6 Practical treatment using mitotane for URRENT PINION adrenocortical carcinoma
Massimo Terzoloª, Barbara Zaggiaª, Barbara Allasinoª, and Silvia De Franciab
Purpose of review
Description of novel findings about the mechanism of action of mitotane and its activity as an adjunctive postoperative measure, or for treatment of advanced adrenocortical carcinoma.
Recent findings
Several in-vitro studies have shown that mitotane suppresses gene transcription of different enzymatic steps of the steroidogenetic pathway. Moreover, mitotane induces CYP3A4 expression, thus accelerating the metabolic clearance of a variety of drugs including steroids. Retrospective studies provided evidence that adjunctive mitotane can prolong recurrence-free survival of treated patients. The concept of a therapeutic window of mitotane plasma concentrations was confirmed also for adjunctive treatment, but the relationship between mitotane concentration and given dose is loose. Genetic variability of the P450-dependent enzymes metabolizing mitotane may explain individual differences.
Summary
Mitotane concentration of 14-20 mg/l should be reached and maintained during treatment also in an adjunctive setting. In advanced adrenocortical carcinoma, a high-dose starting regimen should be employed when mitotane is used as monotherapy. The combination of mitotane with other drugs should consider the possibility of pharmacologic interactions due to mitotane-induced activation of drug metabolism. This concept applies also to steroid replacement in mitotane-treated patients, who need higher doses to adjust for increased steroid metabolism.
Keywords
adjunctive treatment, adrenocortical carcinoma, mitotane, overall survival, recurrence-free survival
INTRODUCTION
A limited range of therapeutic options is available for adrenocortical carcinoma (ACC). Both the rarity and aggressiveness of ACC concur to hamper progress in the development of treatment beyond surgery. Despite recent advancements, knowledge of the molecular pathways underlying ACC develop- ment and progression remains limited and up to now no effective target therapy entered use [1].
In this grim scenario, mitotane remains a cornerstone in the management of patients with ACC. More than 50 years have passed since mitotane was applied in clinical practice; however, we still have many uncertainties on how to use this old drug and what we may expect in terms of activity [2]. Mitotane is currently used in a postoperative adju- vant setting and in advanced disease. However, no results from randomized prospective trials on mitotane are available to guide management.
The objective of this work is to provide a concise review of recent advances in the use of mitotane.
The most interesting articles published over the past 24 months dealt with the mechanism of action of mitotane and its practical use in the management of patients with ACC, and these topics will be addressed in the present review.
MECHANISM OF ACTION OF MITOTANE
Despite the widespread knowledge that mitotane has a profound effect on steroidogenesis [1-3], the specific mechanisms underlying its inhibitory effect are not fully understood. Mitotane action on
ªInternal Medicine I and bPharmacology, Department of Clinical and Biological Sciences, University of Turin, Italy
Correspondence to M. Terzolo, MD, Internal Medicine I, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Regione Gonzole, 10 10043 Orbassano, Italy. Tel: +39 011 9026788; fax: +39 011 6705456; e-mail: terzolo@usa.net
Curr Opin Endocrinol Diabetes Obes 2014, 21:159-165
DOI:10.1097/MED.0000000000000056
KEY POINTS
· Mitochondria are the cellular targets of mitotane where it interferes with the respiratory chain activity and down-regulates expression of steroidogenic enzymes.
· Mitotane induces CYP3A4 gene expression, thus enhancing metabolic clearance of cortisol and a variety of drugs.
. It is still unclear which is the best strategy to give mitotane, even if a high-dose starting regimen provides elevated plasma concentrations in less time.
· Mitotane plasma concentrations should be kept higher than 14 mg/l during adjuvant treatment to attain a better outcome.
· The chemotherapic regimen EDP combined with mitotane is the current standard of care for advanced ACC.
adrenal steroidogenesis has been associated with the inhibition of a number of mitochondrial cytochrome P450-dependent enzymes: cholesterol
side chain cleavage (CYP11A1), 11ß-hydroxylase (CYP11B1), and 18ß-hydroxylase (CYP11B2) [4,5], as well as P450-independent enzymes, such as 3ß-hydroxysteroid-dehydrogenase [6].
Fresh data on this topic come from the study of Lin et al. [7”], who explored the effect of noncyto- toxic concentrations of mitotane on cortisol pro- duction by National Cancer Institute-Human 295 (NCI-H295) cells and found that mitotane interferes with gene transcription of a number of steroido- genic enzymes. Steroidogenic acute regulatory (protein) (StAR) and CYP11A1, which are involved in the rate-limiting step of steroidogenesis, are most sensitive to mitotane (Fig. 1). The effect on CYP11B1 was more stimulatory than inhibitory, contradict- ing early reports of a strong suppression of CYP11B1 activity [8].
The relationship between mitotane and steroi- dogenesis was also recently evaluated in other recent studies. van Koetsveld et al. [9] investigated the effect of mitotane and interferon-ß in primary cultures of ACC and found that both drugs strongly inhibited mRNA expression of StAR, CYP11A1, CYP17A1, and CYP11B1. Combination of mitotane
H
StAR
Cholesterol
H
H
HO
Cholesterol side-chain cleavage enzyme
OH
OH
O
O
O
O
OH
O
3ß-HSD
21a-
11ß-
HO
O
Aldosterone synthase
OH
hydroxylase
hydroxylase
Pregnenolone
Progesterone
Deoxy-
Corticosterone
Aldosterone
HO
O
O
corticosterone
O
O
17a-hydroxylase
OH
ỌH
O
O
O
O
17a-hydroxy pregnenolone
OH
17a-hydroxy gesterone
OH
deoxycortisol
OH
11ß-
HO
OH
3ß-HSD
21a-
hydroxylase
hydroxylase
Cortisol
HO
O
O
O
17,20 lyase
O
O
O
3ß-HSD
Aromatase
Dehydroepi- androsterone
Androstene- dione
Estrone
HO
O
HO
17ß-HSD
OH
OH
OH
3ß-HSD
Aromatase
Androstanediol
Testosterone
Estradiol
HO
O
HO
H
5a-reductase
OH
Dihydrotestosterone
O
H
and interferon-ß induced an additive inhibitory effect on cellular DNA number and cortisol secretion, suggesting that treatment with inter- feron-ß may increase sensitivity of ACC cells to mitotane. Lehmann et al. [10] studied the effect of a 24-h mitotane treatment on NCI-H295R cell via- bility and expression of genes involved in adrenal steroidosynthesis has been analyzed. It was found that mitotane markedly inhibited expression of genes coding for enzymes involved in generation of cortisol and dehydroepiandrosterone sulfate (CYP11A1 and CYP17A1). Moreover, mitotane reduced viability of NCI-H295R cells inducing cell apoptosis triggered by increased caspase 3 and cas- pase 7 activities. The mitotane-induced repression of genes of the steroidogenetic pathway has been confirmed by another study in the same cell line [11].
Chortis et al. [12""] studied the steroid inhibitory effect of mitotane in vivo, using a novel steroidobo- lomic approach, to analyze 24-h urine samples from ACC patients receiving mitotane for adjuvant treatment or metastatic disease. It was found that mitotane down-regulated the initial steps of steroido- genesis, but did not influence 11ß-hydroxylase activity. As previously discussed, in-vitro data are controversial about the mitotane effect on this enzy- matic step. Moreover, mitotane was found to be a strong inducer of CYP3A4 activity leading to gluco- corticoid inactivation and consequent sharp rise in 6ß-hydroxycortisol urinary excretion. It was calcu- lated that mitotane is able to inactivate 50% of administered hydrocortisone and this explains why patients on mitotane have an increased dose require- ment for steroid replacement. Finally, mitotane proved to be a strong inhibitor of 5a-reductase activity and this effect prompts us to use 5x-dihydro- testosterone as androgen substitution in mitotane- treated men. An important mitotane-induced derangement of cortisol and testosterone meta- bolism has been also shown in a similar study [13].
To evaluate which are the intracellular targets of mitotane, Poli et al. [14”] performed electron micro- scopy on human ACC H295R cells and SW13 cell lines. Increasing concentrations of mitotane caused marked alterations in the morphology of mitochon- dria in a dose and time-dependent manner. Mito- chondria were finally disrupted leading to a drastic reduction of cell oxygen consumption. Mitotane was converted by the mitotane-sensitive H295R cells in its active metabolites and exerted cytostatic and cytotoxic effects at doses corresponding to the thera- peutic window (30-50 umol/l). This study showed that mitotane effects seem to be mainly mediated by the mitochondria damage that activates an apoptotic process involving caspase 3 and caspase 7.
Further data showing that mitotane affects mitochondrial function have been reported by Hescot et al. [15”]. In H295R and SW13 cell lines, mitotane inhibited cell proliferation in a dose and a time-dependent manner, and suppressed cortisol and 17-hydroxyprogesterone through inhibition of a number of genes involved in steroidogenesis (StAR, CYP11A1, HSD3B2, CYP11B1, and CYP11B2). Mitotane hampered the mitochondrial respiratory chain function complex IV (cytochrome coxidase) and this was accompanied by enhanced mito- chondrial mass, as a compensatory mechanism in response to the respiratory chain defect. Further- more, mitotane induced morphologic fragmentation of the mitochondrial membranes that are required for respiratory chain activity and presumably steroi- dogenesis.
MITOTANE FOR POSTOPERATIVE TREATMENT
The use of mitotane as an adjunctive postoperative treatment has attracted increasing attention follow- ing publication of a paper of ours showing that patients treated with adjuvant mitotane had a sig- nificantly longer recurrence-free survival (RFS) and overall survival (OS), compared with two independ- ent groups of patients left untreated following surgery [16]. This study also raised fierce criticisms due to its retrospective nature and inherent meth- odological limits [17].
A recent retrospective analysis of the manage- ment of patients with ACC at the University of Michigan, a tertiary referral center for ACC patients in the USA, adds interesting data to this controversy [18""]. Of the 389 patients gathered from 1979 to 2013, 105 patients were treated postoperatively with mitotane, and their outcome was compared with that of 159 patients receiving no adjunctive treat- ment. Despite the fact that the adjuvant group had a worse risk profile than the control group, mitotane treatment was associated with a significantly improved RFS (hazard ratio 0.7, P<0.05). The beneficial effect of mitotane was confirmed in multivariable analysis. In the 42 patients receiving a combined adjunctive treatment consisting of postoperative radiotherapy of the local bed and mitotane, there was a positive interaction between the two treatments (hazard ratio 0.4, P<0.05), suggesting an additional benefit on RFS. However, both therapies failed to prolong significantly OS. The lack of effect on OS may be due to the relatively short follow-up duration (25.6 months in the overall series). Despite the usual limits of being a retrospec- tive analysis, this study has the merit of including a large cohort of well characterized patients from a
single center. Lacking data from controlled prospec- tive trials, the results of this study add further evi- dence in favor of the use of mitotane in an adjuvant setting. The authors conclude that mitotane and radiotherapy may have a synergistic effect in reduc- ing the risk of recurrence. However, radiotherapy was found to be ineffective in another retrospective analysis from the USA [19] and its role in the post- operative management of ACC patients remains even more controversial than mitotane.
Due to the referral pattern of the University of Michigan, which recruits most patients at the time of ACC recurrence, it is likely that the prognosis of ACC depicted in the study appears worse than it is. A study conducted in Germany has already observed a difference in the outcome of stage II ACC between patients referred to expert centers at diagnosis or after tumor recurrence. Patients who received early specialized care have a better prognosis and, inter- estingly, the use of adjuvant mitotane contributed to the difference [20].
Another recent retrospective study provides additional albeit indirect evidence of the value of mitotane as an adjunctive postoperative treatment. This study correlated disease outcome with mito- tane levels recorded in 122 patients with ACC who were radically operated on between 1995 and 2009 and were treated adjuvantly with mitotane at six European centers [21""]. A monitored mitotane treatment targeting concentrations of 14-20 mg/l was done on all patients, but in only 63 of them (52%), the desired concentrations were reached and maintained during a median follow-up of 36 months. The patients with mitotane concentration at target showed a prolonged RFS compared with the remainders [hazard ratio of recurrence 0.497; 95% confidence interval (CI) 0.292-0.844, P=0.01], whereas the increase in OS was of borderline statistical significance (hazard ratio of death, 0.511, 95% CI 0.253-1.029, P=0.06) (Fig. 2). The rather limited duration of follow-up and the low number of events may explain why OS was not significantly changed. Mitotane concentration of 14 mg/l, or higher, was a predictor of RFS in multi- variable analysis and this finding supports the concept of a therapeutic interval of mitotane con- centrations that was originally developed in the setting of advanced disease. The study validated the strategy of targeting a cut-off value of 14 mg/l when giving mitotane for adjunctive purpose [22], and which was previously recommended on an expert opinion basis [1,23,24]. However, the study also demonstrated that maintaining mitotane con- centrations at target for a long time is a difficult task requiring firm commitment by both patients and physicians.
(a)
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| No. of patients at risk | 0 | 20 | 40 | 60 | 80 | 100 | 120 | 140 |
| Group 1 | 63 | 33 | 21 | 14 | 10 | 8 | 7 | 3 |
| Group 2 | 59 | 27 | 12 | 6 | 1 | 1 | – | – |
| No. of patients at risk | 0 | 20 | 40 | 60 | 80 | 100 | 120 | 140 | |
|---|---|---|---|---|---|---|---|---|---|
| Group 1 | 63 | 45 | 26 | 13 | 9 | 7 | 3 | 1 | |
| Group 2 | 59 | 41 | 24 | 8 | 6 | 2 | 2 | 1 |
FIGURE 2. (a) RFS of patients with mitotane levels at least 14 mg/l during follow-up (solid line) and patients with mitotane levels below 14 mg/l (dashed line). (b) OS of patients with mitotane levels at least 14 mg/l during follow- up (solid line) and patients with mitotane levels below 14 mg/l (dashed line). Adapted with permission from [21""]. OS, overall survival; RFS, recurrence-free survival.
The patients included in this study were treated with different dosing regimens of mitotane, accord- ing to the policies at each center. However, there was no difference between low-dose and high-dose regimens in the probability of reaching the target concentrations after 3 months of treatment, suggesting that individual factors may be as import- ant as pharmacologic ones [21""]. Treatment-related toxicity was overall acceptable and manageable with temporary treatment discontinuation, or dose reduction. Although a retrospective analysis may underestimate adverse events, it is likely that the
monitoring of mitotane concentrations contributed to limit severe unwanted effects, which may be linked to circulating mitotane levels exceeding 20 mg/l [1,23,24]. Patients with mild kidney failure (baseline creatinine clearance ≥60 ml/min) do not need specific dose adjustment, but we do not have experience with more severe renal impairment.
Since it is thought that mitotane needs meta- bolic activation to exert its action [2], measurement of mitotane [ortho para’-dichlorodifenyldichloro- ethane (op’-DDD)] only may provide an incomplete figure. The only study that correlated levels of mitotane (op’-DDD) and its metabolites [ortho para’-dichlorodiphenylacetate (op’-DDA) and ortho para’-dichlorodiphenylethene (op’-DDE)] to res- ponse in patients with advanced ACC found that the combined evaluation of op’-DDD and op’-DDA was useful to better characterize mitotane respond- ers. Conversely, measurement of op’-DDE was use- less [22]. The role of mitotane metabolites should be also addressed in the adjuvant setting.
MITOTANE FOR ADVANCED ADRENOCORTICAL CARCINOMA
Mitotane is part of the medical management of advanced ACC, either as monotherapy or combined with cytotoxic chemotherapy [1,24]. A recent prospective study provided novel information on mitotane pharmacokinetics comparing two differ- ent dosing regimens in patients with advanced ACC [25”]. In 13 patients, a low-dose starting regimen was used (a dose of 3 g daily was reached after 12 days), whereas 27 patients were given a high-dose starting regimen (a dose of 6 g daily was reached after 4 days and kept until day 14); further dose adjustments were guided by results of mitotane monitoring. The patients exposed to a greater mitotane dose reached peak plasma levels that were nonsignificantly higher compared with the low-dose group. The difference was significant only among patients not treated with chemotherapy. The frequency and severity of adverse events did not differ between the two groups. These data show that the rise in mitotane concentrations is slow and not fully pre- dictable by the given mitotane dose; different vari- ables factor on the amount of mitotane plasma concentrations and mitotane-related toxicity.
The study confirmed that mitotane is able to enhance hepatic protein synthesis/secretion. Levels of sex hormone-binding globulin (SHBG) increased during the trial, and this may explain why free testosterone levels declined, whereas total testoster- one remained unchanged from baseline levels. Levels of thyroxine-binding globulin (TBG) were also increased, although mitotane levels above
14 mg/l were associated with low FT4 levels and unchanged thyroid stimulating hormone. These peculiar patterns of sex steroid and thyroid hor- mones have been already recognized in a retrospec- tive study in patients treated adjuvantly with mitotane [3]. Mitotane use is also associated with increased levels of cortisol-binding globulin (CBG) that may compound interpretation of serum cortisol levels during treatment [1,3,23,24].
The issue of individual variability of mitotane concentrations has been recently addressed by D’Avolio et al. [26”], who investigated the potential impact of single-nucleotide polymorphisms (SNPs) of CYP2B6 and ABCB1 genes, which are involved in mitotane metabolism, on the kinetics of mitotane levels in ACC patients. A retrospective analysis on 27 patients on postoperative adjunctive mitotane was performed, and CYP2B6 and ABCB1 polymor- phisms were genotyped and tested for association with plasma mitotane concentration. Patients with the GT/TT genotype showed higher mitotane plasma concentrations compared to patients with GG at 3 and 6 months. Multivariate logistic regression analysis showed that only the CYP2B6 rs3745274GT/TT genotype was a predictor of mito- tane concentrations of at least 14mg/l after 3 months of treatment. Thus, this study demon- strated a genetic basis for mitotane variability in blood.
The feasibility of a high-dose regimen in patients treated with mitotane monotherapy was also demonstrated in a prospective study from Insti- tut Gustave Roussy, showing that six of 22 patients (27%) were able to reach a therapeutic mitotane level after 1 month of treatment [27]. Thus, a high-dose strategy may be preferable when treating progressive ACC without the association of cyto- toxic agents that limit patient compliance.
A major advancement in the field was the pub- lication of the first randomized trial in advanced ACC, the FIRM-ACT trial, that compared two cyto- toxic chemotherapy regimens, etoposide, doxorubi- cin, and cisplatin (EDP) versus streptozotocin, both combined with mitotane, as first-line treatment in patients with metastatic ACC [28""]. The study dem- onstrated the superiority of EDP, but since mitotane was part of both regimens, it is difficult to recognize its contribution. Interestingly, in the 54 patients who had a mitotane level of 14 mg/l, or higher, at the start of treatment there was a trend toward increased OS as compared with the 212 patients who did not (hazard ratio for death 0.76, 95% CI 0.54-1.08, P=0.13). Further post-hoc analyses are ongoing to dissect the role of mitotane.
In advanced ACC patients, mitotane is often used in combination with other drugs even if we
have limited knowledge of all the potential pharma- cologic interactions between mitotane and different drugs. A phase II clinical trial done in Germany [29] showed that the association between mitotane and sunitinib is not sound since concomitant mitotane treatment resulted in rapid metabolism and reduced levels of sunitinib. A recent in-vitro study demon- strated that mitotane induces CYP3A4 gene expres- sion, explaining the drug-drug interactions caused by mitotane-enhanced CYP3A4 activity [30]. There- fore, the concomitant administration of mitotane with anticancer drugs metabolized by CYP3A4 and CYP2B6 may result in sub-therapeutic plasma con- centrations of these drugs due to accelerated clear- ance. As discussed before, the fact that mitotane induces CYP3A4 activity is also relevant to steroid replacement therapy of ACC patients.
CONCLUSION
Mitotane acts at the mitochondrial level in ACC cells interfering with cellular respiration and steroidogenesis. These effects contribute to the adrenolytic action of mitotane. Mitotane also affects metabolism of cortisol and a variety of drugs through induction of CYP3A4 activity.
Novel data in favor of adjunctive mitotane treat- ment have been published, but the level of evidence remains low in the absence of prospective studies. However, most experts recommend mitotane fol- lowing extirpation of ACC in patients at high risk of recurrence [1,23,24]. The strategy of adjuvant
Localized ACC
Surgery
High risk of recurrence
Low risk of recurrence
Rx, R1 resection Stage III Ki-67 > 10%
R0 resection Stage I-II Ki-67 ≤ 10%
Adjuvant mitotane
ADIUVO trial
treatment at our center is summarized in Fig. 3. In advanced ACC, the regimen EDP and mitotane has been established as the reference treatment after publication of the first controlled study in this rare tumor, the First International Randomized trial in locally advanced and Metastatic Adrenocortical Carcinoma Treatment trial [28""]. However, the specific contribution of mitotane to the activity of polychemotherapic regimens remains to be fully established.
Acknowledgements
Financial disclosure: M.T. received research grants from the Italian Ministry of University and Scientific Research (FIRB RBAP1153LS_005) and received research grants and speaker honoraria by HRA Pharma.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
of special interest
of outstanding interest
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