Spironolactone is associated with reduced mitotane levels in adrenocortical carcinoma patients
Linus Haberbosch D1, Lukas Maurer1, Arvid Sandforth2,3, Charlotte Wernicke1, Joachim Spranger1,4,5, Knut Mai1,4,5 and Reiner Jumpertz von Schwartzenberg1,2,3
1Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
2Division of Diabetology, Endocrinology and Nephrology, Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany 3Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Partner of the German Center for Diabetes Research (DZD), Germany
4Charité Center for Cardiovascular Research, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
5DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
Correspondence should be addressed to K Mai: knut.mai@charite.de
Abstract
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Mitotane, a derivative of the pesticide dichlorodiphenyltrichloroethane, has been used successfully as first line chemotherapy since the 1960s, if maintained within a narrow therapeutic window. Spironolactone (SPL) is frequently used to treat glucocorticoid excess-associated adverse effects such as severe hypokalemia. Although data of a previous case report indicate a link, valid data regarding SPL use and mitotane plasma concentrations in a human cohort are lacking. This retrospective analysis includes data from 54 mitotane-receiving ACC patients (14 co-administered with SPL) treated between January 2005 and April 2020 (20 male, mean age 54.1 + 2.2 years). All available mitotane concentrations, treatment doses, tumor stage and evidence of hormone activity were collected. Primary outcomes included mitotane levels and concentration/dose ratios as well as time-in-range (TR) in patients with and without additional SPL treatment. The SPL group was characterized by higher glucocorticoid secretion. Other features such as tumor stage, size and anthropometrics were similar between groups. Interestingly, the SPL group had significantly lower mitotane levels despite higher doses. Mitotane TR was significantly reduced in the SPL group, as was time-in-range to progression. These data provide first evidence in a human cohort for potential SPL-mitotane interactions (beyond mentioned case report), which affect dose response and may modulate treatment outcomes. This should caution clinicians to carefully adjust mitotane doses during SPL treatment in ACC patients or choose alternative therapeutic options.
Key Words
mitotane
o,p’-DDD
adrenocortical carcinoma
spironolactone
hypokalemia
Endocrine-Related Cancer (2022) 29, 121-128
| Endocrine-Related | L Haberbosch et al. | Spironolactone and mitotane | 29:3 | 122 |
|---|---|---|---|---|
| Cancer | in ACC patients |
Introduction
Adrenocortical carcinoma (ACC) is a rare endocrine tumor characterized by high recurrence rates and often- fatal prognosis. The overall 5-year survival of patients undergoing tumor surgery is believed to be less than 40% (Bilimoria et al. 2008). Besides surgical removal of the tumor, mitotane is the most widely used treatment option until today (Terzolo et al. 2007). Mitotane is an isomer of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroeth ane (DDD), the insecticide analog of DDT which was first shown to induce adrenal atrophy in dogs in 1948 (Nelson & Woodard 1948). Its first use in humans in chemotherapy of adrenocortical cancer was described by Bergenstal et al. (1960). Numerous publications have documented its use as a chemotherapeutic drug ever since (Luton et al. 1990, Haak et al. 1994, Barzon et al. 1997). Long-lasting treatment experience over many decades and its proven efficacy (compared to other treatment options) makes mitotane an important component in the management of ACC patients, although a high variability of the effect is reported (Fassnacht et al. 2018). Mitotane yielded especially encouraging results in the prognostically poor subgroup of steroid secreting tumors (Abiven et al. 2006). However, due to gastrointestinal and specifically neurotoxic adverse effects, the therapeutic window for this drug is narrow (14-20 mg/L) and frequent monitoring of mitotane levels is mandatory (Allolio & Fassnacht 2006, Kerkhofs et al. 2013, 2014, Terzolo et al. 2013). Its long half-life (18-159 days), the prolonged time to achieve effective plasma mitotane concentrations and enhanced glucocorticoid metabolism, which increases the required glucocorticoid replacement dosage, make mitotane treatment rather complex. Moreover, mitotane is a potent inductor of cytochrome P450 CYP3A4 activity causing numerous interactions with other drugs such as warfarin, midazolam or the tyrosine kinase inhibitor sunitinib (Baudin et al. 2001, Kroiss et al. 2011, van Erp et al. 2011). However, literature on the metabolism of mitotane or other drugs that may affect mitotane levels is surprisingly scarce. Since not all ACC patients respond to mitotane therapy, it is important to define potential drug interactions that may affect mitotane efficacy (Hahner & Fassnacht 2005).
Steroid excess, frequently seen in ACCs (Koschker et al. 2006), may cause hypertension and hypokalemia. Due to its antihypertensive and potassium retention effects, the mineralocorticoid receptor antagonist spironolactone (SPL) is therefore frequently used in those patients.
Interestingly, a potential inhibitory effect of SPL on mitotane-induced adrenal atrophy in dogs was presented
at a scientific meeting in the 1970s (Menard et al. 1977). Human data suggesting such a potential interaction are limited to one case report in 1977 (Wortsman & Soler 1977), in which a patient with pituitary-dependent Cushing’s syndrome was treated with 3 g of mitotane per day (no mitotane plasma concentrations were documented), however never experienced any known adverse effects of mitotane until the discontinuation of SPL. Given the sparsity of convincing data on clinically relevant interactions between SPL and mitotane, until today the use of SPL is warranted in the management of endocrine manifestations of ACC (Veytsman et al. 2009). Considering the frequent combination of mitotane and SPL, the dismal prognosis of patients with ACC and the toxicity of mitotane, it is pivotal to understand the effects of SPL on mitotane concentration and thereby efficacy which may have clinical consequences in ACC patients. We therefore conducted a retrospective data analysis of 54 ACC patients treated with mitotane in our center between January 2005 and April 2020. We provide first evidence that additional SPL treatment is associated with lower mitotane plasma concentrations despite higher dosage. Preliminary survival data support an association with clinical outcomes.
Methods
This retrospective data analysis was approved by the Ethics Committee of the Charité-Universitätsmedizin Berlin (“Ethikkommission der Charité-Universitätsmedizin Berlin”; EA2/021/20).
Patients
We included 54 ACC patients undergoing mitotane treatment with available data on mitotane concentrations in our center between January 1, 2005, and April 1, 2020. The inclusion criteria were age >18, pathologically confirmed diagnosis of ACC and treatment with mitotane. The standard surgical therapy was adrenalectomy. Besides mitotane treatment, patients received adjuvant chemo-, radio- and hormone replacement therapy. Patients’ charts were reviewed and the following information was retrieved for the study: sex, age, BMI, hormone secretion status of the tumor, ACC stage at the start of mitotane treatment, the start date of mitotane therapy, first progression under therapy, loss to follow-up or death. Hormone secretion was determined by respectively elevated androgen precursors (DHEA, 17-hydroxyprogesterone and/or androstenedione),
aldosterone-to-renin ratio and/or a pathologic 1 mg dexamethasone suppression test. The tumor stage was assessed according to the ENSAT classification (Fassnacht et al. 2009).
Mitotane and SPL doses as well as mitotane concentrations were documented at monthly intervals (concurrent with clinical visits) if available. Plasma samples were collected and sent to Lysosafe (a free-of-charge testing service of Laboratoire HRA Pharma, Paris, France) for the measurement of mitotane concentrations. For this, plasma samples were extracted by precipitation with ethanol and tested by a standardized gas chromatography/mass spectrometry method (Inouye et al. 1987). Mitotane plasma concentrations, a concentration/dose ratio, time-in-range (TR) and TR to (first) progression (TRP) of mitotane (both defined as the percentage of the total time of mitotane treatment, starting 1 month after treatment start) were calculated. The concentration/dose ratio was calculated by dividing the serum mitotane concentration (in mg/L) by the total daily dose (in g) taken by the patient at that time, concordant with similar analyses in drug monitoring studies (Fukumoto et al. 2006, Rudberg et al. 2006, Westin et al. 2008, Thölking et al. 2016).
Statistics
All analyses were performed using IBM SPSS Statistics, Version 19.0.0.1 (IBM). Group comparisons with normally distributed variables were analyzed with t tests. If normal distribution was not given, we used Mann-Whitney U tests.
Categorical variables were compared via chi-square tests or Fisher’s exact test, depending on the number of categories. A correlation between mitotane dose and concomitant concentration was calculated via Spearman’s rho. P<0.05 was considered statistically significant. Scatter plots were created in SPSS, Boxplots and jitter plots were created using GraphPad Prism version 7.02 for Windows (GraphPad Software). All plots were colorized and arranged in Adobe Illustrator (Adobe Inc.).
Results
Cohort characteristics
Out of the 54 ACC patients who met the inclusion criteria, 14 patients were treated with SPL at any time during the study interval. We found no significant differences between the SPL group and the no-SPL group regarding age, sex or BMI (Table 1). For the overall cohort (20 male, mean age 54.1 ± 2.2), the most common ENSAT stage was IV (42.6%), with an average maximum tumor diameter of 10.5 cm (±0.7) and an average Ki67-expression of 24.4% (±3.0). In two patients, we were not able to clearly differentiate the ENSAT stage at treatment start between stage III and IV due to lacking or conflicting pathological data. Both patients were removed from all further analyses including the ENSAT stage as a covariate. Of note, maximum tumor diameter and Ki67-expression were similar between groups, albeit the SPL group contained more patients with ENSAT
| Characteristics | Without spironolactone | Spironolactone | P-value | ||
|---|---|---|---|---|---|
| N | Values | N | Values | ||
| Age (years) | 40 | 54.4 ± 2.4 | 14 | 55.1 ± 4.7 | 0.797b |
| Sex (N) | 0.337a | ||||
| Male | 13 | 32.5% | 7 | 50% | |
| Female | 27 | 67.5% | 7 | 50% | |
| BMI (kg/m2) | 40 | 24.2 ± 0.6 | 14 | 25.0 ± 1.5 | 0.557c |
| Disease characteristics | |||||
| Hormone activity | 40 | 14 | |||
| Glucocorticoids | 19 | 47.5% | 12 | 85.7% | 0.027a |
| Mineralocorticoids | 5 | 12.5% | 5 | 35.7% | 0.109ª |
| Androgene precursors | 18 | 45% | 12 | 85.7% | 0.025ª |
| Total | 22 | 55% | 13 | 92.9% | 0.011a |
| Tumor size (mm) | 30 | 100.1 ± 7.4 | 12 | 117.0 ± 16.2 | 0.500b |
| ENSAT stage | 39 | 13 | |||
| Stage II | 7 | 17.5% | 2 | 14.3% | |
| Stage III | 17 | 42.5% | 3 | 21.4% | |
| Stage IV | 15 | 37.5 % | 8 | 57.1% | |
| Ki67 | 19 | 26.2 ± 3.9% | 7 | 19.2 ± 3.7% | 0.319b |
Significant differences between the groups are marked in bold type; The test used for the analysis is specified by the superscript letter following the P-value. aFisher’s exact test, bMann-Whitney U-test, cT-test.
stage IV tumors. In the overall cohort, 65% of carcinomas showed hormonal activity. While 13 of 14 tumors in the SPL group were hormone-secreting, only 22 out of 40 in the control group were hormonally active. The complete cohort characteristics are provided in Table 1.
We found no statistically significant differences regarding adjuvant therapies, albeit with a higher percentage of patients from the spironolactone group receiving etoposide, doxorubicin and cisplatin (EDP).
Mitotane concentrations
We documented a total of 909 mitotane concentrations, with an average of 17 per patient (median: 13, ranging from 2 to 80). Including all available mitotane concentrations, patients in the SPL-treated group had significantly lower mitotane levels compared to no-SPL-treated subjects (7.4 ± 1.4 mg/L vs 11.8 ± 0.8 mg/L, P < 0.001; Fig. 1A), despite higher mitotane doses (3.7± 0.4 g/day vs 2.4 ± 0.2 g/day, P < 0.001; Fig. 1B). The mean concentration/dose ratio was 2.3 (±0.4) for the SPL group and 6.2 (±0.7) for the no-SPL group (Fig. 1C).
To validate these findings and to exclude the possibility of these results only reflecting different starting regimens, we repeated this analysis after the exclusion of any data from the first 6 months of treatment, concordant with the expected time to reach the therapeutic range (Terzolo et al. 2000, 2013, Puglisi et al. 2019). Although 11 patients were additionally excluded by this approach, the findings
of significantly lower mitotane concentration (12.2 ± 1.2 mg/L vs 14.7 ± 0.2 mg/L, P=0.018), higher mitotane doses (2.6 ± 0.3 g/day vs 1.8 ± 0.04 g/day, P=0.020) and a lower concentration/dose ratio (5.8 ± 0.9 vs 9.5 ± 0.2) in the SPL group could be replicated.
We then calculated non-parametric correlations between mitotane dose and concentration at each available time point via Spearman’s rho. While we noted a significant, albeit weak correlation in the no-SPL group (rs = 0.09, P=0.011), we found no correlation in the SPL group (r$ =- 0.28, P =0.773).
To further characterize these findings, we visualized mitotane concentrations and concentration/dose ratios in a scatter plot against time after the start of mitotane treatment (Fig. 1D and E). The concentration scatter decreases with time after the initial start of the therapy in both groups.
Finally, we calculated the overall TR (defined as the percent of mitotane concentration measurements in the therapeutic range per individual (Puglisi et al. 2020)) as well as the TRP. TR was overall low in the no-SPL-treated group (29.3± 3.5%), however even lower in the SPL-treated group with only 7.9% (±0.3) of measurements per individual that were within the therapeutic range (P=0.001 vs no-SPL group). The same was true for TR from mitotane treatment start to first progression (TRP), with a mean value of 28.8% (±4.0) in the no-SPL group compared to 4.7% (±2.5) in the SPL group (P =0.001 for between-group comparison). The results are visualized in Fig. 1F.
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@ 2022 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain
| Endocrine-Related | L Haberbosch et al. | Spironolactone and mitotane | 29:3 | 125 |
|---|---|---|---|---|
| Cancer | in ACC patients |
Discussion
While radical resection remains the first-line therapy of ACC, adjuvant mitotane is recommended in high-risk cases (ENSAT II/IV or Ki-67 >10%) even after complete resection. In cases of Rx or R1 resection as well as ACCs not amenable to radical resection, mitotane therapy is started in addition to possible local therapies and/or chemotherapy. This includes several regimes like EDP or streptozotozine or gemcitabine, all of moderate value (Fassnacht et al. 2018). Small studies also indicate a potential impact of immunotherapy in some of those patients (Fassnacht et al. 2015, Le Tourneau et al. 2018, Carneiro et al. 2019, Habra et al. 2019, Raj et al. 2020).
While mitotane has been shown to significantly prolong recurrence-free survival in patients with advanced ACC (Terzolo et al. 2007), its plasma concentration must be closely monitored and managed to ensure treatment effectivity (Fassnacht et al. 2013) and avoid major adverse effects. In this retrospective analysis, we provide the first clinical evidence in a human cohort that SPL treatment in ACC patients receiving mitotane chemotherapy is closely linked with reduced mitotane concentrations, concentration/dose ratios and TR. This aggravates the known clinical difficulties in adequately dosing ACC patients to achieve therapeutic concentrations over long intervals. Recently, a study in 110 ACC patients found time in a target range of plasma mitotane to be a significant predictor of recurrence-free survival independent of the Ki67 index (Puglisi et al. 2019, Puglisi et al. 2020). This underscores the importance of stable and therapeutic mitotane concentrations in ACC patients, especially in those with steroid hypersecretion. In this context, the effects of SPL on mitotane concentrations may have adverse effects on clinical outcomes in ACC patients who already bear a high mortality risk.
Albeit, adequately mitotane dosing is complicated by the low oral bioavailability and lipophilicity of mitotane, the latter leading to a large distribution volume and slow accumulation (Arshad et al. 2018, Corso et al. 2021). A further complicating factor is the complex and not fully understood metabolism of mitotane, leading to a considerable influence on individual pharmacogenetics (Altieri et al. 2020, Yin et al. 2021). Current integrative pharmacokinetic models strive toward predicting mitotane levels in individual patients, moving toward individualized mitotane dosing (Kerkhofs et al. 2015, Cazaubon et al. 2019).
Mitotane is itself a potent inhibitor of steroidogenesis and is used for this specific effect as a treatment for Cushing’s
syndrome at lower doses (Daniel & Newell-Price 2015). But due to the aforementioned challenges, Mitotane treatment alone is often insufficient to rapidly control severe steroid hypersecretion and the resulting hypokalemia in a relevant percentage of ACC patients (Allolio & Fassnacht 2006). This often necessitates additional anti-hormonal treatment, which can be initiated together with mitotane. Metyrapone, a 116-hydroxylase inhibitor, is the first therapeutic choice for the management of advanced ACC patients with severe Cushing’s syndrome, as it is well tolerated and has no reported interactions with mitotane (Fassnacht et al. 2018). Recently, the similarly acting osilodrostat was approved as a therapeutic alternative. Ketoconazole blocks several enzymes of the adrenal steroidogenesis, but the hepatotoxicity often contraindicates the co-administration with mitotane, especially at the start of the treatment. Levoketokonazole might improve on this, although clinical data are currently lacking (Castinetti et al. 2021). Mifepristone as a glucocorticoid receptor antagonist is also an option, but it is difficult to monitor and the high circulating cortisol levels induce mineralocorticoid effects, including hypertension and hypokalemia.
Nevertheless, a fraction of ACC patients, particularly with glucocorticoid- and mineralocorticoid secreting tumors, suffer from severe hypokalemia (Fassnacht et al. 2009) requiring specific treatment or replacement beyond hypercortisolism treatment (Allolio & Fassnacht 2006). Therefore, supporting pharmacological therapy with either mineralocorticoid receptor antagonists (MRA, eplerenone and SPL) or epithelial sodium channel (ENaC) blockers (amiloride and triamterene) is frequently required.
The most commonly used and most ubiquitously available of all these pharmacological agents is SPL, now amassing over 60 years of clinical use (Kolkhof & Barfacker 2017). Aside from the well-known adverse effects related to its affinity to the androgen receptor, a possible interaction with mitotane has been discussed for some time, with only anecdotal evidence amounting to only one published case report (Wortsman & Soler 1977). Still, due to lack of evidence, the administration of SPL is recommended in educational articles, reviews and guidelines for the clinical management of patients with hormone-secreting adrenocortical cancer (Veytsman et al. 2009, Lacroix 2010, Rao & Habra 2016). Considering our observations indicating potential pharmacological interactions of SPL and mitotane treatment, which may lead to difficulties to achieve effective mitotane concentrations and may thereby have potential deleterious effects on clinical outcomes, we would like to caution clinicians regarding the use of SPL in mitotane-receiving ACC patients. ENaC blockers, with
preferential use of amiloride, might be the favored first-line treatment of hypokalemia in these patients (Quinkler & Stewart 2010, Fassnacht et al. 2018). At therapy failure or if MRAs are strongly indicated for other reasons, eplerenone rather than SPL should be used, although possibly higher doses of eplerenone are needed due to CYP3A4 interactions. If SPL is unavoidable, close monitoring of mitotane levels is essential, and the patient will likely require higher doses than usually administered.
The mechanism of action behind this potential interaction remains unknown. One possible way of interaction is SPL interfering with mitotane metabolism via the cytochrome P450-system. Mitotane (o,p’- DDD) is primarily transformed and metabolized in adrenocortical mitochondria (Hahner & Fassnacht 2005). The transformation requires ß-hydroxylation followed by rapid dechlorination to a reactive acyl chloride thought to bind adrenocortical binucleophiles in target cells to exert an adrenolytic effect via enhanced oxygen activation (Waszut et al. 2017). The metabolic reaction is known to be inhibited by ketoconazole but not by aminoglutethimide, metyrapone, or other steroids (Veytsman et al. 2009). SPL, like ketoconazole, is a broad cytochrome P450-inhibitor and its metabolites canrenone and canrenoate-k have been shown to inhibit 116- and 18-hydroxylation in human adrenal cortical mitochondria (Lund & Lund 1995). Moreover, inhibition of 26, 60, 156 and 18-hydroxylation was also demonstrated by other metabolites in the rat model (Decker et al. 1989, Colby et al. 1991). Although it seems not implausible that SPL could inhibit those initial hydroxylation steps, induction of microsomal elimination might also be involved. This is supported by animal studies hinting toward a faster elimination of DDT-metabolites when administered with pentobarbital (Fries et al. 1971), with a similar effect described for SPL (Solymoss et al. 1969). This may additionally contribute to lower mitotane concentrations during SPL treatment.
And while unchanged mitotane appears to be eliminated largely through biliary excretion (but can also undergo enterohepatic circulation) (Kroiss et al. 2011), its less hydrophobic metabolite o,p’-DDA is subject to rapid renal elimination (Corso et al. 2021).
These data underscore the further need for exploring the metabolism of mitotane, as well as the interaction of mitotane and SPL, since other pharmacological agents may also interfere with the pharmacokinetics of this key drug for ACC therapy.
This study is limited by its retrospective character and thus does not provide direct proof that SPL treatment reduces mitotane concentrations. Considering ACC is
a rare disease the cohort size seems well dimensioned, however, the overall number of patients is rather low, which limits the analysis with further confounders. Additionally, the mechanism for the interaction of SPL and mitotane remains unknown and might include further mediators or moderators. Confirmatory studies are needed to adequately address confounders and analyze survival data in a larger cohort.
Still, considering these limitations, we find that this study contributes important first clinical evidence in a human cohort indicating potential deleterious SPL- mitotane interactions.
We believe that these data should caution clinicians to consider this potential interaction when treating hypokalemia in ACC patients and to carefully adjust mitotane doses if spironolactone treatment is unavoidable or prefer alternative therapeutic agents such as amiloride. Future studies should address the mechanism of action behind this interaction and investigate other possible interaction candidates.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
Knut Mai and Reiner Jumpertz von Schwartzenberg: authors contributed equally to this work.
Acknowledgement
The authors would like to thank Kathrin Zopf for her help with data collection.
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Received in final form 17 December 2021 Accepted 11 January 2022 Accepted Manuscript published online 11 January 2022