosphamide have been successfully used to treat primary amyloidosis3 and autoimmune diseases,4,5 respectively. Finally, in the last few years reduced-intensity conditioning regimens have been applied to patients undergoing allogeneic HSC transplantation to reduce drug toxicity while maintaining the potential for achieving disease remission exploiting the graft-versus-leukemia effect.6 Cardiac complications have been documented in several series, with reported incidence varying among investigators from 04,5,7,8,9 to 43%,10 and mortality up to 9%10 in earlier studies. Although HD chemotherapy-associated cardiac toxicity has become less common in recent years using current preparative regimens, high incidence of severe cardiac toxicity, including toxic death, is still being reported in some series.
Despite thousands of patients having been treated, pharmacokinetic/dynamic variables, identification of risk factors and definition of cost-effective strategies for cardiologic evaluation of HD chemotherapy candidates and subsequent monitoring have not been established yet. This lack of knowledge has important clinical implications, as in some instances, toxicity to the cardiovascular system may be the dose-limiting factor in determining the treatment regimen.
Therefore, we have scanned the literature from the last 30 years (using the PubMed database and lateral references) in order to provide a systematic overview of the general features of cardiotoxic effects of HD chemotherapy and nonmyeloablative HSC transplantation and an approach to their diagnosis, management and prevention. Knowledge gained from our own personal experience has been used to supplement the many gaps in the literature.
Cardiac toxicity due to conditioning regimen
Cyclophosphamide
A wide variety of HD chemotherapy regimens have been used, and cardiac toxicity has been associated mostly with HD cyclophosphamide-containing regimens. Since its initial description 30 years ago,11 it has been reported by many others,10,12,13,14,15,16,17,18,19,20,21,22,23 with a wide spectrum of incidence, manifestation and severity.10,12,13,14,15,16,20,21,22,23 On the basis of post-mortem examination,10,11,12,14,15,20,21,24 the pathophysiology of HD cyclophosphamide-associated cardiac toxicity is thought to depend upon toxic endothelial damage followed by extravasation of toxic metabolites with resultant myocyte damage and interstitial hemorrhage and edema. HD cyclophosphamide-associated cardiotoxicity occurs during or soon after (within 3 weeks) administration. It is manifested clinically as acute or subacute onset of congestive heart failure (CHF) with pulmonary congestion, weight gain and oliguria. Pericardial effusion, in some cases with cardiac tamponade, may be part of the clinical picture10,12,14,15 or the only manifestation of cardiac toxicity.10,15,18,22,24 Although HD cyclophosphamide-associated cardiac toxicity is potentially reversible, in patients who develop severe, progressive CHF, this complication may lead to death within few weeks.
Studies from the 1970s and 1980s using combination regimens reported an incidence up to 43%.10 However, in recent years, the percentage of patients receiving single-agent HD cyclophosphamide up to 7 g/m2 or 200 mg/kg experiencing cardiotoxicity has diminished to nearly zero with the adoption of multifractionated schedule of administration.4,5,7,8,9,25 Available evidence indicates that single-agent HD cyclophosphamide-associated cardiac toxicity is dose and schedule dependent, and it is not related to the cumulative drug dose.13,16,21 No pharmacokinetic parameter has been consistently associated with cardiotoxicity, although a significant inverse association between a reduced HD cyclophosphamide area under the curve (AUC) (ie accelerated clearance due to an increased conversion to active metabolites) and cardiotoxicity was found in three independent studies,17,26,27 but not confirmed in a larger one.28 A common finding in these studies has been a considerable interpatient variation in the AUC, raising the possibility that such variability could produce differences in the pharmacodynamic outcome. The pathways of drug clearance or inactivation exhibit polymorphic differences. Interindividual, race-specific and age-related responses to chemotherapeutic agents are common. Genetic variants in the drug target itself, disease pathway genes or drug-metabolizing enzymes may all be used as predictors of drug efficacy or toxicity. A DNA-based approach focused on predicting of toxic responses to drugs and selecting the best individual and combinations of anticancer drugs would shift the current prescribing paradigm from its empirical nature to a more patient-specific model.29
Combinations including cyclophosphamide
Several widely employed combinations of HD cyclophosphamide are not associated with an increased risk of cardiotoxicity over single-agent HD cyclophosphamide.26,28,30,31,32,33,34,35 However, the risk for HD cyclophosphamide-associated cardiac toxicity may be increased by the concomitant administration of cytarabine or mitoxantrone.
Cytarabine
Administration of HD cytarabine has been associated with both cardiac arrhythmias36,37 and pericarditis.38 However, the highest incidence and severity of cardiac toxicity was reported when the two drugs were coadministered in different combination regimens,10,12,14,15,20,39,40,41,42 with the partial exception of the BEAC (carmustine, etoposide, cytarabine, cyclophosphamide) conditioning regimen, which has not been associated with excessive cardiac toxicity.43,44,45,46
Mitoxantrone
Significant cardiotoxicity has also been reported for the association of HD cyclophosphamide and HD mitoxantrone.47,48 HD mitoxantrone is commonly used as part of conditioning regimens not including HD cyclophosphamide, where its acute and long-term cardiac toxicity has been acceptable in a large series of patients.7,9,49,50 However, in one report, four out of six patients with no pre-existing cardiac disease experienced severe cardiac toxicity with two treatment-related deaths following administration of cyclophosphamide 2.4 g/m2 (an 'intermediate' dose not associated with cardiac toxicity) and mitoxantrone 35–45 mg/m2.47 In another study, administration of HD cyclophosphamide at the maximum tolerated dose (ie 200 mg/kg) divided into only two daily fractions may have played a role in determining a 25% incidence of CHF with one treatment-related death, besides the potential contribution of HD mitoxantrone in patients previously exposed to anthracyclines.48
Overall, it is worth noting that considerable differences in cardiotoxicity profile were observed between combinations of cytarabine39,40,41,42,43,44,45 or HD mitoxantrone,47,48,49,51,52,53 and HD cyclophosphamide for relatively minor differences in sequence and schedule of administration.
Other chemotherapeutic agents
Cardiotoxicity has seldom been reported for other cytotoxic drugs. HD thiotepa has been associated with a 5% cardiac toxicity in two studies,54,55 while other series did not confirm these findings.8,25 HD ifosfamide cardiotoxicity is reported in only two studies more than 20 years old.56,57 Anecdotal evidence is reported for HD carmustine-associated cardiac toxicity.58
Recently, nonmyeloablative transplant regimens have been developed to exploit the graft-versus-tumor effect of allogeneic T-cell chimerism while reducing the toxicities associated with myeloablative conditioning. Particularly, the combination of HD melphalan and fludarabine has been used to condition patients with advanced hematologic malignancies.59 HD melphalan has not been shown to be cardiotoxic,7,9,25,50,60,61,62,63,64 with the exception of atrial fibrillation.65,66,67 Fludarabine has also been rarely associated with cardiac dysfunction.68 Surprisingly, after an initial report59 of about 2.5% incidence of grade IV/V cardiac toxicity with this combination, this unexpected side effect has been confirmed in three other reports, with incidence up to 14% and outcomes variable from complete reversibility with standard medical treatment69 to toxic deaths.70,71 These data clearly contrast with the reported rarity of cardiotoxicity with either agent individually. The mechanism of this unique toxicity is not known, as none of the patients had a history of cardiac disease and all of them had normal pre-transplant cardiac function and limited, if any, previous exposure to anthracyclines. The potential for cardiac toxicity of the HD melphalan and purine analogues association is highlighted also by the report of two grade IV/V cardiac toxicity in eight patients conditioned with HD melphalan and cladribine, which is not associated with cardiotoxicity when used as a single agent.59
A summary of clinical cardiac toxicities associated with HD chemotherapy reported in the literature is listed in Table 1.
Table 1 - Clinical cardiac toxicity of single-agent HD chemotherapeutic agents and their combination.
Full table Management of HD chemotherapy-associated cardiac toxicity
Diagnosis and treatment of HD chemotherapy-associated cardiac toxicity do not differ from the general approach to heart failure patients. Following administration of HD cyclophosphamide, nonspecific and transient electrocardiogram (ECG) abnormalities10,15,18,21 and left ventricular ejection fraction (LVEF) drops10,15,23 have been recorded with no predictive value for the subsequent development of clinically relevant cardiotoxicity. These alterations are expected to return toward baseline within a few days or weeks in most cases.8,10,15,18,21,23 Therapy with diuretics should be started in the first instance. The addition of an angiotensin-converting enzyme inhibitor in case of ECG and/or two-dimensional echocardiogram (2D echo) evidence of impaired left ventricular contraction, the patient not being hypotensive, should be considered according to established guidelines.73,74 Oral dygoxin therapy may also be considered if heart failure persists. For HD cyclophosphamide-associated cardiac toxicity, experimental therapeutic interventions guided by clinical observations suggesting insights into the pathophysiology have also been conducted, but given the limited number of patients treated, they cannot be suggested as standard treatment.20 Sustained or recurrent cardiac arrhythmias should be treated with appropriate antiarrhythmic agents and correction of possible precipitating factors, including sepsis and electrolyte disturbances. In the case of pericardial effusion, therapeutic aspiration is indicated if there is evidence of cardiac tamponade.
Finally, anecdotal reports indicate that late cardiomyopathy can be treated successfully by orthotopic cardiac transplantation.75
Risk factors and prevention of cardiac complications
Previous anthracycline exposure
Several studies, while showing a reduced LVEF in patients who had received anthracyclines in comparison with those who had not, failed to demonstrate a relationship between previous anthracycline exposure and development of cardiac toxicity following HD chemotherapy.8,10,17,18,26,76,77,78,79 On the other hand, Steinherz et al22 observed that HD cyclophosphamide-associated cardiac damage was most frequent in pediatric patients receiving cyclophosphamide 
170 mg/kg or in those receiving 120 mg/kg who had received 100 mg/m2 anthracyclines prior to transplant. Other authors found a trend towards significance also.78,80
Besides the inconsistent data in the literature, the potential contribution of previous anthracycline exposure to HD chemotherapy-associated cardiac toxicity should be reconsidered based upon recent insights about the progressive establishment of cardiac damage by anthracyclines. The long known assumption that the incidence of chronic cardiomyopathy is minimized by restricting the cumulative doxorubicin dose less than 400 mg/m281 has been recently challenged. Also patients treated with a cumulative dose of anthracyclines below this threshold may experience subclinical or even clinical toxicity during or many years after therapy, if they are carefully monitored.82,83,84 In particular, besides early-onset cardiac toxicity occurring within 1 year after the start of the anthracycline therapy, the incidence of late-onset cardiac effects (a year or longer after the completion of therapy) increases with longer follow-up. The incidence of echocardiographically measurable abnormality in systolic function increased from 14% after 4 to 6 years, to 24% after 7 to 9 years, to 38% after more than 10 years following exposure to anthracyclines in childhood.82 Moreover, the incidence of severe cardiac dysfunction (fractional shortening <20%) was 0% at 4 to 6 years, 8% at 7 to 9 years and 15% after 10 years.82 Consistent results have been reported also for adults.83,84 These findings suggest that a much larger number of cancer survivors than previously suspected, particularly survivors of childhood cancers, may have myocardial dysfunction as a result of anthracycline therapy.
In the light of these data, other strategies in addition to restriction of cumulative dose to reduce the cardiotoxic potential of anthracycline would be of interest. For example, the impact of anthracycline exposure on cardiac performance may be reduced by the application of cardioprotectors.84 It is believed that the mechanism for anthracycline-associated cardiac toxicity is free radical formation with subsequent lipid peroxidation. Dexrazoxane, an antioxidant that functions by chelating iron, thereby reducing free radical formation, is the only cardioprotective drug approved by the Food and Drug Administration and recommended by the American Society of Clinical Oncology guidelines for patients receiving >300 mg/m2 doxorubicin.85 Dexrazoxane consistently reduces the cardiotoxic effects of anthracyclines, allowing higher anthracycline doses to be used safely.86 Complete protection, however, could not be achieved in most of the studies, and it is not known yet whether dexrazoxane provides any protection against late cardiovascular effects. Importantly, the weight of evidence shows that dexrazoxane does not affect the antitumor activity of anthracyclines.86
Another strategy is the development of liposomal drug formulations of the anthracyclines. Liposomal encapsulation alters the tissue distribution of anthracyclines: tissues with a sinusoidal capillary system preferentially take up liposomes, so the continuous capillaries of cardiac muscles would reduce heart exposure to the drug. A further reduction in the risk of cardiac toxicity may be obtained by pegylated liposomal anthracyclines, whose pharmacokinetic is characterized by slow release of the drug avoiding high peak plasma concentration. Pegylated liposomal doxorubicin has shown similar efficacy with a significantly lower incidence of cardiac side effects compared with conventional doxorubicin. The long-term cardiac safety of these agents, however, is unknown yet.87
Radiation treatment
The heart volume exposed to irradiation influences the risk of cardiac toxicity.88 Accordingly, prior radiation therapy to the mediastinum or left chest wall likely represents a risk factor.28,88 Moreover, radiation to the above fields appears to increase the cardiotoxicity of anthracyclines, although the two have different mechanisms of injury,88 making patients with a history of both therapies possibly at higher risk for HD chemotherapy-associated cardiotoxicity.
The potential role of total body irradiation administered with HD cyclophosphamide (8–12 Gy) in increasing the risk for cardiac toxicity has been ruled out by several studies.10,19,89,90
Weight
It has been suggested that cardiac toxicity can be avoided if HD cyclophosphamide is administered at a dose per m2 rather than per kilogram.16 In fact, children (who have a relatively smaller ratio of weight to body surface area than do adults) and obese patients, if treated on an mg/kg basis, would receive undertreatment and overtreatment, respectively. Optimal chemotherapy dosing in obese patients is one of the most controversial aspects of HD chemotherapy. Since obese individuals have altered pharmacokinetics (eg decreased clearance) for many medications including chemotherapeutic agents,91,92,93 when compared with the nonobese, in several HD chemotherapy programs, there is a systematic approach to attenuation of chemotherapy doses in patients who are significantly above their ideal weight to avoid excessive toxicity. Indeed, association of obesity with cardiac toxicity can be spotted throughout the literature.25,50 However, no uniform clinical dosing guidelines have been established, leading to a marked variability among institutions according to the method of dose adjustment used.94 As a practical approach, in our experience and that of other groups, reduction of HD cyclophosphamide dosage in patients whose actual weight exceeds by >20% the ideal weight is a safety measure that does not affect the efficacy of chemotherapy and minimizes the risk of toxicity.7,8,95,96 A formula to calculate adjusted weight has been suggested (adjusted weight is ideal weight plus 25% of the difference between actual and ideal weight) as a rule to calculate the dose of HD cyclophosphamide in these patients.7,8,25,96
Age
It is commonly felt that patients over the age of 50 years may be at risk for future cardiac complications, especially if HD cyclophosphamide is part of the planned conditioning regimen. Patients up to 65–70 years of age are now being enrolled into HD chemotherapy or nonmyeloablative HSC transplantation programs. Some authors have found that older age represents a risk factor for the development of cardiovascular side effects,28,80 while others have not.17,70,97,98 It should be noted, however, that studies in which a positive correlation was found are those in which older patients (up to 65 years old) were included. Finally, an association of risk of CHF with age has been proposed for patients receiving anthracycline-based chemotherapy.81,84,99
A summary of all suspected risk factors for HD chemotherapy-associated cardiac toxicity and relative preventive strategies is listed in Table 2.
Predictive value of pre-HD chemotherapy cardiologic evaluation of patients
Preserved cardiac function is generally required for enrollment in clinical trials of HD chemotherapy. This is commonly defined as an LVEF >50% and no other significant cardiac disease. In at least seven studies, LVEF measured at rest was unable to predict future cardiac toxicity.17,28,79,80,100,104,105 One of these studies also showed that measurement of cardiac reserve during exercise could not predict cardiac morbidity or mortality.104 On the other hand, three studies reported a significant association between pre-transplant LVEF and cardiotoxicity18,54,77 and two more described a trend in the same direction.76,101 However, measurement of LVEF before HD chemotherapy is of limited practical value: increased rates of minor cardiac events, rather than increased mortality due to severe cardiac toxicity, were recorded among patients with diminished (ie 50–54%) baseline LVEF, and 2/3 major cardiac events occurred in patients with normal LVEF.100 Overall, resting LVEF measurement in every HD chemotherapy candidate is not recommended;76,100 published evidence7,25,76,79,100,106 suggests that for patients undergoing front-line HD chemotherapy cardiologic evaluation including a detailed history, physical examination, chest X-ray and resting ECG is likely to be a sufficient screening tool to recognize candidates at high risk for cardiac complications. On the other hand, full pre-transplant evaluation with resting 2D echo of patients with history, symptoms or signs of cardiac disease or a history of anthracycline exposure and/or left chest wall radiotherapy remains prudent. Interestingly, it has been recently reported that resting ECG may be a powerful screening tool for prediction of HD chemotherapy-associated cardiac toxicity. QT dispersion analysis (ie the difference between the maximum and minimum QT intervals on standard 12-lead ECG), as a measure of cardiac electrical heterogeneity for identification of patients at increased risk for serious ventricular arrhythmias and sudden cardiac death, has been conducted in multiple disease states and showed promising results. QT dispersion and corrected QT interval (QTc) (ie QT interval corrected according to Bazett's formula) have been reported to predict acute heart failure following HD chemotherapy, particularly HD cyclophosphamide-containing regimens, more effectively than 2D echo parameters.39,98,107 It can be speculated that increases in QT dispersion and QTc may reflect local or multifocal abnormalities of cardiac muscle that can be detected only by ECG. Moreover, these ventricular repolarization indices can be easily calculated at most hospitals and certainly deserve further investigation in a larger number of patients.
HD chemotherapy in patients with subclinical cardiac dysfunction
In light of the limited predictive value of cardiologic evaluation, exclusion from HD chemotherapy programs of patients with slightly depressed (ie subclinical) cardiac function as measured by LVEF should be reconsidered. As a matter of fact, several studies suggest that such patients can tolerate HD chemotherapy. In the report by Hertenstein et al,100 none of the eight patients with an LVEF <50% experienced cardiac toxicity. Three women with an LVEF <50% (47
2%) underwent a sequence of HD cyclophosphamide (5 g/m2), HD melphalan (140 mg/m2) and HD thiotepa (900 mg/m2) without any clinical cardiotoxicity.102 In this series of patients, however, the patient with the lowest baseline LVEF (33%) had CHF, although easily managed.102 Another report showed that patients undergoing HD chemotherapy with LVEF <50% (range 49–39%) do not necessarily experience more pronounced cardiac deterioration than patients starting from LVEF >50% when treated with different HD chemotherapy regimens, including HD cyclophosphamide.90 Six patients with initial LVEF <50% (427%) were given enalapril and they underwent conditioning regimens containing HD cyclophosphamide 120 mg/kg even twice with no cardiac function deterioration at a median follow-up of 18 months.103 Finally, in 11 patients whose pre-transplant LVEF was <50%, no signs of heart failure were recorded at prolonged follow-up after HSC transplantation.79 Therefore, patients with subclinical impairment of cardiac function should not be excluded a priori from HSC transplantation if otherwise indicated, but thorough cardiologic evaluation and monitoring are warranted.
New diagnostic strategies to detect and monitor HD chemotherapy-associated cardiac toxicity
In addition to overt clinical impairment of cardiac function, studies have also reported subclinical cardiotoxicity, that is, any alteration of functional and/or biochemical values from baseline measured by different diagnostic techniques. Markers of subclinical cardiotoxicity with predictive value for subsequent development of clinical cardiac toxicity would allow identification of patients who need careful cardiologic monitoring and therapy to prevent major complications. This is relevant not only for patients undergoing HD chemotherapy but also for HD chemotherapy candidates who receive anthracycline-based chemotherapy, as development of cardiac failure several months or years after the last administration82,99,108,109 is preceded by treatable, asymptomatic but progressive cardiac dysfunction.110
Echocardiography/radionuclide angiocardiography
Two major Consensus Guidelines111,112 recommended LVEF estimation with radionuclide angiocardiography or 2D echo for detecting/monitoring chemotherapy-associated cardiotoxicity during and shortly after the end of treatment. Despite its wide clinical use, including HD chemotherapy,10,15,23,50,90,113,114 LVEF measurement is a relatively insensitive technique for detecting drug-induced cardiotoxicity at an early stage. However, traditional 2D echo allows measurement of various parameters of both systolic and diastolic function, anatomic dimensions and afterload. As diastolic modifications from baseline values occur earlier in other clinical settings,110 there has been an increasing interest in measuring diastolic, rather than systolic, parameters to detect subclinical cardiac toxicity in patients receiving chemotherapy. Indeed, one recent study suggests that indexes of early diastolic function are predictive for the early detection of anthracycline-associated cardiac toxicity.115 In the HD chemotherapy setting, single-agent HD cyclophosphamide resulted in a transient but significant E/A (early and atrial diastolic velocities) ratio change in 5/168 and 1/21 patients,89 without changes in traditional systolic indexes, suggesting that reversible reduction of left ventricular diastolic compliance may represent the initial sign of reversible cardiac dysfunction following HD cyclophosphamide administration.8
However, 2D echo evaluation of both systolic and diastolic indexes potentially suffers from inter- and intraobservatory variability as well as changes in hemodynamic conditions such as heart rate, preload and afterload, which may vary over the course of treatment.110 To diminish the confounding effect of varying hemodynamic conditions, recently developed ultrasound techniques such as Doppler Tissue Imaging and Color M-Mode mitral flow propagation study intrinsic diastolic myofiber properties (relaxation and elastic recoil).110 More significant (>35%) and earlier changes of these indexes from basal values than standard diastolic indexes (E/A ratio and isovolumetric relaxation time) have been recorded in patients treated with anthracycline-based chemotherapy (GM Benvenuto, unpublished data). These promising techniques warrant further investigation in larger cohorts of patients, as their advantages include applicability to virtually all patients, including those with poor quality echogenic windows, and a good intra- and interobservatory variability; however, specific skills and experience are required to perform and interpret these new echo technologies.
Circulating markers
Troponins are actin-associated regulatory proteins, not normally present in serum. Therefore, an increase in serum cardiac troponin (cTn) level is a sensitive and specific marker for myocardial necrosis.116 Cardiac troponins (cTnT and cTnI, the diagnostic and prognostic values of the two isoforms are clinically identical) are released within 4 to 12 h following an episode of myocardial necrosis with a peak value 12 to 48 h following the injury. cTn's have recently been applied to the early detection of chemotherapy-induced cardiac toxicity,117 where they have shown predictive value for long-term, cumulative cardiac damage by anthracycline.118 In the HD chemotherapy setting, plasma cTnI levels were measured for up to 72 h after every HD chemotherapy cycle (often containing anthracyclines) with repeated 2D echo examination for up to 7 months after therapy in a large series of patients. Patients with cTnI levels <0.4 ng/ml had a small median drop in LVEF at 3 months follow-up examination, which subsequently normalized, whereas those with cTnI levels >0.4 ng/ml had a greater decrease in LVEF (16%), which was still evident at later follow-up.97 In the latter group, a close correlation between maximally elevated cTnI levels and decrease of LVEF was also observed. In a recent update of their series, the same authors could stratify patients at different risk of cardiac events following HD chemotherapy based on even minimal elevations of cTnI levels recorded soon after chemotherapy and 1 month later.119 However, the vast majority of patients showing a rise in cTnI received high-dose epirubicin, while cTnI measurements after single-agent HD cyclophosphamide (7 g/m2) in 49 patients of these series were not reported.97 In our experience and that of other groups, serial plasma measurements of cTnI or cTnT after single-agent HD cyclophosphamide were uniformly negative.8,89 Differences in pathophysiological mechanisms underlying anthracycline- and HD cyclophosphamide-associated cardiac toxicity, respectively, may explain the difference. Since cTn's are markers of myocardial cell necrosis with plasma levels paralleling the extent of damage, they primarily detect toxicity from chemotherapeutic agents directly damaging myocardial cell membrane and not from those primarily affecting endothelium and/or interstitium, as it has been proposed for HD cyclophosphamide.8 Therefore, the absence of cTn elevations following single-agent HD cyclophosphamide possibly reflects the absence of direct membrane damage, as further suggested by a study using indium-111 monoclonal antimyosin antibody scintigraphy, which can detect small areas of myocardial damage or necrosis in a variety of diseases binding intracellular myosin after sarcolemmal disruption. The scan was negative in 14/14 patients treated with the HD cyclophosphamide-containing regimen STAMP-V (cyclophosphamide, thiotepa and carboplatin).120
Natriuretic peptides (atrial natriuretic peptide, ANP and brain natriuretic peptide, BNP) are cardiac hormones released in response to atrial or ventricular load-induced stresses, and their plasma levels are inversely correlated with measures of cardiac function.121 Existing data suggest a strong correlation between natriuretic peptide measurement and myocardial dysfunction following standard dose anthracycline chemotherapy.122,123 Importantly, unlike cTn's, BNP elevation may reflect chemotherapy-associated diastolic abnormalities123,124 and the level may be increased by myocardial stress without necrosis,125 thus potentially increasing their sensitivity over that afforded by cTn's. In the HD chemotherapy setting, patients who developed clinical heart failure exhibited elevated plasma BNP level in several measurements before the onset of signs/symptoms, although lesser elevations, and only on a single measurement were detected also in patients who did not experience cardiac toxicity.126 In another series of patients, elevations of natriuretic peptides were observed on days 1 and 14 following HD chemotherapy, but neither peak was predictive of cardiac toxicity.127
Overall, the utility and applicability of new 2D echo-based techniques have not been determined yet, and their use should be restricted to specific clinical studies addressing the risk of HD chemotherapy-associated cardiotoxicity in patients with a history of anthracycline exposure. The technically simpler dosage of circulating markers is partly countered by the lack of knowledge about optimal timing of measurement, and its potential use as a diagnostic and predictive tool also remains investigational. However, the reported potential for cTnI to stratify patients at risk for cardiac complications following anthracycline-containing HD chemotherapy119 warrants further investigation. Finally, dosage of cardiac markers in patients undergoing conditioning regimens associated with unexpected and completely unexplained cardiac toxicity59,69,70,71 may provide insights into the underlying pathophysiology.
Currently available tools for early detection and monitoring of chemotherapy-associated cardiac toxicity with their present limitations and future perspectives are summarized in Table 3.
Conclusions
Conflicting data were found in the literature about all aspects of HD chemotherapy-associated cardiac toxicity. Several reasons may account for the variability observed, particularly differences in conditioning regimens, patient selection and application of different grading systems.76,128,129 This makes it difficult to compare results between studies and to identify predisposing risk factors. However, based on published evidence and our own personal experience, some general features have been identified. HD cyclophosphamide is the agent most frequently associated with cardiac toxicity. Dosage,16 application regimens18 and simultaneous use of other cytotoxic drugs.10,12,14,15,20,39,40,41,42,47,48,107 have emerged as risk factors. Although once common, clinically significant cardiac complications now occur in less than 5% of patients.7,8,25,106,130 Nonetheless, grade IV cardiac toxicity39,48 and toxic deaths42,47,48 are still being recorded. Moreover, cardiotoxicity has emerged as an unexpected side effect of HD melphalan and fludarabine administration.59,69,70,71 Pharmacokinetic and pharmacodynamic studies have provided little insight into the mechanisms underlying HD chemotherapy-associated cardiac toxicity. As of today, no widely accepted parameter before or during HD chemotherapy exists to predict which patients will develop cardiac dysfunction. Therefore, a risk-adapted pre-transplant cardiologic evaluation should be adopted, with 2D echo evaluation limited to patients with a history of cardiac disease or pre-transplant exposure to anthracyclines and/or radiation therapy to the mediastinum or left chest wall. An important finding of our retrospective analysis is that patients with a slightly depressed cardiac function (LVEF 40–49%) can undergo HD chemotherapy and HSC transplantation with acceptable risk of cardiac toxicity79,90,100,102,103 as long as it represents the only potentially curative treatment option available.
ECG-39,98,107 and 2D echo-based diagnostic techniques8,89,110 and circulating markers8,97,119,123 are being investigated as candidate highly sensitive and specific tools to identify patients at risk for cardiac complications from HD chemotherapy and to permit early diagnosis.110
Finally, the few data available about long-term cardiologic follow-up of patients after HD chemotherapy and HSC transplantation suggest that HD chemotherapy does not cause per se late development of cardiac toxicity,5,79,90 although subclinical alteration of cardiac performance may last long.50,90,109,131,132,133,134 This is particularly important for the proportion of patients who may need a potentially cardiotoxic agent after HD chemotherapy for their relapsing disease.135
References
| 1. | Craddock C. Haemopoietic stem-cell transplantation: recent progress and future promise. Lancet Oncol 2000; 1: 227−234. | Article | PubMed | ChemPort | |
| 2. | Urbano-Ispizua A, Schmitz N & de Witte T et al. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: definitions and current practice in Europe. Bone Marrow Transplant 2002; 29: 639−646. | Article | PubMed | ChemPort | |
| 3. | Sanchorawala V, Wright DG & Seldin DC et al. An overview of the use of high-dose melphalan with autologous stem cell transplantation for the treatment of AL amyloidosis. Bone Marrow Transplant 2001; 28: 637−642. | Article | PubMed | ChemPort | |
| 4. | Brodsky RA, Sensenbrenner LL & Smith BD et al. Durable treatment-free remission after high-dose cyclophosphamide therapy for previously untreated severe aplastic anemia. Ann Intern Med 2001; 135: 477−483. | PubMed | ChemPort | |
| 5. | Storb R, Blume KG & O'Donnell MR et al. Cyclophosphamide and antithymocyte globulin to condition patients with aplastic anemia for allogeneic marrow transplantations: the experience in four centers. Biol Blood Marrow Transplant 2001; 7: 39−44. | Article | PubMed | ChemPort | |
| 6. | Slavin S, Nagler A & Naparstek E et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756−763. | PubMed | ISI | ChemPort | |
| 7. | Gianni AM, Bregni M & Siena S et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997; 336: 1290−1297. | Article | PubMed | ISI | ChemPort | |
| 8. | Morandi P, Ruffini PA & Benvenuto GM et al. Serum cardiac troponin I levels and ECG/Echo monitoring in breast cancer patients undergoing high-dose (7 g/m(2)) cyclophosphamide. Bone Marrow Transplant 2001; 28: 277−282. | Article | PubMed | ChemPort | |
| 9. | Ghielmini M, Zappa F & Menafoglio A et al. The high-dose sequential (Milan) chemotherapy/PBSC transplantation regimen for patients with lymphoma is not cardiotoxic. Ann Oncol 1999; 10: 533−537. | Article | PubMed | ChemPort | |
| 10. | 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. | PubMed | ChemPort | |
| 11. | Santos GW, Sensenbrenner LL & Burke PJ et al. The use of cyclophosphamide for clinical marrow transplantation. Transplant Proc 1972; 4: 559−564. | PubMed | ChemPort | |
| 12. | Appelbaum F, Strauchen JA & Graw RG, Jr et al. Acute lethal carditis caused by high-dose combination chemotherapy. A unique clinical and pathological entity. Lancet 1976; 1: 58−62. | Article | PubMed | ChemPort | |
| 13. | Mullins GM, Anderson PN & Santos GW. High-dose cyclophosphamide therapy in solid tumors. Therapeutic, toxic and immunosuppressive effects. Cancer 1975; 36: 1950−1958. | PubMed | ChemPort | |
| 14. | Mills BA & Roberts RW. Cyclophosphamide-induced cardiomyopathy: a report of two cases and review of the English literature. Cancer 1979; 43: 2223−2226. | PubMed | ChemPort | |
| 15. | Gottdiener JS, Appelbaum FR & Ferrans VJ et al. Cardiotoxicity associated with high-dose cyclophosphamide therapy. Arch Intern Med 1981; 141: 758−763. | Article | PubMed | ChemPort | |
| 16. | Goldberg MA, Antin JH, Guinan EC & Rappeport JM. Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor. Blood 1986; 68: 1114−1118. | PubMed | ChemPort | |
| 17. | Ayash LJ, Wright JE & Tretyakov O et al. Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response. J Clin Oncol 1992; 10: 995−1000. | PubMed | ChemPort | |
| 18. | 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. | PubMed | ChemPort | |
| 19. | Baello EB, Ensberg ME & Ferguson DW et al. Effect of high-dose cyclophosphamide and total-body irradiation on left ventricular function in adult patients with leukemia undergoing allogeneic bone marrow transplantation. Cancer Treat Rep 1986; 70: 1187−1193. | PubMed | ChemPort | |
| 20. | Lee CK, Harman GS, Hohl RJ & Gingrich RD. Fatal cyclophosphamide cardiomyopathy: its clinical course and treatment. Bone Marrow Transplant 1996; 18: 573−577. | PubMed | ChemPort | |
| 21. | Buckner CD, Clift RA & Fefer A et al. Aplastic anemia treated by marrow transplantation. Transplant Proc 1973; 5: 913−916. | PubMed | ChemPort | |
| 22. | Steinherz LJ, Steinherz PG & Mangiacasale D et al. Cardiac changes with cyclophosphamide. Med Pediatr Oncol 1981; 9: 417−422. | PubMed | ChemPort | |
| 23. | Kupari M, Volin L & Suokas A et al. Cardiac involvement in bone marrow transplantation: serial changes in left ventricular size, mass and performance. J Intern Med 1990; 227: 259−266. | PubMed | ChemPort | |
| 24. | 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. | PubMed | ChemPort | |
| 25. | Gianni AM, Siena S & Bregni M et al. Efficacy, toxicity, and applicability of high-dose sequential chemotherapy as adjuvant treatment in operable breast cancer with 10 or more involved axillary nodes: five-year results. J Clin Oncol 1997; 15: 2312−2321. | PubMed | ChemPort | |
| 26. | Petros WP, Broadwater G & Berry D et al. Association of high-dose cyclophosphamide, cisplatin, and carmustine pharmacokinetics with survival, toxicity, and dosing weight in patients with primary breast cancer. Clin Cancer Res 2002; 8: 698−705. | PubMed | ChemPort | |
| 27. | Slattery JT, Kalhorn TF & McDonald GB et al. Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients. J Clin Oncol 1996; 14: 1484−1494. | PubMed | ChemPort | |
| 28. | Nieto Y, Cagnoni PJ & Bearman SI et al. Cardiac toxicity following high-dose cyclophosphamide, cisplatin, and BCNU (STAMP-I) for breast cancer. Biol Blood Marrow Transplant 2000; 6: 198−203. | PubMed | ChemPort | |
| 29. | Kallianpur A. Genomic screening and complications of hematopoietic stem cell transplantation: has the time come? Bone Marrow Transplant 2004; in: press. |
| 30. | Peters WP, Ross M & Vredenburgh JJ et al. High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 1993; 11: 1132−1143. | PubMed | ISI | ChemPort | |
| 31. | Bergh J, Wiklund T & Erikstein B et al. Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study. Lancet 2000; 356: 1384−1391. | Article | PubMed | ISI | ChemPort | |
| 32. | Hortobagyi GN, Buzdar AU & Theriault RL et al. Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst 2000; 92: 225−233. | Article | PubMed | ChemPort | |
| 33. | Rodenhuis S, Bontenbal M & Beex LV et al. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med 2003; 349: 7−16. | Article | PubMed | ChemPort | |
| 34. | Tallman MS, Gray R & Robert NJ et al. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med 2003; 349: 17−26. | Article | PubMed | ChemPort | |
| 35. | Stadtmauer EA, O'Neill A & Goldstein LJ et al. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med 2000; 342: 1069−1076. | Article | PubMed | ISI | ChemPort | |
| 36. | Willemze R, Zwaan FE, Colpin G & Keuning JJ. High- dose cytosine arabinoside in the management of refractory acute leukaemia. Scand J Haematol 1982; 29: 141−146. | PubMed | ChemPort | |
| 37. | Stamatopoulos K, Kanellopoulou G & Vaiopoulos G et al. Evidence for sinoatrial blockade associated with high dose cytarabine therapy. Leukemia Res 1998; 22: 759−761. | Article | ChemPort | |
| 38. | Vaickus L & Letendre L. Pericarditis induced by high-dose cytarabine therapy. Arch Intern Med 1984; 144: 1868−1869. | Article | PubMed | ChemPort | |
| 39. | Nakamae H, Tsumura K & Hino M et al. QT dispersion as a predictor of acute heart failure after high-dose cyclophosphamide. Lancet 2000; 355: 805−806. | Article | PubMed | ChemPort | |
| 40. | Trigg ME, Finlay JL, Bozdech M & Gilbert E. Fatal cardiac toxicity in bone marrow transplant patients receiving cytosine arabinoside, cyclophosphamide, and total body irradiation. Cancer 1987; 59: 38−42. | PubMed | ChemPort | |
| 41. | Petersen FB, Appelbaum FR & Buckner CD et al. Simultaneous infusion of high-dose cytosine arabinoside with cyclophosphamide followed by total body irradiation and marrow infusion for the treatment of patients with advanced hematological malignancy. Bone Marrow Transplant 1988; 3: 619−624. | PubMed | ChemPort | |
| 42. | Kanda Y, Matsumura T & Maki K et al. Fatal cardiac toxicity in two patients receiving same-day administration of cyclophosphamide and cytarabine as conditioning for hematopoietic stem cell transplantation. Haematologica 2001; 86: 1002−1003. | PubMed | ChemPort | |
| 43. | Philip T, Guglielmi C & Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 1995; 333: 1540−1545. | Article | PubMed | ChemPort | |
| 44. | Kluin-Nelemans HC, Zagonel V & Anastasopoulou A et al. Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study. J Natl Cancer Inst 2001; 93: 22−30. | Article | PubMed | ChemPort | |
| 45. | Vose JM, Sharp G & Chan WC et al. Autologous transplantation for aggressive non-Hodgkin's lymphoma: results of a randomized trial evaluating graft source and minimal residual disease. J Clin Oncol 2002; 20: 2344−2352. | Article | PubMed | |
| 46. | van Besien K, Tabocoff J & Rodriguez M et al. High-dose chemotherapy with BEAC regimen and autologous bone marrow transplantation for intermediate grade and immunoblastic lymphoma: durable complete remissions, but a high rate of regimen-related toxicity. Bone Marrow Transplant 1995; 15: 549−555. | PubMed | ChemPort | |
| 47. | Gralow JR & Livingston RB. University of Washington high-dose cyclophosphamide, mitoxantrone, and etoposide experience in metastatic breast cancer: unexpected cardiac toxicity. J Clin Oncol 2001; 19: 3903−3904. | PubMed | ChemPort | |
| 48. | Dazzi C, Cariello A & Rosti G et al. Neoadjuvant high dose chemotherapy plus peripheral blood progenitor cells in inflammatory breast cancer: a multicenter phase II pilot study. Haematologica 2001; 86: 523−529. | PubMed | ChemPort | |
| 49. | Mulder PO, Sleijfer DT & Willemse PH et al. High-dose cyclophosphamide or melphalan with escalating doses of mitoxantrone and autologous bone marrow transplantation for refractory solid tumors. Cancer Res 1989; 49: 4654−4658. | PubMed | ChemPort | |
| 50. | Tarella C, Zallio F & Caracciolo D et al. High-dose mitoxantrone+melphalan (MITO/L-PAM) as conditioning regimen supported by peripheral blood progenitor cell (PBPC) autograft in 113 lymphoma patients: high tolerability with reversible cardiotoxicity. Leukemia 2001; 15: 256−263. | Article | PubMed | ChemPort | |
| 51. | Attal M, Canal P & Schlaifer D et al. Escalating dose of mitoxantrone with high-dose cyclophosphamide, carmustine, and etoposide in patients with refractory lymphoma undergoing autologous bone marrow transplantation. J Clin Oncol 1994; 12: 141−148. | PubMed | ChemPort | |
| 52. | Damon LE, Wolf JL & Rugo HS et al. High-dose chemotherapy (CTM) for breast cancer. Bone Marrow Transplant 2000; 26: 257−268. | Article | PubMed | ChemPort | |
| 53. | Stiff PJ, McKenzie RS & Alberts DS et al. Phase I clinical and pharmacokinetic study of high-dose mitoxantrone combined with carboplatin, cyclophosphamide, and autologous bone marrow rescue: high response rate for refractory ovarian carcinoma. J Clin Oncol 1994; 12: 176−183. | PubMed | ChemPort | |
| 54. | Alidina A, Lawrence D & Ford LA et al. Thiotepa-associated cardiomyopathy during blood or marrow transplantation: association with the female sex and cardiac risk factors. Biol Blood Marrow Transplant 1999; 5: 322−327. | PubMed | ChemPort | |
| 55. | Bengala C, Pazzagli I & Innocenti F et al. High-dose thiotepa and melphalan with hemopoietic progenitor support following induction therapy with epirubicin−paclitaxel-containing regimens in metastatic breast cancer (MBC). Ann Oncol 2001; 12: 69−74. | Article | PubMed | ChemPort | |
| 56. | Kandylis K, Vassilomanolakis M, Tsoussis S & Efremidis AP. Ifosfamide cardiotoxicity in humans. Cancer Chemother Pharmacol 1989; 24: 395−396. | Article | PubMed | ChemPort | |
| 57. | Quezado ZM, Wilson WH & Cunnion RE et al. High-dose ifosfamide is associated with severe, reversible cardiac dysfunction. Ann Intern Med 1993; 118: 31−36. | PubMed | ChemPort | |
| 58. | Kanj SS, Sharara AI & Shpall EJ et al. Myocardial ischemia associated with high-dose carmustine infusion. Cancer 1991; 68: 1910−1912. | PubMed | ChemPort | |
| 59. | Giralt S, Thall PF & Khouri I et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood 2001; 97: 631−637. | Article | PubMed | ISI | ChemPort | |
| 60. | Schmitz N, Pfistner B & Sextro M et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet 2002; 359: 2065−2071. | Article | PubMed | ChemPort | |
| 61. | Chopra R, McMillan AK & Linch DC et al. The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin's disease. A single-center eight-year study of 155 patients. Blood 1993; 81: 1137−1145. | PubMed | ChemPort | |
| 62. | Santini G, Salvagno L & Leoni P et al. VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 1998; 16: 2796−2802. | PubMed | ChemPort | |
| 63. | Samuels BL & Bitran JD. High-dose intravenous melphalan: a review. J Clin Oncol 1995; 13: 1786−1799. | PubMed | ChemPort | |
| 64. | Cunningham D, Paz-Ares L & Milan S et al. High-dose melphalan and autologous bone marrow transplantation as consolidation in previously untreated myeloma. J Clin Oncol 1994; 12: 759−763. | PubMed | ChemPort | |
| 65. | Olivieri A, Corvatta L & Montanari M et al. Paroxysmal atrial fibrillation after high-dose melphalan in five patients autotransplanted with blood progenitor cells. Bone Marrow Transplant 1998; 21: 1049−1053. | Article | PubMed | ChemPort | |
| 66. | Moreau P, Milpied N & Mahe B et al. Melphalan 220 mg/m2 followed by peripheral blood stem cell transplantation in 27 patients with advanced multiple myeloma. Bone Marrow Transplant 1999; 23: 1003−1006. | Article | PubMed | ChemPort | |
| 67. | Phillips GL, Meisenberg B & Reece DE et al. Amifostine and autologous hematopoietic stem cell support of escalating-dose melphalan: a phase I study. Biol Blood Marrow Transplant 2004; 10: 473−483. | Article | PubMed | ChemPort | |
| 68. | Spriano M, Clavio M & Carrara P et al. Fludarabine in untreated and previously treated B-CLL patients: a report on efficacy and toxicity. Haematologica 1994; 79: 218−224. | PubMed | ChemPort | |
| 69. | Ritchie DS, Seymour JF & Roberts AW et al. Acute left ventricular failure following melphalan and fludarabine conditioning. Bone Marrow Transplant 2001; 28: 101−103. | Article | PubMed | ChemPort | |
| 70. | Van Besien K, Devine S & Wickrema A et al. Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies. Bone Marrow Transplant 2003; 32: 471−476. | Article | PubMed | ChemPort | |
| 71. | Martino R, Caballero MD & Canals C et al. Allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: results of a prospective multicentre study. Br J Haematol 2001; 115: 653−659. | Article | PubMed | ChemPort | |
| 72. | Cavet J, Lennard A & Gascoigne A et al. Constrictive pericarditis post allogeneic bone marrow transplant for Philadelphia-positive acute lymphoblastic leukaemia. Bone Marrow Transplant 2000; 25: 571−573. | Article | PubMed | ChemPort | |
| 73. | ACC/AHA guidelines for the evaluation and the management of chronic heart failure in the adult:executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2001; 38: 2101−2113. | Article | PubMed | ISI | ChemPort | |
| 74. | HFSA guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction: pharmacological approaches. Heart Failure Society of America. Pharmacotherapy 2000; 26: 1376−1398. |
| 75. | Ramrakha PS, Marks DI & O'Brien SG et al. Orthotopic cardiac transplantation for dilated cardiomyopathy after allogeneic bone marrow transplantation. Clin Transplant 1994; 8: 23−26. | PubMed | ChemPort | |
| 76. | Bearman SI, Petersen FB & Schor RA et al. Radionuclide ejection fractions in the evaluation of patients being considered for bone marrow transplantation: risk for cardiac toxicity. Bone Marrow Transplant 1990; 5: 173−177. | PubMed | ChemPort | |
| 77. | Fujimaki K, Maruta A & Yoshida M et al. Severe cardiac toxicity in hematological stem cell transplantation: predictive value of reduced left ventricular ejection fraction. Bone Marrow Transplant 2001; 27: 307−310. | Article | PubMed | ChemPort | |
| 78. | Fraiser LH, Kanekal S & Kehrer JP. Cyclophosphamide toxicity. Characterising and avoiding the problem. Drugs 1991; 42: 781−795. | PubMed | ChemPort | |
| 79. | Lehmann S, Isberg B, Ljungman P & Paul C. Cardiac systolic function before and after hematopoietic stem cell transplantation. Bone Marrow Transplant 2000; 26: 187−192. | Article | PubMed | ChemPort | |
| 80. | Brockstein BE, Smiley C, Al-Sadir J & Williams SF. Cardiac and pulmonary toxicity in patients undergoing high-dose chemotherapy for lymphoma and breast cancer: prognostic factors. Bone Marrow Transplant 2000; 25: 885−894. | Article | PubMed | ChemPort | |
| 81. | Von Hoff DD, Layard MW & Basa P et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979; 91: 710−717. | PubMed | ChemPort | |
| 82. | Kremer LC, van der Pal HJ & Offringa M et al. Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review. Ann Oncol 2002; 13: 819−829. | Article | PubMed | ISI | ChemPort | |
| 83. | Meinardi MT, Van Der Graaf WT & Gietema JA et al. Evaluation of long term cardiotoxicity after epirubicin containing adjuvant chemotherapy and locoregional radiotherapy for breast cancer using various detection techniques. Heart 2002; 88: 81−82. | Article | PubMed | ChemPort | |
| 84. | Swain SM, Whaley FS & Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003; 97: 2869−2879. | Article | PubMed | ChemPort | |
| 85. | Schuchter LM, Hensley ML, Meropol NJ & Winer EP. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2002; 20: 2895−2903. | Article | PubMed | |
| 86. | Swain SM & Vici P. The current and future role of dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review. J Cancer Res Clin Oncol 2004; 130: 1−7. | Article | PubMed | ChemPort | |
| 87. | Safra T. Cardiac afety of liposomal anthracyclines. Oncologist 2003; 8 Suppl 2: 17−24. | PubMed | ChemPort | |
| 88. | Adams MJ, Lipshultz SE & Schwartz C et al. Radiation-associated cardiovascular disease: manifestations and management. Semin Radiat Oncol 2003; 13: 346−356. | Article | PubMed | |
| 89. | Auner HW, Tinchon C & Brezinschek RI et al. Monitoring of cardiac function by serum cardiac troponin T levels, ventricular repolarisation indices, and echocardiography after conditioning with fractionated total body irradiation and high-dose cyclophosphamide. Eur J Haematol 2002; 69: 1−6. | Article | PubMed | ChemPort | |
| 90. | Carlson K, Backlund L & Smedmyr B et al. Pulmonary function and complications subsequent to autologous bone marrow transplantation. Bone Marrow Transplant 1994; 14: 805−811. | PubMed | ChemPort | |
| 91. | Rodvold KA, Rushing DA & Tewksbury DA. Doxorubicin clearance in the obese. J Clin Oncol 1988; 6: 1321−1327. | PubMed | ChemPort | |
| 92. | Powis G, Reece P, Ahmann DL & Ingle JN. Effect of body weight on the pharmacokinetics of cyclophosphamide in breast cancer patients. Cancer Chemother Pharmacol 1987; 20: 219−222. | Article | PubMed | ChemPort | |
| 93. | Lind MJ, Margison JM & Cerny T et al. Prolongation of ifosfamide elimination half-life in obese patients due to altered drug distribution. Cancer Chemother Pharmacol 1989; 25: 139−142. | Article | PubMed | ChemPort | |
| 94. | Grigg A, Harun MH & Szer J. Variability in determination of body weight used for dosing busulphan and cyclophosphamide in adult patients: results of an international survey. Leukemia Lymphoma 1997; 25: 487−491. | PubMed | ChemPort | |
| 95. | Dickson TM, Kusnierz-Glaz CR & Blume KG et al. Impact of admission body weight and chemotherapy dose adjustment on the outcome of autologous bone marrow transplantation. Biol Blood Marrow Transplant 1999; 5: 299−305. | PubMed | ChemPort | |
| 96. | Navarro WH. Impact of obesity in the setting of high-dose chemotherapy. Bone Marrow Transplant 2003; 31: 961−966. | Article | PubMed | ChemPort | |
| 97. | Cardinale D, Sandri MT & Martinoni A et al. Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. J Am Coll Cardiol 2000; 36: 517−522. | Article | PubMed | ChemPort | |
| 98. | Akahori M, Nakamae H & Hino M et al. Electrocardiogram is very useful for predicting acute heart failure following myeloablative chemotherapy with hematopoietic stem cell transplantation rescue. Bone Marrow Transplant 2003; 31: 585−590. | Article | PubMed | ChemPort | |
| 99. | Jensen BV, Skovsgaard T & Nielsen SL. Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol 2002; 13: 699−709. | Article | PubMed | ChemPort | |
| 100. | Hertenstein B, Stefanic M & Schmeiser T et al. Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant. J Clin Oncol 1994; 12: 998−1004. | PubMed | ChemPort | |
| 101. | Goldberg SL, Klumpp TR, Magdalinski AJ & Mangan KF. Value of the pretransplant evaluation in predicting toxic day-100 mortality among blood stem-cell and bone marrow transplant recipients. J Clin Oncol 1998; 16: 3796−3802. | PubMed | ChemPort | |
| 102. | Rose M, Lee FA & Gollerkeri A et al. The feasibility of high-dose chemotherapy in breast cancer patients with impaired left ventricular function. Bone Marrow Transplant 2000; 26: 133−139. | Article | PubMed | ChemPort | |
| 103. | Kakavas PW, Ghalie R & Parrillo JE et al. Angiotensin converting enzyme inhibitors in bone marrow transplant recipients with depressed left ventricular function. Bone Marrow Transplant 1995; 15: 859−861. | PubMed | ChemPort | |
| 104. | Zangari M, Henzlova MJ & Ahmad S et al. Predictive value of left ventricular ejection fraction in stem cell transplantation. Bone Marrow Transplant 1999; 23: 917−920. | Article | PubMed | ChemPort | |
| 105. | Jain B, Floreani AA & Anderson JR et al. Cardiopulmonary function and autologous bone marrow transplantation: results and predictive value for respiratory failure and mortality. The University of Nebraska Medical Center Bone Marrow Transplantation Pulmonary Study Group. Bone Marrow Transplant 1996; 17: 561−568. | PubMed | ChemPort | |
| 106. | Murdych T & Weisdorf DJ. Serious cardiac complications during bone marrow transplantation at the University of Minnesota, 1977−1997. Bone Marrow Transplant 2001; 28: 283−287. | Article | PubMed | ChemPort | |
| 107. | Nakamae H, Hino M & Akahori M et al. Predictive value of QT dispersion for acute heart failure after autologous and allogeneic hematopoietic stem cell transplantation. Am J Hematol 2004; 76: 1−7. | Article | PubMed | |
| 108. | Kremer LC, van Dalen EC, Offringa M & Voute PA. Frequency and risk factors of anthracycline-induced clinical heart failure in children: a systematic review. Ann Oncol 2002; 13: 503−512. | Article | PubMed | ChemPort | |
| 109. | Rovelli A, Pezzini C & Silvestri D et al. Cardiac and respiratory function after bone marrow transplantation in children with leukaemia. Bone Marrow Transplant 1995; 16: 571−576. | PubMed | ChemPort | |
| 110. | Benvenuto GM, Ometto R & Fontanelli A et al. Chemotherapy related cardiotoxicity: new diagnostic and preventive strategies. Ital Heart J 2003; 4: 655−667. | PubMed | |
| 111. | Ritchie JL, Bateman TM & Bonow RO et al. Guidelines for clinical use of cardiac radionuclide imaging: A report of the American College of Cardiology/American Heart Association Task Force on assessment of diagnostic and therapeutic cardiovascular procedures (Committee on Radionuclide Imaging) − developed in collaboration with the American Society of Nuclear Cardiology. J Nucl Cardiol 1995; 2: 172−192. | PubMed | ChemPort | |
| 112. | Steinherz LJ, Graham T & Hurwitz R et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Childrens Cancer Study Group. Pediatrics 1992; 89: 942−949. | PubMed | ChemPort | |
| 113. | Basser RL, Abraham R & To LB et al. Cardiac effects of high-dose epirubicin and cyclophosphamide in women with poor prognosis breast cancer. Ann Oncol 1999; 10: 53−58. | Article | PubMed | ChemPort | |
| 114. | Lele SS, Durrant ST & Atherton JJ et al. Demonstration of late cardiotoxicity following bone marrow transplantation by assessment of exercise diastolic filling characteristics. Bone Marrow Transplant 1996; 17: 1113−1118. | PubMed | ChemPort | |
| 115. | Suzuki J, Yanagisawa A & Shigeyama T et al. Early detection of anthracycline-induced cardiotoxicity by radionuclide angiocardiography. Angiology 1999; 50: 37−45. | PubMed | ChemPort | |
| 116. | Lindahl B, Toss H & Siegbahn A et al. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med 2000; 343: 1139−1147. | Article | PubMed | ChemPort | |
| 117. | Herman EH, Zhang J & Lipshultz SE et al. Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin. J Clin Oncol 1999; 17: 2237−2243. | PubMed | ChemPort | |
| 118. | Kremer LC, van Dalen EC & Offringa M et al. Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study. J Clin Oncol 2001; 19: 191−196. | PubMed | ChemPort | |
| 119. | Cardinale D, Sandri MT & Colombo A et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 2004; 109: 2749−2754. | Article | PubMed | ChemPort | |
| 120. | Erselcan T, Kairemo KJ & Wiklund TA et al. Subclinical cardiotoxicity following adjuvant dose-escalated FEC, high-dose chemotherapy, or CMF in breast cancer. Br J Cancer 2000; 82: 777−781. | Article | PubMed | ChemPort | |
| 121. | Yasue H, Yoshimura M & Sumida H et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994; 90: 195−203. | PubMed | ISI | ChemPort | |
| 122. | Nousiainen T, Jantunen E & Vanninen E et al. Natriuretic peptides as markers of cardiotoxicity during doxorubicin treatment for non-Hodgkin's lymphoma. Eur J Haematol 1999; 62: 135−141. | PubMed | ChemPort | |
| 123. | Nousiainen T, Vanninen E & Jantunen E et al. Natriuretic peptides during the development of doxorubicin-induced left ventricular diastolic dysfunction. J Intern Med 2002; 251: 228−234. | Article | PubMed | ChemPort | |
| 124. | Kazanegra R, Cheng V & Garcia A et al. A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study. J Card Fail 2001; 7: 21−29. | Article | PubMed | ChemPort | |
| 125. | Fleming SM, O'Gorman T & O'Byrne L et al. Cardiac troponin I and N-terminal pro-brain natriuretic peptide in umbilical artery blood in relation to fetal heart rate abnormalities during labor. Pediatr Cardiol 2001; 22: 393−396. | PubMed | ChemPort | |
| 126. | Snowden JA, Hill GR & Hunt P et al. Assessment of cardiotoxicity during haemopoietic stem cell transplantation with plasma brain natriuretic peptide. Bone Marrow Transplant 2000; 26: 309−313. | Article | PubMed | ChemPort | |
| 127. | Niwa N, Watanabe E & Hamaguchi M et al. Early and late elevation of plasma atrial and brain natriuretic peptides in patients after bone marrow transplantation. Ann Hematol 2001; 80: 460−465. | Article | PubMed | ChemPort | |
| 128. | Appelbaum FR. Hammering away at solid tumors. Cancer Treat Rep 1987; 71: 115−117. | PubMed | ChemPort | |
| 129. | Green S & Weiss GR. Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 1992; 10: 239−253. | Article | PubMed | ISI | ChemPort | |
| 130. | Feneley M & Lim CA. Cardiac complications. In: Atkinson K (ed.).Clinical Bone Marrow and Blood Stem Cell Transplantation Cambridge University Press: London 2000; pp 952−957. |
| 131. | Leahey AM, Teunissen H & Friedman DL et al. Late effects of chemotherapy compared to bone marrow transplantation in the treatment of pediatric acute myeloid leukemia and myelodysplasia. Med Pediatr Oncol 1999; 32: 163−169. | Article | PubMed | ChemPort | |
| 132. | Leung W, Hudson MM & Strickland DK et al. Late effects of treatment in survivors of childhood acute myeloid leukemia. J Clin Oncol 2000; 18: 3273−3279. | PubMed | ChemPort | |
| 133. | Liesner RJ, Leiper AD, Hann IM & Chessells JM. Late effects of intensive treatment for acute myeloid leukemia and myelodysplasia in childhood. J Clin Oncol 1994; 12: 916−924. | PubMed | ChemPort | |
| 134. | Pihkala J, Saarinen UM & Lundstrom U et al. Effects of bone marrow transplantation on myocardial function in children. Bone Marrow Transplant 1994; 13: 149−155. | PubMed | ChemPort | |
| 135. | Keefe DL. Trastuzumab-associated cardiotoxicity. Cancer 2002; 95: 1592−1600. | Article | PubMed | ISI | ChemPort | |
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