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MISS MALENE VIKNER (Orcid ID : 0000-0003-4362-6524) DR MIKKEL ANDREASSEN (Orcid ID : 0000-0002-1656-3516)
Article type : Original Article - Europe, excluding UK
Title page
Metabolic and hormonal side effects of mitotane treatment for adrenocortical carcinoma: A retrospective study in 50 Danish patients
Abbreviated title:
Metabolic and hormonal side effects of mitotane treatment for adrenocortical carcinoma
Authors name and institution:
☒ Malene Elbæk Vikner, Department of Endocrinology, Rigshospitalet, Faculty of Health Science, University of Copenhagen, Denmark
Jesper Krogh, Department of Endocrinology, Rigshospitalet, Faculty of Health Science, University of Copenhagen, Denmark
Gedske Daugaard, Department of Oncology, Rigshospitalet, Faculty of Health Science, University of Copenhagen, Denmark
Mikkel Andreassen, Department of Endocrinology, Rigshospitalet, Faculty of Health Science, University of Copenhagen, Denmark
Key terms:
☒ Adrenocortical carcinoma
Mitotane treatment
☒
Hypercholesterolemia Hypothyroidism Hypergonadotropic hypogonadism
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/CEN.14345
Disclosure Statement:
The authors have no conflicts of interest to declare concerning this study.
Funding Sources: This study has not received any external funding.
Data Sharing and Data Accessibility:
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Corresponding author: Stud.med. Malene Elbæk Vikner Department of Endocrinology 3132 Rigshospitalet Blegdamsvej 3, 2100 Copenhagen, Denmark mqp154@alumni.ku.dk
Word count: 4059
Abstract
Objective: Mitotane is used in the treatment of adrenocortical carcinoma (ACC). Metabolic and hormonal side effects of mitotane, the effect of subsequent treatment with statins and hormones and the effects of discontinuation of mitotane were assessed.
Patients and methods: Fifty patients were included. Lipid profiles, thyroid hormones, sex hormones, and adrenal function from first year of mitotane treatment and after cessation were evaluated.
Results: After 6 months of mitotane treatment total cholesterol increased from (median) 5.1 (IQR 4.3 to 5.8) to 7.4 (6.2-9.0) mmol/L, p < 0.001. LDL, HDL, and triglyceride also increased, all p ≤ 0.03. Three months of treatment with statins decreased total and LDL-cholesterol, and cessation of mitotane led to further reduction in lipids. Plasma thyroxine decreased from 90 (78-111) to 57 (47- 63) nmol/L and free thyroxine from 16.0 (13.0-18.3) to 11.7 (10.5-12.6) pmol/L on mitotane, both p < 0.001, while TSH remained unchanged. Treatment with thyroxin significantly increased plasma thyroxine and free thyroxine and decreased TSH. Cessation of mitotane increased total T4
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(p < 0.001). Mitotane increased plasma SHBG from 36 (22-51) to 189 (85-259) nmol/L and LH from 4.6 (1.6-8.1) to 20.0 (10.0-34.9) IU/L, both p < 0.001. In males the changes were accompanied by an increase in testosterone from 9.8 (7.2-14.5) to 27.0 (15.3-34.8) nmol/L, p < 0.03. Fifteen of 24 tested patients regained normal adrenal function 6 (3-16) months after cessation of mitotane.
Conclusions: Mitotane treatment exerts multiple severe side effects involving both the metabolic and endocrine systems that may require treatment, but the effect appears to be partially reversible.
Introduction
Adrenocortical carcinoma (ACC) is a rare and aggressive disease affecting 1-2 people per million every year (1). The overall 5-year survival is less than 50% (2). Mitotane treatment is recommended in guidelines as a therapeutic drug for disseminated disease or as an adjuvant treatment in patients with a high risk of recurrence after radical surgery (3). Patients with advanced disease are either treated with mitotane alone or in combination with chemotherapy. Mitotane is a derivative of the insecticide dichloro-diphenyltrichloroethane (DDT) (4) with a direct cytotoxic effect on the adrenal cortex. Alterations in the mitochondrial respiratory chain activity and inhibition of Sterol-O-acyl transferase 1 results in endoplasmic reticulum stress in ACC cells, in turn leading to apoptosis. Furthermore, mitotane inhibits steroidogenesis as well as induces steroid clearance (1), resulting in adrenal insufficiency. Mitotane has been shown to increase recurrence-free survival and overall survival for patients when administered as adjuvant treatment (observational studies) (5). However, long-term use of mitotane is limited because of multiple side effects and discontinuation of mitotane is often seen before reaching the therapeutic plasma level of mitotane.
Based on small series (n ≤ 38) and case reports mitotane seems to exert multiple and complex metabolic and endocrine effects (6-10). An increase in both total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglyceride has been reported (6, 8, 10). Furthermore, mitotane-induced hypothyroidism has been observed with a reduction of free thyroxine (T4) levels with no change in thyroid-stimulation hormone (TSH) (6, 11, 12). In male patients treated with mitotane, increased sex-hormone binding globulin (SHBG) and decreased
free testosterone resulting in clinical manifestations of hypogonadism has been reported (4, 6, 13). Finally, adrenal insufficiency following mitotane treatment is frequently observed. There is however very limited data on how these metabolic and hormonal changes should be treated (3, 6) as well as if the changes are reversible after cessation of mitotane.
This study aims to elucidate the metabolic and hormonal side effects attributed to mitotane, the effects of subsequent treatment with statins and hormone replacement and the chance of metabolic and hormonal normalization after discontinuation of mitotane treatment.
Patients and Methods
We conducted a retrospective study in a cohort of patients treated at the Department of Endocrinology and Department of Oncology at Rigshospitalet, Copenhagen. Rigshospitalet is a tertiary center for treating ACC. The Department of Endocrinology takes care of mitotane treatment in all patients with local disease after curative surgery in eastern Denmark (2.5 million people), as well as all patients with metastatic disease in Denmark (5.6 million people), whereas the Department of oncology takes care of other oncological treatments of all patients with disseminated disease in Denmark. Eligible patients had histologically confirmed ACC and started treatment with mitotane during the period 1st of January 2009 to 31st of December 2019. ACC could have been diagnosed before this period. Fifty-four patients met these criteria. Two patients were excluded due to missing blood test results and two due to active Cushing syndrome (no substitute glucocorticoid requirements) despite oncological treatment. Adjuvant mitotane treatment was administered after radical surgery with the intention of at least two years of therapy, although an individual approach with consideration of the patient’s compliance and tolerability of side effects was often necessary (3). Based on patient’s files we collected data from the first year of mitotane treatment; lipid profiles (total cholesterol, HDL, LDL, and triglyceride), thyroid hormones (TSH, total T4, and free T4), gonadal hormones (LH, SHBG, total testosterone and free testosterone), results of ACTH stimulation tests as well as duration of mitotane treatment, dosage and plasma concentration. We did not have complete data for all variables. Data were included in the analyses if we had baseline data and at least one measurement during mitotane treatment. Numbers of included individuals for each variable varied from n=5 to n=39. Details are given under the result section and in table legends.
Throughout the years, various methods with different normal ranges were used to analyze the lipid profiles and hormone levels. Plasma mitotane concentration was measured by the Lysosafe service provided by HPA Pharma (www.lysosafe.com). According to the patient’s files the baseline blood tests were measured before treatment start or at the latest 3 weeks after. When analyzing changes in blood test results we aimed to include test results 6 months after initiation of mitotane treatment, or as close to 6 months as possible without additional treatment or just before additional treatment was initiated. The patients included in the study were followed-up until March 2020. We dealt with missing data by excluding the patient from certain analyses if their files did not contain the data for the required variable.
To summarize patient demographic and clinical characteristics we used descriptive statistics. A paired sample t-test was used to assess changes in lipid and hormonal levels at baseline vs. six months of treatment. Furthermore, paired sample t-test was applied to assess the changes in lipid profiles and thyroid hormones after treatment with lipid-lowering medication and thyroxine or after discontinuation of mitotane. Because of non-parametric data, tested with the Shapiro-Wilk test, a Spearman correlation test was applied to analyze the correlation between the absolute rise or fall in plasma lipids and hormone levels vs. mitotane concentration, as well as the relationship between dosage of mitotane vs. mitotane concentration. In the investigation of regaining adrenal function after the discontinuation of mitotane an independent t-test was used to explain if treatment duration had an impact. The Chi2-test was used when analyzing if tumor cortisol production could predict whether the patient would regain adrenal function after discontinuation of mitotane or not. Database management and all statistical analyses were performed by using the software SPSS version 26. P values were considered significant at p ≤ 0.05. Unless other is specified, normally distributed data are presented as mean + 1 SD whereas non-normally distributed data are presented as median (IQR).
The study was approved by the Danish Data Protection Agency at Rigshospitalet (P-2019-248) and by the Danish Patient Safety Authority (3-3013-3102/1). Due to the retrospective design informed consent was not required.
Results
The characteristics of the included 50 patients are summarized in Table 1. The majority of patients were female (35/50) with a median age of 54 (range 18-79) years. Twenty-six of the 50 patients had local disease (52%). Patients with local disease had mostly non-functioning ACC (15/26), while patients with metastatic disease had functioning ACC (18/24, p = 0.007), with (15/18) producing cortisol. Most patients (21/24) with metastatic disease were treated with chemotherapy in addition to mitotane. The median treatment duration of mitotane was 14 (5-36) months for patients with local disease and 9 (6-17) months for patients with metastatic disease. Due to mitotane-induced adrenal insufficiency patients were either treated with hydrocortisone (n=37, 60 (50-60) mg) or dexamethasone (n=13, 2.0 (1.1-3.3) mg). Ten patients presented with clinical signs of mineralocorticoid deficiency (high potassium, low sodium and/or low blood pressure) and were treated with florinef (0.1 (range 0.05-0.20) mg). Median renin concentration before initiation of treatment was 24 (7.8-407) x10-3 (normal range 4.2-60.0 x10-3) IU/L (n=7), while aldosterone mostly was under lower limited of detection (<103 pmol/L, n=7), excluding two patients with respectively 278 pmol/L and 684 pmol/L. The majority of patients (37/50) discontinued mitotane, mainly as a result of side effects. The side effects varied among patients, but common complaints were fatigue, diarrhoea, nausea, vomiting and weight loss. Among patients with local disease (20/26) discontinued the treatment due to intolerable side effects.
Mitotane plasma concentration increased during the first year of treatment. After 3, 6, 9 and 12 months of treatment the median plasma concentration was 6.3 (4.0-9.3) mg/L, 11.6 (7.3-14.6) mg/L, 13.7 (10.5-16.3) mg/L and 13.5 (9.7-16.2) mg/L. After 6 months of treatment the median dosage was 3.5 (2.5-4.0) grams. Therapeutic mitotane plasma levels (14-20 mg/L) were achieved at least once in 50% of the cohort, after a median of 6 (5-9) months. Adjusted for weight, plasma mitotane concentration correlated with mitotane dosage (r = 0.50, p = 0.002).
Lipids
Total cholesterol, LDL, HDL, and triglyceride (n=39, all p < 0.02) increased significantly on mitotane therapy (Table 2). After 6 (2-6) months the total concentration of LDL increased from 2.9 (2.4-3.7) mmol/L to 5.8 (3.4-6.4) mmol/L. A significant correlation was found between absolute increase in HDL levels and mitotane concentration in plasma (r = 0.43, p = 0.006, Figure
1a). Changes in total cholesterol, LDL, and triglycerides were not correlated with plasma mitotane.
Twenty-six patients were treated with lipid-lowering statins while on mitotane, but biochemical data were only available in 17 patients: 15 patients were treated with simvastatin (10-40 mg), one was treated with atorvastatin (10-80 mg) and one with rosuvastatin. After 3.2 (± 0.8) months of statin treatment total cholesterol and LDL levels decreased significantly, both p < 0.001. LDL decreased from 6.2 (5.2-7.4) mmol/L to 4.3 (3.2-5.2) mmol/L (figure 2). Statins had no significant effect on HDL or triglyceride. Measurements of lipid profiles 12 (4-33) months after cessation of mitotane (n=30) showed a significant reduction of total cholesterol (p<0.001), HDL (p=0.004) and LDL levels (p=0.001). LDL levels decreased from 3.4 (2.7-4.6) mmol/L to 2.7 (2.3-3.6) mmol/L (Table 2). Thirteen of the 31 patients who discontinued mitotane received lipid-lowering statins at the time of the measurement.
Thyroid hormones
Total T4 (n=27) and free T4 (n=26) decreased while patients were treated with mitotane (both p < 0.001), whereas TSH (n=37) levels did not change significantly (Table 3). After 6 (3-6) months of treatment total T4 decreased from 90 (78-111) nmol/L to 57 (47-63) nmol/L. Two patients were treated with thyroxine before mitotane treatment was initiated, and additionally 22 patients started thyroxine treatment while receiving mitotane therapy. After 3-6 months of thyroxine treatment the median dose was 513 (350-700) micrograms/week, and both plasma total T4 (from 49 (42-59) nmol/L to 71 (52-85) nmol/L) and free T4 (from 11.4 (10.3-12.1) pmol/L to 14 (12.2-16.6) pmol/L) increased significantly (n=22, both p < 0.001), whereas TSH decreased (p=0.016). Total T4 (n=30) levels increased significantly when measured 9 (3.5-18) months after discontinuation of mitotane (Table 3). Ten of the 31 patients received thyroxine treatment at the time of the measurement.
Sex hormones
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LH (n=27) and SHBG (n=18) increased significantly (both p < 0.001) and also when men were investigated separately (p < 0.05) (Table 4). After 6 (2-9) months SHBG increased from 36 (22- 51) nmol/L to 189 (85-259) nmol/L, and LH increased from 4.6 (1.6-8.2) IU/L to 20 (10-34.9) IU/L. The absolute rise in LH (r = 0.43, p = 0.026) and in SHBG (r = 0.66, p = 0.003) correlated
significantly to mitotane concentration (Figure 1b and c). Both correlations were significant when analyzing men and women together (n=27 and n=19, respectively), but not when only men were included (n=7 and n=6, respectively). Total testosterone in men (n=8) levels did also increase (from 9.8 (7.2-14.5) to 27.0 (15.3-34.8) nmol/L, p ≤ 0.01) when measured 7 (6-9) months after initiation of mitotane therapy, whereas levels of free testosterone (n=6) did not change significantly (p=0.07). SHBG (n=5) decreased (p=0.017) when measured 10 (3-33) months after cessation of mitotane. Discontinuation of mitotane did not affect other sex hormones significantly (Table 4).
Four of the male patients (age at ACC diagnosis, 26 to 52 years) presented with hypogonadal symptoms including tender gynecomastia and were treated with testosterone (testosterone injections 250 mg every 2-4 week or testosterone gel). Patient 1 (Table 5) discontinued the treatment because of lack of symptom relief. Patient 2 and 3 discontinued the treatment together with cessation of mitotane. There was no significant effect of testosterone treatment on symptoms. Patient 4 experienced improved sexual function on testosterone treatment, but an increase in tender gynecomastia. Treatment with an aromatase inhibitor (Letrozole 2.5 mg every day) was added with symptom relief, and he is still on testosterone and Letrozole treatment. Treatment with testosterone did not lead to any major changes in hormones or in SHBG levels, individual data are provided in Table 5. Before initiation of testosterone therapy levels of dihydrotestosterone (DHT) were measured in 2 patients (patient 1 and 4). In patient 1 DHT was highly elevated (8.3 nmol/L (normal range 0.8-2.8 nmol/L)) with a corresponding elevated testosterone level of 52 nmol/L, whereas DHT in patient 1 was within normal range (1.4 nmol/L) with an elevated testosterone level of 42 nmol/L.
Adrenal function
Twenty-four of the patients who discontinued mitotane treatment were repeatedly tested with the ACTH stimulation test from 2 months after discontinuation and the latest follow up was 35 months after discontinuation. Based on the test result 15 patients regained adrenal function with subsequent cessation of glucocorticoid treatment. All patients, except one, who regained adrenal function had localized disease and received mitotane as an adjuvant treatment. There were no statistically significant differences between the duration of mitotane treatment, weight adjusted
mitotane dose or whether or not the tumor was producing cortisol and the chance of regaining adrenal function. For those who regained function, the median recover time was 6 (3-16) months.
Discussion
Since ACC is a rare and aggressive disease, patient populations are small and studies investigating treatment for ACC are scarce. Only a few studies have examined the consequences of mitotane treatment and none have examined the effects of discontinuation. We found a significant increase in lipid levels, a decrease in T4 levels, and an increase in levels of LH, SHBG and testosterone. Treatment with statins and thyroxine had a positive effect on hypercholesterolemia and hypothyroidism when analyzing blood samples. Patients who discontinued mitotane treatment showed beneficial effects on lipid and hormone levels and the majority of tested patients regained adrenal function, independently of cortisol production and treatment duration.
This study population of 50 Danish patients has many of the same characteristics as observed in previous studies; a predominantly female cohort with hormone-producing tumors, mainly secreting cortisol (6, 14). Fifty percent of patients reached therapeutic levels of mitotane plasma concentration, which is somewhat lower than reported in previous studies (6, 10, 15, 16). In addition, few or none of the patients in previous studies discontinued mitotane therapy due to side effects (5, 6, 10, 14) as opposed to this study where most patients discontinued treatment mainly due to intolerable side effects. The evidence for the effect of mitotane is scarce, especially for adjuvant treatment (3) where no randomized controlled trials have been conducted. This may explain why specialists in our center often support patients’ wishes to terminate treatment when side effects become too unendurable. In particular treatment of patients with disseminated disease and concomitant chemotherapy can be challenging since common side effects of mitotane such as gastrointestinal side effects and fatigue are difficult to differentiate from side effects of chemotherapy.
Two studies have found total cholesterol to increase significantly during mitotane treatment, mainly due to an increase of LDL, but also HDL (6, 8). Our study confirms these findings. In addition, we found a significant increase in triglyceride. Two different mechanisms to explain the rise in lipids have been proposed; mitotane might stimulate the activity of 3-hydroxy-3- methylglutaryl-coenzyme A reductase, which is the rate-limiting enzyme in the cholesterol
synthesis, and thus, mitotane increases cholesterol levels by inducing endogenous synthesis (17). Alternatively, it has been suggested that mitotane inhibits CYP11A1, which would result in a decrease in conversion rate of cholesterol to pregnenolone (4). In turn, this would decrease substrate flow into the steroidogenic pathway and contribute to the increase of cholesterol levels. We found the absolute increase in HDL to directly correlate with mitotane plasma concentration, confirming previous studies (6, 8). The mechanism is still unclear, but it has been hypothesized that mitotane cause scavenger receptor B1 dysfunction, thereby decreasing the selective uptake of HDL in the liver (8).
If considered clinical relevant we recommend that treatment with lipid-lowering drugs are administered when LDL-levels start to rise. The indication for lipid lowering drugs are cardiovascular risk reduction as well as reduction in risk of gallstone attacks which we have seen in one of our patients requiring cholecystectomy. Obviously patient life expectancy and compliance are included in the decision. The majority were treated with simvastatin and only a few with atorvastatin. We found total cholesterol and LDL to decrease significantly after three months of treatment. The only other study investigating statins effect on total cholesterol levels (n = 17) found a decrease by 14% at the last follow-up after mitotane therapy (6). No information on type of statins, dosage or treatment duration were provided. Two studies have shown that mitotane induces a marked increase of the CYP3A4 enzyme which in turn theoretically should metabolize commonly used statins including simvastatin and atorvastatin (4, 18). Therefore, the recent published European guideline for ACC recommend pravastatin or rosuvastatin for treatment of hypercholesterolemia, although this recommendation is not based on any clinical data (3). Our clinical study demonstrates common statins as effective drugs for mitotane-induced hypercholesterolemia with a clinically relevant decrease of average 1.9 mmol/L in LDL. Further investigations are needed, in order to prove pravastatin or rosuvastatin to be more effective in terms of cholesterol reduction. Moreover, our study shows the effect of mitotane on the lipid profile to be partially reversible when mitotane treatment is discontinued. This is a novel observation, excluding one case report from 2014 (9). A substantial fraction of our patients was still treated with statins at the final analyses and therefore, we are not able to elucidate whether or not lipid metabolism normalizes completely after cessation of mitotane treatment.
We observed a significant reduction in total and free T4 levels in patients treated with mitotane, whereas TSH did not change. Thus, the changes in the thyroid axis induced by mitotane mimics central hypothyroidism. These findings confirm previous studies (6, 11). Several explanations have been proposed. One in vitro study in a mouse cell line found mitotane to directly reduce TSH secretion and expression, as well as TRH responsivity on the pituitary level (12) suggesting a direct effect on the pituitary gland. We did not find TSH to decrease during mitotane treatment. However, central hypothyroidism caused by pituitary disease is characterized by secretion of biologically inactive TSH molecules (11). The presence of biologically inactive TSH could explain low T4 levels and normal TSH levels. Two studies included free T3 levels when collecting data on mitotane treated patients (6, 11). They found free T3 levels to be within the normal range, but the free T3/free T4 ratio to be high. Since T3 is 3-4 times as potent as T4 (19) enhanced conversion of T4 to T3 could also explain the biochemical findings. Unfortunately, we have not measured T3 in our patients. Due to low levels of T4 and symptoms that might be attributed to hypothyroidism many of our patients were treated with thyroxine in accordance with guidelines (3). We found total T4 and free T4 to increase and TSH to decrease when levels were measured six months after thyroxine therapy initiation. To the best of our knowledge, no other study has examined the biochemical effect of thyroxine treatment in mitotane-treated patients. We did not make any structured evaluation of the effects of thyroxine, but based on our everyday clinical experience we have no clear indications of beneficial effects on symptoms. Symptoms of hypothyroidisms like decreased general wellbeing, tiredness, and gastrointestinal symptoms overlap common mitotane side effects, complicating evaluation of thyroid hormone replacement therapy. Research is needed to evaluate the clinical effects of thyroxine treatment. We found a normalization of T4 levels after the discontinuation of mitotane therapy indicating that the change in thyroid function is reversible.
SHBG increased considerably and rapidly when patients were administered mitotane. Most likely as a result of increased levels of SHBG and subsequent reduced testosterone action, we observed a substantial increase in LH, in turn, increasing total testosterone levels in men. Calculated free testosterone remained unchanged which is in contrast to a previous study which found free testosterone to decrease and correlate inversely with mitotane plasma concentration (6). We found both the absolute increase in LH and SHBG to correlate with mitotane plasma concentration in
opposition to previous research (6, 13). A novel observation, was the partial normalization of SHBG after the discontinuation of mitotane treatment.
Despite increasing levels of total testosterone, some of our male patients presented with hypogonadal symptoms, suggesting that the increased testosterone levels cannot compensate for the rapid increase in SHBG. Two studies rapport a decrease in testosterone levels after an initial increase. Production exhaustion or a delayed cytotoxic effect of mitotane on testicular steroidogenesis has been proposed as potential mechanisms (4, 6, 20). We did not observe this phenomenon in our cohort, where levels of total testosterone remained high during mitotane treatment. One study, investigating steroid metabolites in urine, demonstrated mitotane to strongly inhibit 5a-reductase activity. 5a-reductase plays a significant role in the conversion of testosterone to DHT, an androgen 10 times as potent as testosterone (21). The authors speculated that low levels of DHT might be responsible for hypogonadal symptoms in this group of patients, and specifically gynecomastia as a result of enhanced conversion of testosterone to 17B-estradiol by the potent CYP19A1 enzyme. Additionally, the authors suggested that patients should be treated with 5a-reduced androgens and not with testosterone (4). We measured serum levels of DHT in two patients on mitotane treatment. One had equally elevated levels of testosterone and DHT not supporting impaired conversion of testosterone to DHT, whereas the other had elevated testosterone with normal levels of DHT. There are to our knowledge no clinical data regarding treatment with 5a-reduced androgens in patients treated with mitotane. We initiated testosterone treatment in 4 symptomatic men with limited success on symptoms and with no change in elevated levels of LH and SHBG. The reasons could be impaired conversion to DHT, or that levels of circulating testosterone were still insufficient to overcome deactivation by high levels of SHBG. This is contrary to the study by F. Daffara et al., who administered testosterone to four hypogonadal men with subsequent improvement in strength, mood, and sexual drive (6). One concern by adding extra testosterone is increased conversion to estradiol with risk of worsening of gynecomastia. This phenomenon was observed in one of our patients where treatment with an aromatase inhibitor was needed.
One of the main effects of mitotane is the inhibition of adrenal steroidogenesis with subsequent need of simultaneous glucocorticoid supplementation therapy (22) and often in higher dosage than usual (3). Mitotane accumulates in the adipose tissue, and releases slowly to the bloodstream,
with a half-life between 18 and 159 days (23). Fifteen of 24 patients tested with ACTH stimulation test regained adrenal function after discontinuation of mitotane. This confirms a recent study by Poirier at al., who found 78% of patients treated with adjuvant mitotane to completely recover their adrenal function and thus discontinue glucocorticoid replacement (24). Hypotheses explaining prolonged adrenal insufficiency, are a long-lasting inhibitory effect on secretion of ACTH from the pituitary (25) or that interparenchymal and intraglandular levels of mitotane remain at a sufficient level to inhibit the steroidogenesis long after plasma mitotane concentration become undetectable (7).
Our study has some limitations. Half of the patients were treated with concomitant chemotherapy which is a potential confounder. Only patients treated with mitotane were included, precluding any analysis of the effect of mitotane compared to an untreated patient group with ACC. In addition, the retrospective nature of the study is a source of selection bias, which we attempted to reduce by setting few inclusion and exclusion criteria for the cohort. Finally, the size of some subgroups was small and some patients were treated for only a short period, thus the effect of mitotane might not have shown.
In conclusion, side effects of mitotane like hypercholesterolemia, hypothyroidism, and changes in sex hormone levels are common and to be expected, but treatable and often reversible. Specialists treating cancer patients with mitotane should be aware of these common side effects, as well as being informed on how to treat them accordingly. Although ACC has an overall poor prognosis, patients treated in an adjuvant setting after curative surgery might live years on and after cessation of mitotane with a normal life expectancy. Future studies should focus on efficacy of different lipid lowering drugs, clinical benefits of thyroxin treatment and clinical benefits of treatment with androgens in males.
Disclosure Statement
The authors have no conflicts of interest to declare concerning this study.
Funding Sources
This study has not received any external funding.
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21. Vardanyan RS, Hruby VJ. Male Sex Hormones and Anabolic Steroids. Synthesis of Essential Drugs. 1st ed: Elsevier; 2006. p. 381-7.
22. Hogan TF, Citrin DL, Johnson BM, Nakamura S, Davis TE, Borden EC. o,p’-DDD (mitotane) Therapy of Adrenal Cortical Carcinoma: Observations on Drug Dosage, Toxicity, and Steroid Replacement. Cancer. 1978;42:2177-81.
23. Moolenaar AJ, van Slooten H, van Seters AP, Smeenk D. Blood levels of o,p’-DDD following administration in various vehicles after a single dose and during long-term treatment. Cancer chemotherapy and pharmacology. 1981;7(1):51-4.
24. Poirier J, Gagnon N, Terzolo M et al. Recovery of Adrenal Insufficiency is Frequent After Adjuvant Mitotane Therapy in Patients with Adrenocortical Carcinoma. Cancers. 2020;12.
25. Reimondo G, Puglisi S, Zaggia B et al. Effects of mitotane on the hypothalamic-pituitary- adrenal axis in patients with adrenocortical carcinoma. Eur J Endocrinol. 2017;177(4):361-7.
Figure legends
| Characteristic | Overall (n = 50) | Local disease (n = 26) | Metastatic disease |
|---|---|---|---|
| (n = 24) | |||
| Age (year) | |||
| Median (IQR) | 55 (42-67) | 53 (42-65) | 56 (43-68) |
| Sex (N, %) | |||
| Men | 15 (30%) | 9 (35%) | 6 (25%) |
| Women | 35 (70%) | 17 (65%) | 18 (75%) |
| Weiss-score | |||
| Median (IQR) | 6 (4-8) | 6 (4-7) | 8 (6-9) |
| Functional status (N, %) | |||
| Cortisol | 18 (35%) | 7 (27%) | 10 (42%) |
| Accenteo Cortisol + androgens | 9 (17%) | 3 (11%) | 5 (21%) |
| Androgens | 2 (4%) | – | 2 (8%) |
| Estrogens | 1 (2%) | – | 1 (4%) |
| Non-functional tumors | 21 (40%) | 15 (58%) | 6 (25%) |
| Unknown | 1 (2%) | 1 (4%) | – |
| Median treatment time (months) | |||
| Median (IQR) | 11 (5-26) | 14 (5-36) | 9 (6-17) |
Article
Discontinuation of mitotane (N, %)
37 (71%)
22 (85%)
15 (58%)
Due to side effects
29
20
9
Due to progression
8
2
6
| Variable | Baseline (n = 39)ª | 6 months on mitotane (n = 39)ª | 3 months on statins (n = 17) | After discontinuation of mitotane (n = 30) |
|---|---|---|---|---|
| Total cholesterol, mmol/L | 5.1 (4.3 to 5.8) | 2.2 (1.4 to 3.7)* | -1.9(-3.0 to -1.2)* | -1.2 (-2.5 to -0.4)* |
| HDL, mmol/L | 1.4 (1.2 to 1.6) | 0.2 (0.0 to 0.5)º | 0.2 (-0.3 to 0.4) | -0.4 (-0.8 to 0.0)4 |
| LDL, mmol/L | 2.9 (2.4 to 3.7) | 2.0 (0.9 to 3.6)* | -1.9(-2.9 to -1.1)* | -1.1 (-1.7 to 0.1)4 |
| Triglyceride, mmol/L | 1.2 (1.0 to 1.9) | 0.6 (0.0 to 1.2) | -0.1 (-0.3 to 0.2) | -0.1 (-0.6 to 0.5) |
Baseline values are measured before initiation of mitotane therapy. After 6 months of treatment or just before initiation of treatment with statins a second measurement occurred, shown in the second column as a delta-value. The stated p-value in the second column indicate a significant change from baseline to the 6-months mark. The p-value indicated in the third column indicates significant change from just before initiation of statins and 3 months after treatment introduction, again values are shown as delta-values. Last columns p-values indicate significant change from just before discontinuation of mitotane and the latest measurement known, presented with delta-values. Data are expressed as median (IQR). * P < 0.001, AP ≤ 0.01,°P ≤0.03.ªLDL measurement, n =37.
rticle
| Variable | Baseline (n = 37)ª | 6 months on mitotane (n = 37)ª | 6 months on thyroxine (n = 23)b | After discontinuation of mitotane (n = 30)c |
|---|---|---|---|---|
| TSH, IU/L | 1.2 (0.7 to 1.7) | -0.1 (-0.5 to 1.0) | -0.4 (-1.7 to 0.0)º | 0.3 (0.1 to 1.0) |
| Total T4, nmol/L | 90 (78 to 111) | -32 (-44 to -18)* | 18 (10 to 31)* | 17 (7 to 33)* |
| Free T4, pmol/L | 16.0 (13.0 to 18.3) | -4.4 (-5.8 to -2.1)* | 2.4 (1.0 to 4.5)* | 1.3 (-1.3 to 3.3) |
Baseline values are measured before initiation of mitotane therapy. After 6 months of treatment or just before initiation of treatment with thyroxine a second measurement occurred, shown in the second column as a delta- value. The stated p-value in the second column indicate a significant change from baseline to the 6-months mark. The p-value indicated in the third column indicates significant change from just before initiation of thyroxine and 6 months after treatment introduction, again values are shown as delta-values. Last columns p- values indicate significant change from just before discontinuation of mitotane and the latest measurement known, presented with delta-values. Data are expressed as median (IQR). * P< 0.001, AP ≤ 0.01,°P ≤0.03. “Total T4, n = 27, free T4 measurement, n = 26. bFree T4 measurement, n = 22. “Free T4, n = 28.
Accentes
ticle
| Variable | Baseline | 6 months on mitotane | After discontinuation of mitotane |
|---|---|---|---|
| LH (M+F), IU/L | 4.6 (1.6 to 8.2) | 8.9 (3.0 to 17.4)* | -0.8 (-8.6 to 2.3) |
| LH (M), IU/L | 1.9 (1.3 to 7.0) | 11.8 (8.9 to 17.4)º | -1.2 (-9.7 to 2.8) |
| SHBG (M+F), nmol/L | 36 (22 to 51) | 168 (29 to 211)* | -132 (-201 to -68)° |
| SHBG (M), nmol/L | 40 (24 to 49) | 65 (28 to 170)° | |
| Total testosterone (M), nmol/L | 9.8 (7.2 to 14.5) | 15.1 (8.1 to 20.6)4 | |
| Free testosterone (M), nmol/L | 0.2 (0.2 to 0.3) | 0.1 (0.0 to 0.1) |
Baseline values are measured before initiation of mitotane therapy. The stated p-value in the second column indicate a significant change from baseline to the 6-months mark, presented with delta-values. Last columns p- values indicate significant change from just before discontinuation of mitotane and the latest measurement known, again values are shown as delta-values. LH at baseline and after 6 months of treatment, n = 27 (men, n = 8). LH after the discontinuation of mitotane n = 27 (men, n = 10). SHBG at baseline and after 6 months of treatment n = 18 (men, n = 6). SHBG after the discontinuation of mitotane are n = 5. Total testosterone is n = 8, while free testosterone is n = 6 at baseline and at the 6-months mark. SHBG, total testosterone and free testosterone for men after discontinuation are not calculated as n = 3. Data are expressed as median (IQR). M, male; F, female. * P < 0.001, 4P ≤ 0.01, °P ≤0.03.
Accentra
| Patient number | LH baseline | LH before T | LH during T | T baseline | T before T | T during T | SHBG baseline | SHBG before T | SHBG during T | Free T baseline | Free T before T treat. | Free T during T treat. | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| treat. | treat. | treat. | treat. | treat. | treat. | ||||||||
| 1 | - | 30.6 | 33.0 | - | 52.0 | 49.0 | - | - | - | - | - | - | |
| 2 | 1.9 | 10.8 | 7.8 | 15.0 | 49.9 | 44.0 | 40 | 127 | 148 | 0.30 | 0.47 | 0.34 | |
| 3 | - | 31.6 | 32.1 | 23.0 | 36.0 | 50.0 | 59 | 248 | 232 | 0.42 | 0.20 | 0.24 | |
| 4 | 1.7 | 46.7 | 53.9 | 9.0 | 17.0 | 35.0 | 22 | 186 | 174 | 0.22 | 0.24 | 0.21 |
Baseline refer to measurements before initiation of mitotane therapy. Before testosterone treatment refer to latest measurement on mitotane, but before initiation of testosterone therapy. During testosterone refer to measurement taken 3-6 months after initiation of testosterone. T = testosterone, treat. = treatment. LH was measured in IU/L. SHBG, T and free T was measured in nmol/L.
Accepted
(a) (b) (c) Accepted Article
r = 0.43, p = 0.006
2
Absolute change in HDL, mmol/L
1
.
0
-1
-2
0
5
10
15
20
25
30
Plasma mitotane concentration, mg/L
r = 0.43, p = 0.026
Absolute change in LH, IU/L
60
40
20
0
8
0
5
10
15
20
25
30
Plasma mitotane comcentration, mg/L
r= 0.66, p = 0.003
400
Absolute change in SHBG, nmol/L
300
200
100
0
-100
0
5
10
15
20
25
30
Plasma mitotane concentration, mg/L
Correlation between plasma mitotane and (a) the absolute increase in HDL (n = 40), (b) the absolute increase in LH (n =27), (c) the absolute increase in SHBG (n = 19).
9
8
7
6
LDL, mmol/L
5
4
3
2
1
0
Before statin treatment
After statin treatment
Individual changes in LDL levels in 17 patients treated with statins during mitotane treatment. The dotted line represents the median change.
Accepter