No evidence for relevant QT interval prolongation in mitotane-treated patients with adrenocortical carcinoma
S. Ederhy1,2, A. Cohen1,2, G. Dufaitre1,2, R. Chaderevian3, H. Abbas4, X. Bertagna5,6, and R. Libé5,6
1Department of Cardiology, Saint-Antoine University; 2Department of Cardiology, Medical School and Université Pierre et Marie Curie; 3Laboratoire HRA Pharma; 4Toxicology, Assistance Publique-Hôpitaux de Paris, Cochin Hospital; 5INCa-COMETE Network for Adrenal Cancers and Departement of Endocrinology, Assistance Publique-Hôpitaux de Paris, Cochin Hospital; 6Centre National de la Recherche Scientifique Unité Mixte de Recherche, Institut Cochin, U1016, Paris Descartes University, Paris, France
ABSTRACT. Objective: We designed a single-center retro- spective study to assess the QT interval duration and to de- scribe cardio vascular events among patients treated with mi- totane for a adrenocortical carcinoma (ACC). Design: We se- lected 14 patients (6 males and 8 females) that met the fol- lowing criteria: ACC treated with mitotane, for whom an elec- trocardiogram (ECG) at baseline (before mitotane initiation) was available and for whom at least one ECG was available during the course of mitotane therapy together with a con- comitant mitotane plasma level determination. Results: Mean mitotane plasma level at baseline and after treatment showed a significant increase (mean level increased from 0 to 14.9±2 mg/l). At baseline and before mitotane was initiated all QTc intervals were <450 msec for men and <460 msec for women. During the treatment phase with mitotane, no QTc>470 msec
was found in any patients respectively for men and women. In addition, no patient showed any significant QTc prolongation (>5% or >10 msec) at any time during mitotane treatment. During a mean follow-up of 15.9+3.5 months (range 2-45 months). No cardiovascular deaths or hospitalization for car- diovascular events was documented. No torsades de pointes were documented on ECG. No syncope, dizziness, heart failure were observed during follow up. Six out of 14 patients died during the follow-up, in five cases due to the progression of the disease, one patient died suddenly at home during follow- up. Conclusion: This short and retrospective series shows no evidence that mitotane induce any QT prolongation, even when plasma levels are well above the therapeutic window. (J. Endocrinol. Invest. 35: 911-914, 2012) @2012, Editrice Kurtis
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare malignancy as- sociated with a dismal prognosis, the survival rate at 5 yr being between 16% and 38% among series (1, 2) Surgery remains the only curative modality in those patients with localized tumors that can undergo complete surgical re- moval (3-5).
Mitotane (o,p’-DDD) is a pharmacological agent avail- able for treatment of metastatic or recurrent ACC since many decades (3). It has been recently shown also to de- crease the probability of recurrence when given in an ad- juvant setting after complete surgery (6).
Mitotane has a narrow therapeutic window that lies be- tween 14 and 20 mg/l (7). Monitoring mitotane plasma concentrations is the key to obtain efficient tumor re- gression while avoiding serious adverse events. A con- centration of ≥14 mg/l is admitted for anti-tumor re- sponse and the probability of adverse effects increases when mitotane plasma levels are greater than 20 mg/l (8). More than 80% of all patients experience undesirable effects, mainly from gastrointestinal or from the central nervous systems (9, 10). These undesirable effects are re- versible after cessation of mitotane or by decreasing the
dose. Until now, no cardiovascular undesirable effects have been reported (11, 12)
Recently, QT prolongation was reported in a single pa- tient receiving mitotane for a metastatic ACC (12) rais- ing the question as to whether mitotane could contribute to prolong the QT interval.
Although the extensive clinical and literature data have not shown any other evidence of an association between exposure to mitotane and QT prolongation, we designed a single-centre retrospective study to assess the QT in- terval duration and to describe cardiovascular events among patients treated with mitotane for ACC and whose mitotane blood levels were available.
PATIENTS AND METHODS Patients
We analyzed the records of ACC patients followed in the En- docrinology Department of Cochin Hospital who were treat- ed with mitotane (Lysodren HRA-pharma) between April 2004 and October 2008. We selected 14 patients (6 males and 8 fe- males) that met the following criteria: ACC treated with mi- totane, for whom an electrocardiogram (ECG) at baseline (be- fore mitotane initiation) was available and for whom at least one ECG was available during the course of mitotane therapy together with a concomitant mitotane plasma level determi- nation. Ten patients were excluded because no pre-treatment ECG was available.
Using medical report, clinical examination, routine biological evaluation (potassium, sodium, creatinemia), concomitant treat- ments were recorded for each patients, at each time point of ECG evaluation (before and after mitotane treatment). Cardio-
Key-words: ???
Correspondence: A. Cohen, MD, Departments of Cardiology, Saint -Antoine Univer- sity and Medical School, Paris, France and Université Pierre et Marie Curie, 184 rue du faubourg St Antoine 75012 Paris, France.
E-mail: ariel.cohen@sat.aphp.fr
Accepted August 2, 2012.
First published online September 24, 2012.
vascular risk factors, history of acute coronary syndrome, of thromboembolism were also evaluated. Moreover, sudden death, torsade de pointes (TdP), hospitalization for heart failure, syncope, and dizziness were recorded.
QT measurement and ECG evaluation
A total of 42 ECG were performed in the 14 patients with ACC ECG performed before mitotane initiation (no .= 14) and during treatment (no .= 28) were manually reviewed by an independent single investigator (SE) who was blinded to the results of mi- totane plasma levels. Rhythm, auricular and ventricular delay, QRS axis, QRS duration, Q wave, and ventricular arrhythmias were noted on the 12-lead. All ECG were also assessed for de- tection of electrocardiogramagnoses and morphological changes.
QT interval was measured manually and according to the fol- lowing recommendation:
1.QT interval duration was measured manually using the lead that best showed the end of the T wave
2. QT interval duration was averaged and determined as a mean value derived from at least 3 to 5 cycles.
QT intervals were corrected for heart rate (HR) using both Bazett’s and Fridericia’s correction formula. Whichever formula was used a QTc was considered abnormally prolonged when measured above 470 msec for males and 480 msec for females (12).
Twenty randomly chosen ECG were re-measured 3 months lat- er by the same observer and by another observer to assess re- producibility.
The intra- and interobserver coefficients of variation were 1.8 and 1.9%, respectively.
Mitotane measurement
All determinations of mitotane plasma levels were assayed using an isocratic high-performance liquid chromatography in the De- partment of Biochemistry at Cochin Hospital. Briefly, samples were subjected to deproteinization with cold acetone, and O,p- DDD levels were quantified using a diode-array detector with 1,1-dichloro, 2,2-bis (p-chlorophenyl) ethylene as an internal standard (13).
RESULTS Patients
Fourteen patients with ACC (6 males and 8 females; me- dian age 44.2±4.5 yr; range 20-67 yr) treated with mi- totane and for whom serial ECG and mitotane determi- nation were available for the study population.
The main characteristics are detailed in Table 1.
No cardiovascular diseases were presents in the 14 pa- tients. Six patients were treated for hypertension, four patients for dyslipidemia, none had diabetes mellitus. Two patients were current smokers and smoke with- drawal was noticed in 3.
ECG assessments and QT evaluation
The QT interval is measured from the beginning of the QRS complex to the end of the T wave and approximates the time it takes the ventricles to repolarize.
At baseline and before mitotane was initiated no QTc prolongation (i.e >470 msec for men and >480 msec for women) was found. All QTc intervals were <450 msec for men and <460 msec for women. During the treatment phase with mitotane, no QTc >470 msec was found in any patients respectively for men and women. In addi- tion no patient showed any significant QTc prolongation (>5% or >10 msec) at any time during mitotane treat- ment.
Mean mitotane plasma level at baseline and after treat- ment showed a significant increase (mean level increased from 0 to 14.9±2 mg/l) (Table 2).
Cardiovascular events during follow-up
Mean±SE follow-up duration was 15.9±3.5 months (range 2-45 months). No cardiovascular deaths or hospi- talization for cardiovascular events was documented. One patient developed deep venous thrombosis and a non fatal pulmonary embolism. No TdP were documented on ECG. No syncope, dizziness, heart failure were observed during follow-up. Six out of 14 patients died during the follow-up, five of them due to the progression of the dis-
| Pt # | Gender (M/F) | Age (yr) | MacFarlane/ EnS@T stage | Hypertension (Y/N) | ECG during follow-up (no.) | Follow-up (months) | Alive (Y/N) | Cause of death | Serum potassium (mmol/l) | Max dose mitotane (g/day) | Max plasma mitotane (µg/ml) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 24 | 4 | Y | 4 | 7 | N | ACC related | 3.6 | 4.5 | 23.5 |
| 2 | M | 67 | 4 | N | 2 | 5 | N | ACC related | 3.9 | 1.0 | 13 |
| 3 | F | 52 | 4 | Y | 2 | 13 | N | ACC related | 5.1 | 1.5 | 16.5 |
| 4 | F | 45 | 4 | N | 2 | 8 | N | ACC related | 3.3 | 4.5 | 16.5 |
| 5 | F | 25 | 4 | Y | 3 | 43 | N | Unknown | 3.5 | 3.0 | 10 |
| 6 | F | 20 | 4 | N | 3 | 15 | Y | 3.9 | 2.0 | 6 | |
| 7 | M | 44 | 4 | N | 1 | 18 | N | ACC related | 3.8 | 4.5 | 27 |
| 8 | M | 56 | 4 | Y | 1 | 15 | Y | 4.1 | 4.5 | 8.5 | |
| 9 | M | 46 | 4 | N | 3 | 45 | Y | 4.1 | 4.5 | 29 | |
| 10 | F | 57 | 2 | N | 1 | 2 | Y | 3.8 | 1.5 | 7.5 | |
| 11 | F | 65 | 2 | Y | 2 | 14 | Y | 3.5 | 4.5 | 12 | |
| 12 | F | 30 | 2 | N | 1 | 19 | Y | 3.8 | 6.0 | 6.5 | |
| 13 | M | 64 | 2 | Y | 2 | 12 | Y | 3.7 | 3.0 | 18.5 | |
| 14 | M | 24 | 2 | N | 1 | 6 | Y | 3.9 | 2.0 | 14.5 |
Pt: patient; M: male; F: Female; ECG: electrocardiogram; Y: yes; N: no.
| Pt # | QTc (msec) Baseline | QTc (msec) / mitotane blood level (mg/l) | QTc (msec) / mitotane blood level (mg/l) | QTc (msec) / mitotane blood level (mg/l) | QTc (msec) / mitotane blood level (mg/l) |
|---|---|---|---|---|---|
| 1 | 409 | 399/8.5 | 397/14 | 406/23.5 | 406/23 |
| 2 | 440 | 449/13 | 432/10.5 | ||
| 3 | 415 | 420/1.5 | 412/16.5 | ||
| 4 | 390 | 392/4.5 | 399/16.5 | ||
| 5 | 400 | 396/3 | 402/2.5 | 406/8.7 | |
| 6 | 388 | 379/2 | 389/2 | 396/6 | |
| 7 | 445 | 447/7.5 | |||
| 8 | 390 | 400/12 | |||
| 9 | 436 | 435/4.5 | 425/27 | 420/25 | |
| 10 | 370 | 369/6 | |||
| 11 | 400 | 400/3 | 409/18.5 | ||
| 12 | 420 | 415/4.5 | |||
| 13 | 398 | 407/4.5 | 392/29 | ||
| 14 | 447 | 440/14.5 |
n
ease. One patient (#5 in Table 1) died suddenly at home during follow-up. She had a metastatic ACC (MacFarlane 4), treated with mitotane with mitotane plasma level above the range of 14 µg/ml. The QT interval was always below 480 msec on three occasions. The cause remains unknown, as autopsy was not performed.
DISCUSSION
In the present study, no significant QT prolongation was found in a series of patients treated with mitotane for metastatic ACC. This is in disagreement with the single case report of a 56-yr-old woman treated with mitotane for a metastatic ACC in whom ECG evaluation after 2 yr of mitotane treatment showed a prolonged QT interval, while mitotane plasma level was of 21.8 mg/l (13). The QT interval was found to be reduced after decreasing the mitotane doses and consequently mitotane plasma levels. Although the causal relationship cannot be ruled out in this case, the following limits should be noticed. Indeed, the patient exhibited other possible causes of long QT, such as left ventricular hypertrophy and hypo- magnesia.
In our study, no patient, even those who reached a mi- totane plasma above the therapeutic window (level >20 mg/l), showed an abnormal QT interval. This upper limit has been linked with increasing the risk of adverse events and more particularly neurotoxicity. Moreover, during fol- low up, we found no cardiovascular events that could have been explained by TdP. Although this study is ret- rospective and includes a limited number of patients, it is strengthened by the fact that mitotane levels were regu- larly monitored in all of them. In 7 out the 14 patients mi- totane levels values reached a level ≥14 mg/l (50%), that is better than usually reported in the medical practice (7). However, no difference in QT measurement was found among the 3 groups of patients (those with mitotane lev- el <14, between 14-20 and >20) (data not shown).
Apart from the known genetic causes in which hundreds of mutations in 10 genes were identified (long-QT syn-
drome), metabolic disorders such as hypocalcemia, hy- pokalemia, hypomagnesemia, hypothyroidism, and var- ious drugs may also be associated with prolonged QT interval (14). Among toxicities associated with new drugs, particularly in molecularly targeted oncology therapies, one of the most threatening complications of angiogenic inhibitors or new cancer drug could be QT prolongation with the risk of TdP and sudden death. QT prolongation and TdP accounted for 29% of cardiac and non cardiac post-marketing withdrawals. The assessment of the ef- fects of drugs on cardiac repolarization is the subject of recent guidelines and recommendations. Regulatory agencies now require practically every new pharmaceu- tical compound to undergo a thorough investigation of its propensity to modify cardiac repolarization. Howev- er, mitotane is not a molecularly-targeted therapy and it has been widely used in the clinical setting for more than 50 yr for treatment ACC, a disease with poor prognosis. The QT interval indicates the duration of ventricular de- polarization and repolarization caused by the transmem- brane flow of ions. TdP are the main complication of QT prolongation. They can be identified on a 12-lead ECG or on Holter ECG monitoring. TdP denotes a polymorphic ventricular tachycardia with characteristic beat by beat QRS complexes of changing amplitude that appear to be twisting around the isoelectric line (14). Clinical man- ifestations vary considerably from a lack of symptoms in case of short and self-terminating episodes to longer episodes which can cause syncope, cardiac arrest by ven- tricular fibrillation, or sudden death. Measurement and interpretation of the QT interval is subject to substantial variability and misinterpretation. Several factors are known to influence the value of the QT interval and should be taken into account when interpreting the mea- surement of the QT interval. Women have a longer QT in- terval than men and their QTc cut-off values are conse- quently higher (14). The QT interval value is influenced and depends on the HR. Rate acceleration leads to QT shortening, whereas bradycardia leads to QT prolonga- tion.
Several QT HR correction methods using linear regres- sion (Framingham and Hodges) and non-linear formulas (Bazett, Fridericia) have been developed to mathemati- cally correct QT for HR variation. The most effective for- mula in identifying and predicting patients at higher risk of a clinical event such as syncope or TdP is currently un- known (14).
Apart from any therapy, ECG abnormalities are frequent in oncology patients. In women treated with radiothera- py for breast cancer, 19% were found to have T wave changes before treatment (15). A retrospective study con- ducted in patients treated in phase 1 and 2 trials sug- gests that cancer patients may have a baseline QTc that is prolonged compared to other populations. If cancer patients were to be excluded from a clinical trial based on the presence of a borderline or prolonged baseline QTc, approximately 15% would have been excluded based on this analysis.
Patients bearing metastatic ACC are exposed to a variety of cardiovascular risks, related to their disease: excess of glucocorticoids and/or mineralocorticoids may induce high blood pressure, diabetes, lipid disorders, hy- pokalemia, and coagulation disorders. The latter can be sometimes aggravated by estrogen excess from the tu- mors.
By reducing tumor hypersecretion, mitotane should im- prove all these disorders. Its only known, potential, ad- verse effect on the cardiovascular system should be in- direct, through its possible estrogen-like action (16) and to the increase in LDL-cholesterol (15, 17). This study does not provide evidence for any direct action at the heart level that would modify the depolarization of car- diac cells.
Our study has some limitations, due to a small number of patients, and its retrospective nature, with no 24-h Holter ECG monitoring. There is also the question about this single subject who died suddenly at home, for a reason that was not identified: this patient, however, had nor- mal QTc in three occasions and was also on treatment with plasma mitotane levels which never exceed 10 mg/l. Moreover, we cannot exclude that other risk factors for QT interval prolongation, as metabolic disorders (hypo- calcemia, hypokalemia, hypomagnesemia) may have an additive role in patients on mitotane treatment.
In conclusion, this short and retrospective series shows no relevant evidence that mitotane induce any QT pro- longation, even when plasma levels are well above the therapeutic window.
ACKNOWLEDGMENTS
This work was sponsored by the Department of Endocrinology, Cochin Hospital, INCa COMETE Network for Adrenal Cancers and supported by a grant of HRA pharma.
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