Comparison of Two Mitotane Starting Dose Regimens in Patients With Advanced Adrenocortical Carcinoma

Kerkhofs, Thomas M.A.; Baudin, Éric; Terzolo, Massimo; Allolio, Bruno; Chadarévian, Rita; Mueller, H. P.; Skogseid, Britt; Leboulleux, Sophie; Mantero, Franco; Haak, HR; Fassnacht, Martin

doi:10.1210/jc.2013-2281

Cited by 79 publications

(60 citation statements)

References 28 publications

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“…Mitotane might therefore, through its deleterious effect on mitochondria, inhibit gonadal steroidogenesis, in addition to its established effect on the adrenal cortex (4, 7). Evidence of an effect on testicular steroidogenesis has indeed been reported, thereby strengthening this hypothesis (8,12). These authors showed a decrease in testosterone levels in men, associated with an increase in circulating LH levels, suggesting impaired Leydig cell steroidogenesis.…”

Section: Discussionmentioning

confidence: 64%

“…One unresolved question is whether the inhibitory effect of this drug on steroidogenesis is specific to the adrenal cortex or also concerns other steroidogenic glands such as the gonads. Some recent studies suggest that the testicles may be affected (8), but the ovarian effects of mitotane have not yet been studied, despite the fact that Cushing's disease (CD) and adrenocortical carcinomas (ACCs) are more common in women and can occur before the menopause. In this study, we describe for the first time the ovarian hormonal and gonadotropic impact of mitotane in 21 premenopausal patients.…”

Section: Introductionmentioning

confidence: 99%

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Ovarian macrocysts and gonadotrope–ovarian axis disruption in premenopausal women receiving mitotane for adrenocortical carcinoma or Cushing's disease

Salenave

Bernard

Cao

et al. 2015

European Journal of Endocrinology

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Context: Mitotane is an adrenolytic and anticortisolic drug used in adrenocortical carcinoma (ACC), Cushing's disease (CD), and ectopic ACTH syndrome. Its effects on the ovaries are unknown. Objective: To evaluate the ovarian and gonadotrope effects of mitotane therapy in premenopausal women. Patients: We studied 21 premenopausal women (ACC: nZ13; CD: nZ8; median age 33 years, range 18-45 years) receiving mitotane at a median initial dose of 3 g/day (range 1.5-6 g/day). Methods: Gynecological history was collected and ovarian ultrasound was performed. Four women also underwent ovarian CT or magnetic resonance imaging. Serum gonadotropin, estradiol (E 2 ), androgens, sex hormone-binding globulin (SHBG), and circulating mitotane levels were determined at diagnosis and during mitotane therapy. Results: In the women included, ovarian macrocysts (bilateral in 51%) were detected after a median 11 months (range: 3-36) of mitotane exposure. The median number of macrocysts per woman was two (range: 1-4) and the median diameter of the largest cysts was 50 mm (range: 26-90). Menstrual irregularities and/or pelvic pain were present in 15 out of 21 women at macrocyst diagnosis. In two women, the macrocysts were revealed by complications (ovarian torsion and hemorrhagic macrocyst rupture) that required surgery. Mitotane therapy was associated with a significant decrease in androstenedione and testosterone levels and a significant increase in LH levels. Serum FSH and E 2 levels were also increased, and SHBG levels rose markedly. Conclusions: Mitotane therapy causes significant morphological and ovarian/gonadotrope hormonal abnormalities in premenopausal women. Follicular thecal steroid synthesis appears to be specifically altered and the subsequent increase in gonadotropins might explain the development of macrocysts. The mechanisms underlying these adverse effects, whose exact prevalence in this population still needs to be determined, are discussed. European Journal of EndocrinologyClinical Study S Salenave, V Bernard and others Ovarian effects of mitotane 172:2 141-

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Ovarian macrocysts and gonadotrope–ovarian axis disruption in premenopausal women receiving mitotane for adrenocortical carcinoma or Cushing's disease

Salenave

Bernard

Cao

et al. 2015

European Journal of Endocrinology

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“…3; Terzolo & Berruti 2008, Hermsen et al 2011, Terzolo et al 2013. Kerkhofs et al (2013c), who investigated the optimal dosing strategy, showed that 50% (10/20) of patients from the high dose starting regimen and 33% (4/12) of patients from the low-dose regimen reached the therapeutic level within 3 months. No significant differences were observed in frequency and severity of adverse events.…”

Section: Current Therapeutic Strategiesmentioning

confidence: 99%

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

Creemers¹,

Hofland²,

Korpershoek³

et al. 2015

Endocrine-Related Cancer

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Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Discrimination between ACCs and adrenocortical adenomas (ACAs) remains challenging, with the current gold standard being the Weiss score, consisting of several histopathological characteristics. However, new markers like Ki67, a marker for proliferation, and the staining of reticulins are promising not only as it comes to identifying malignancy but also as prognostic markers in patients with ACC. Currently, surgery is still the only curative treatment for ACC. Mitotane, an adrenolytic drug, is used in the adjuvant setting and in case of metastatic or advanced disease. Patients with progressive disease are frequently treated with mitotane, alone or in combination with etoposide, doxorubicine and cisplatin. Radiotherapy is indicated in selected cases. The low response rates and high toxicity of the systemic therapies emphasize the need for markers that enable the identification of responders and non-responders. Consequently, research is focusing on predictive factors varying from the expression of DNA repair genes to clinical patient characteristics. Subgroups of ACC with different prognosis have been identified based on transcriptome characteristics. As a conclusion from large molecular studies, ACCs appear to harbor many abnormalities compared to ACAs. Altered pathways driving ACC pathogenesis include the IGF, TP53 and the Wnt signaling pathway, allowing these as new potential targets for medical therapy. However, despite efforts in preclinical and clinical studies investigating efficacy of targeting these pathways, most novel therapies appear to be effective in only a subset of patients with ACC. New treatment concepts are therefore urgently needed.

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“…In order to limit drug toxicity, 20 mg/l is considered the upper limit of the therapeutic window (9). In general, the build-up of plasma levels is slow, taking 3-4 months on average, but interindividual differences are large (11,12,13). As knowledge on mitotane pharmacokinetics is sparse, current dosing regimens are based on clinical experience and adjusted according to plasma levels and tolerability.…”

Section: Introductionmentioning

confidence: 99%

Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring

Kerkhofs

Derijks

Ettaieb

et al. 2014

European Journal of Endocrinology

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Objective: Mitotane is the drug of choice in patients with adrenocortical carcinoma. The anti-neoplastic effect is correlated with mitotane plasma levels, which render it crucial to reach and maintain the concentration above 14 mg/l. However, mitotane pharmacokinetics is poorly understood. The aim of this study was to investigate the variation in plasma mitotane levels during the day and the influence of a single morning dose. Design: A prospective case-control study was conducted to investigate the variation in plasma mitotane levels. Methods: Patients who had been treated for at least 24 weeks and had reached the therapeutic plasma level (14 mg/l) at least once were eligible. In the first group, mitotane levels were determined hourly for the duration of 8 h after administration of a single morning dose. In the second group, mitotane levels were assessed similarly without administration of a morning dose. Results: Ten patients were included in this study, and three patients participated in both groups. Median plasma level at baseline was 16.2 mg/l (range 11.3-23.3 mg/l) in the first group (nZ7) and 17.0 mg/l (13.7-23.8) in the second group (nZ6). Plasma levels displayed a median increase compared with baseline of 24% (range 6-42%) at tZ4 after morning dose and a change of 13% (range K14 to 33%) at tZ4 without morning dose (PZ0.02). Conclusion: A substantial increase in mitotane plasma levels was observed in steady-state patients within a period of 8 h after morning dosing. Without morning dose, mitotane curves showed a variable profile throughout the day. This implies that random sampling could yield incidentally high levels. For this reason, we recommend early-morning trough sampling as standard management in monitoring mitotane treatment.

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Comparison of Two Mitotane Starting Dose Regimens in Patients With Advanced Adrenocortical Carcinoma

Cited by 79 publications

References 28 publications

Ovarian macrocysts and gonadotrope–ovarian axis disruption in premenopausal women receiving mitotane for adrenocortical carcinoma or Cushing's disease

Ovarian macrocysts and gonadotrope–ovarian axis disruption in premenopausal women receiving mitotane for adrenocortical carcinoma or Cushing's disease

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring

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