Med. Oncol. & T , mor Pharmacother. Vol. 2, No, 2. pp. 93-97. 1985 073(v--0118/85 $3,(1(I + (I.11(I Printed in Great Britain Pergamon Press Ltd.

P O S S I B L E E N H A N C E M E N T O F T H E C A R D I O T O X I C I T Y O F D O X O R U B I C I N W H E N C O M B I N E D W I T H M I T O M Y C I N C

FABRIZIO VILLANI,* ROBERTO COMAZZI,* GEMMA LACAITA.* ANTONIO GUINDANI,* VALERIO GENITONI,* ALBERTO V O L O N T E R | O t and MARIA CRISTINA BRAMBILLA';

Servizio di Cardiologia e Fisiopatologia Respiratoria, and tDivisione di Oncologia Medica, Istituto Nazionale per 1o Studio e la Cura dei Tumori, Milan, Italy

Forty-six patients with recurrent metastatic breast cancer were treated with a combination chemotherapy including doxorubicin and mitomycin C. Myocardial contractility was monitored by means of echocardiography. During therapy there was a progressive deterioration of myocardial function, and this phenomenon was found to be linearly correlated to the cumulative dose of doxorubicin. Six patients (13.8%) developed congestive heart failure during therapy; it occurred after the median cumulative dose of 322 mg/m 2 (range 135-472). Possible risk factors of cardiomyopathy could be identified in only two patients. These results suggest that mitomycin C could enhance the cardiotoxicity of doxorubicin.

Key words: Cardiotoxicity, Doxorubicin, Mitomycin C.

INTRODUCTION

A dose-dependent cardiomyopathy is the major factor that limits the use of doxorubicin in long-term treatment. I-2 At present, doxorubicin is widely used in regimens that include other antineoplastic treat- ment or agents, some of them potentially cardiotox- ic, therefore much effort has been made to define the occurrence and the importance of factors other than the cumulative dose of doxorubicin that could increase the risk of onset of anthracycline-delayed cardiomyopathy. Some factors that could increase the risk of cardiomyopathy have been identified: they include mediastinal irradiation, -~9 advanced age, 3"4 some drugs such as actinomycin D, 1~ mith- ramycin, l~ cyclophosphamide, r melphalan, 13 vincristine when given both before and concomi- tantly with doxorubicin, 8 bleomycin when given before doxorubicin, s and hypertensive and valvular heart disease associated with cardiac hypertrophy. 1 t

Some years ago, a significantly increased incid- ence of late onset of congestive heart failure was observed in patients with advanced breast cancer, previously treated with doxorubicin, who sub- sequently received mitomycin C as a second-line therapy.t4 More recently, two groups also observed a high incidence of congestive heart failure and

Address for reprints: Dr F. Villani, Servizio di Cardio- Iogia e Fisiopatologia Respiratoria, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy.

93

cardiopulmonary deaths in patients treated with adriamycin in combination with mitomycin C. 15"1~'

In this article we report retrospective data on myocardial function recorded in 46 advanced cancer patients subjected to a combined chemotherapy with doxorubicin plus mitomycin C. The analysis of toxic findings suggests the possibility that mitornycin C could enhance the cardiotoxicity of doxorubicin.

PATIENTS AND METHODS

The study was conducted on 46 women with recurrent metastatic breast cancer. The median age was 55 + 1.3 (range 33-67 years). Thirty-seven patients were treated with a single i.v. injection of doxorubicin, 45 mg/m-', every third week and with 10 mg/m 2 i.v. of mitomycin C every sixth week; 9 patients with 60 mg/m 2 of doxorubicin every third week and with 10 mg/m 2 of mitomycin C every sixth week. After 500 mg/m 2 of doxorubicin, treatment was continued with mitomycin C (20 rag/m-" at 6-week intervals). Four patients had previously been treated with tamoxifen plus radiotherapy; two with CMF, nine with radiotherapy, one with CMF plus radiotherapy, and one with doxorubicin (cumulative dose 125 mg/m-').

Of the patients considered in this study, three suffered from mild hypertension and had been treated with diuretics, three from diabetes (treated with oral antidiabetic drugs), three from glucose

94 F. Villani et al.

intolerance, and one from Rejnaud syndrome. No patient had previously suffered from congestive heart failure or severe arrythmias, and none had an abnormal ECG upon entering the study. None of the patients had any clinical signs of congestive heart failure.

Possible risk factors for doxorubicin car- diomyopathy were determined for all patients: they included age, history of heart disease (hypertension, valvular heart disease, ECG abnormalities, arter- iosclerotic heart disease), prior irradiation to the left or right chest wall, and prior therapy with anthracy- clines or other antineoplastic drugs with possible cardiotoxic activity (5-fluorouracil, cyclophospham- ide, bleomycin, vincristine).

Cardiologic evaluation consisted of systemic recording of arterial blood pressure, heart rate, ECG, echocardiography. In particular, echocar- diography examination was recorded before drug administration and three weeks after reaching the cumulative doses of 100, 200, 300, 400 and 500 mg/m z. The last control was done four weeks after completing therapy with doxorubicin. M-mode echocardiography was performed with an Ekoline 21 Smith-Kline Instrument. The percentage of the fractional shortening of the left ventricular minor axis and the relative velocity of contraction were used as indices of left ventricular contractility.

Percent minor axis fractional shortening (MAS%) was defined as (LVIDd-LVIDs)/(LVIDd) where LVIDd = left ventricular diameter in end dyastole and LVIDs = left ventricular diameter in end systole. The relative velocity of contraction (RVC) was defined, according to Knapp 7 as (VCF)/(0.14 + 0.014HR) where VCF = mean velocity of circum- ferential fiber shortening and HR = heart rate.

RESULTS

Of the 46 patients treated with doxorubicin + mitomycin C, 16 received a cumulative dose of less than 300 mg/m 2, 22 between 301 and 500 mg/m 2, and eight more than 500 mg/m 2. Of those who received

dose in excess of 500 mg/m z, four were treated with single doses of 45 mg/m 2 of doxorubicin and four with doses of 60 mg/m 2.

ECG abnormalities observed during the treament were mainly represented by tachycardia and arrhyth- mia (in particular, atrial and ventricular ectopic beats). Some patients developed nonspecific changes of the ST-T segment (mainly flattening of the T wave). ECG abnormalities were observed in 53.1% of patients.

Cardiac toxicity in chronically treated patients was monitored by echocardiography. The analysis of serial echocardiograms obtained from eight patients who received up to 500 mg/m 2 indicated that a linear regression relationship exists between the indices of left ventricular contractility (the percentage of the fractional shortening of the left ventricular axis and the relative velocity of contraction) and the cumula- tive dose of doxorubicin: these results confirm the existence of a progressive cumulative cardiotoxic effect 18-19 (Fig. 1).

RVC

1.0

0.9

0.8

0.T

Y= 0.879-'( 0.000319 X ) R-- 0.87

M~SZ Y=32.1- (0.0127 X ) 3S " t ' r R---0.82

2S

/ 0 100 200 300 400 S00

O X R CUMULATIVE DOSE rag/rn 2

Fig. 1, Relative velocity of contraction (RVC) and minor axis shortening % (MAS%) recorded after different cumulative doses of doxorubicin (mean __. SE of 8

patients).

Six patients (13.0%) developed congestive heart failure during the treatment. Cardiomyopathy was observed after a median dose of 322 mg/m2: three

Table 1. Clinical and cardiac functional data in patients with heart failure

Patient Heart Dispnea Rales $3 Heart enlargement Echo No. rate at chest X-ray MAS% RVC

1 109 + + + - 17.4 0.44 2 132 + + + - 28.4 0.57 3 107 + + + + 14.3 0.40 4 90 + + + + 26.2 0.79 5 103 + + - + 18.9 0.51 6 107 + + - - 20.2 0.46

MAS%: minor axis shortening %; RVC: Relative velocity of contraction.

cases at a dose less than 300 mg/m 2, three between 301 and 500 mg/m 2.

Clinical and cardiac functional data of these patients are reported in Table 1. It shows that five of six patients had tachicardia, all had dyspnea, all had rales and in three of six heart enlargement could be demonstrated at chest x-ray. Percent decrease of QRS voltage than 20% was present in four patients. Minor axis shortening percent was found less than 24 in four patients while relatively velocity of contrac- tion less than 0.8 in all patients.

The characteristics of patients who developed congestive heart failure in relation to the possible risk factors are reported in Table 2. The median age was 59 years (range 55-65), which is slightly higher than the whole group (53 years). The mean hemog- lobin was 12.6 + 0.3 g/100 ml compared to 12.7 _ 0.2 of patients who had no myocardial disfunction. (e > 0.05).

None of the patients who developed congestive heart failure had preexisting heart disease. How- ever, the fourth patient had suffered for more than three years from mild hypertension and was treated with diuretics + reserpine. Patient 3 had been treated four years before with CMF and two years before had received irradiation on the left chest wall.

DISCUSSION

The clinical and pathologic findings observed in this study are represented by ECG changes, a progressive deterioration of myocardial contractil- ity, and in some patients by the sudden onset of a severe cardiomypathy with cardiac failure. ECG changes were not different from those observed in patients treated with doxorubicin alone, but the incidence observed in this study (53%) is higher than that reported after doxorubicin ~,,8 or other anthracycline analogs 19-2~ or doxorubicin in

Enhancement of cardiotoxicity of doxorubicin 95

combination with other antineoplastic drugs. ~ As regards the effect on myocardial contractility it

was found that during the combined treatment with doxorubicin and mitomycin C there was a progress- ive dose-dependent deterioration of myocardial contractility, as has been described for doxorubicin. 2~-= In particular there was a progress- ive decrease of the relative velocity of contraction and of the percentage of the minor axis shortening. In contrast, the incidence of congestive heart failure observed in this study (13%) was significantly higher than that expected with doxorubicin alone or in combination chemotherapy without mitomycin. 8''8 On the other hand this incidence of cardiac toxicity was higher than that expected with F.A.M. a combination of doxorubicin, fluorouracil and mitomycin C largely utilized for the t r e a t m e n t o f cancer of lung,'-'- digestive tract 24-2s and prostate. 26.

The analysis of risk factors in patients who developed congestive heart failure showed that two patients were at moderate risk of anthracycline cardiomyopathy (patients 3 and 4, Table 2), but no known risk factor could be identified in four patients (8.6%). These results suggest that. mitomycin C could enhance the cardiotoxicity of doxorubicin when the two drugs are used in combination. The biochemical basis of the phenomenon remains to be ascertained, since there are no convincing reports of mitomycin C as a potential cardiotoxic agent. 27 For instance, hemorrhages have been described in the endocardium and pericardium of dogs that received mitomycin C, but it should be stressed that this lesion is not specific of cardiac toxicity since hemorrhage is the most conspicuous gross finding in many other organs. 2s

More recently, it was demonstrated that in iso- lated guinea pig heart, mitomycin C does not significantly inhibit contractile force or enhance the doxorubicin-induced negative inotropic effect. 29

Another possibility is that mitomycin C, although

Table 2. Possible cardiomyopathy risk factors in patients who developed congestive heart failure

Patient Age Pre-existing Pre-existing Pre-existing Doxorubicin No. (yr) pathologic ECG treatment dose

conditions changes (m~m 2)

Cumulative Cumulative mitomycin doxorubicin

dose at which dose at which CHF occurred CHF occurred

1 6 5 - - - - - - 45 2 55 - - - - - - 45 3 58 - - - - 4 years before, 45

CMF + RT on left chest wall

4 57 Mild hypertension - - - - 60 Glucose intolerance

5 55 Lung metastases - - - - 45 6 67 - - - - - - 6O

50 405 20 135 75 472

35 390

55 265 40 270

CMF: cyclophosphamide + methotrexate + 5-fluorouracil; CHF: congestive heart failure; RT: radiotherapy.

96 F. Villani et al.

devoid of cardiotoxic properties, might potentiate the doxorubicin-induced cardiotoxicity by an in- direct mechanism: in particular, cardiomyopathy could be favoured by hypoxia induced by a severe anemia. Nevertheless, patients who developed congestive heart failure did not suffer from severe hematologic toxicity or relevant anemia. Therefore , anemic hypoxia does not seem to have played an important role in determining cardiac toxicity.

A further possibility is that some patients had indeed subclinical heart disease prior to receiving doxorubicin: this could be suggested by the fact that the base line value of minor axis shortening percent and of the relative velocity of contraction before treatment were at the inferior limit of normal range.

On the other hand it must be remembered that M-mode echocardiography is less sensitive than two-dimensional echocardiography, in the detection of abnormalities in left ventricular contraction, which are somet imes the first sign of an underlying subclinical cardiomyopathy.

In conclusion, the unexpected high incidence of cardiac toxicity observed in this study is still unex- plained and the possibility that mitomycin C could enhance the cardiotoxicity of doxorubicin cannot be excluded.

Patients submitted to a combined treatment with doxorubicin and mitomycin C should therefore be monitored closely for the possibility of congestive heart failure during treatment.

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