Accepted Manuscript
PCSK-9 Inhibitor use in the management of resistant hypercholesterolemia induced by mitotane treatment for adrenocortical cancer
Efthymia D. Tsakiridou, Evangelos Liberopoulos, Zoe Giotaki, Stelios Tigas
| PII: | S1933-2874(18)30150-8 |
| DOI: | 10.1016/j.jacl.2018.03.078 |
| Reference: | JACL 1279 |
| To appear in: | Journal of Clinical Lipidology |
| Received Date: | 29 December 2017 |
| Revised Date: | 1 March 2018 |
| Accepted Date: | 5 March 2018 |
Journal of Clinical Lipidology
Official Journal of the National Lipid Association
na
Please cite this article as: Tsakiridou ED, Liberopoulos E, Giotaki Z, Tigas S, PCSK-9 Inhibitor use in the management of resistant hypercholesterolemia induced by mitotane treatment for adrenocortical cancer, Journal of Clinical Lipidology (2018), doi: 10.1016/j.jacl.2018.03.078.
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PCSK-9 Inhibitor use in the management of resistant hypercholesterolemia induced
by mitotane treatment for adrenocortical cancer
Efthymia D Tsakiridou1, Evangelos Liberopoulos2, Zoe Giotaki1, Stelios Tigas1
1Department of Endocrinology, Ioannina University Hospital, Ioannina, Greece
2Department of Internal Medicine, Ioannina University Hospital, Ioannina, Greece
Running title: Evolocumab use in mitotane-induced hypercholesterolemia
Corresponding author:
Stelios Tigas
Email: stigas@cc.uoi.gr
University Hospital of loannina Stavros Niarchos Avenue 45500 Ioannina Greece
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Keywords
Mitotane; Adrenocortical carcinoma; ACC; Hypercholesterolemia; PCSK9 inhibitors; PCSK9, Evolocumab
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Introduction
Adrenocortical carcinoma (ACC) is a rare malignancy with an unfavorable prognosis. Surgical excision is the only potentially curative therapy. In patients with advanced disease, medical therapy with mitotane is recommended, either alone or in combination with conventional chemotherapy. Mitotane (o,p’DDD) derives from the insecticide dichlorodiphenyltrichloroethane (DDT) and has been in use since 1959. It is administered orally and apart from its anti-neoplastic activity it also blocks the biosynthesis of cortisol and is therefore useful as a treatment for Cushing’s syndrome. Mitotane is increasingly used as adjunct treatment of ACC as there is evidence that it improves the recurrence-free and overall survival after surgical removal of the primary tumor (1,2).
The use of mitotane is however limited due to multiple adverse effects (mainly from the gastrointestinal and nervous systems), including hyperlipidemia (3). Its hyperlipidemic action is mediated by stimulation of 3-hydroxy-3-methylglutatarate- coenzyme A (HMG-COA) reductase, resulting in an increase in cholesterol synthesis (3,4).
We herein present the case of a female patient with probable heterozygous familial hypercholesterolemia (FH) and mitotane-induced resistant hypercholesterolemia on potent lipid-lowering therapy, who was managed with the addition of a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor.
Case Study
A 55-year-old woman had been diagnosed at the age of 48 with a 8.8 x 7.6 x 3.5 cm adrenal tumor and biochemical features of autonomous cortisol production; she
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underwent right adrenalectomy and histopathological examination at the time revealed ACC with a Weiss score of 6/9 (nuclear grade IV, atypical mitotic figures, mitotic rate 33/50 on high power field, necrosis, capsular and venous invasion) and an MIB-1 index of 20% (5). Following surgical resection, she was treated with adjuvant mitotane and oral hydrocortisone replacement. After 2 years, she was treated with radiofrequency ablation (RFA) for a solitary hepatic metastasis, whilst 3 years later she presented with local recurrence of the ACC, which was effectively managed surgically. The patient is a smoker (30 pack-years), and her past medical history includes essential hypertension and hypercholesterolemia that preexisted the diagnosis of ACC (Table 1). Her mother suffered from coronary artery disease, diagnosed at the age of 55 years. Three of her 4 sisters have a history of hypercholesterolemia. Patient’s untreated low-density lipoprotein (LDL) cholesterol (LDL-c) level prior to initiation of mitotane treatment was 292 mg/dL. A diagnosis of probable FH was established based on a Dutch Lipid Clinic Network (DLCN) score of 6 (6).
Adjuvant mitotane was initiated following surgery for ACC, together with lipid- lowering treatment. Simvastatin 40 mg had been initially prescribed, which was subsequently switched to rosuvastatin 40 mg in combination with ezetimibe 10 mg daily. Nevertheless, LDL-c levels remained markedly elevated (Table 1). Mitotane treatment was however discontinued on at least 2 occasions due to side-effects (mainly hypercholesterolemia and liver toxicity) and could not be administered at doses sufficient to achieve therapeutic plasma levels (14-20 mg/L).
Therefore, evolocumab 140 mg s.c. every 2 weeks was added to her lipid-lowering regime. The addition of evolocumab led to a 70% reduction in LDL-c (from 536 to 160
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mg/dL). At that time mitotane levels had declined from 13.3 to 9.0 mg/L. The beneficial effect of evolocumab was evident from the first month and allowed an increase in the daily dose of mitotane from 2.0 g to 4.5 g/day, to achieve therapeutic plasma mitotane levels (Table 1). Sixteen months from initiation of evolocumab, the patient’s plasma mitotane levels were within the therapeutic range but LDL-c levels increased to 341 mg/dL (representing a modest reduction of 36% compared to baseline). During this period, evolocumab was well tolerated and no adverse effects were reported.
| Parameters | Before initiation of mitotane | On mitotane and simvastatin 40 mg | On mitotane and rosuvastatin 40 mg plus ezetimibe 10 mg | On mitotane and rosuvastatin 40 mg plus ezetimibe 10 mg plus evolocumab 140 mg/ 2 weeks (8 months of therapy) | On mitotane and rosuvastatin 40 mg plus ezetimibe 10 mg plus evolocumab 140 mg/2 weeks (16 months of therapy) |
|---|---|---|---|---|---|
| TC, (mg/dL) | 391 | 479 | 681 | 276 | 468 |
| LDL-c, (mg/dL) | 292 | 359 | 536 | 160 | 341 |
| Triglycerides, (mg/dL) | 131 | 128 | 102 | 70 | 147 |
| HDL-c, (mg/dL) | 73 | 94 | 125 | 102 | 98 |
| Mitotane plasma level, (mg/L). Therapeutic range: 14-20 | - | 6.9 | 13.3 | 9.0 | 16.0 |
HDL-c: high-density lipoprotein cholesterol, LDL-c: low-density lipoprotein cholesterol, TC: total cholesterol
Table 1 Patient lipid profile, lipid-lowering treatment and plasma mitotane level
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Discussion
To our knowledge, this is the first report of PCSK9 inhibitor use in a patient with probable FH and resistant hypercholesterolemia due to mitotane treatment for ACC. ACC is a rare malignancy, with an incidence of 1-2 cases per million population per year. Depending on the stage, the 5-year survival rate varies, from 60-80% in patients with localized disease, to 35-50% in those with locally advanced disease and to 13-28% in patients with metastases (2). Surgical resection is the only curative option for localized disease, while adjuvant therapy with mitotane is recommended to minimize the possibility of recurrence (1). Mitotane has 2 major actions; an anti- neoplastic (through production of free radicals that mediate cytotoxicity) and an inhibitory effect on the pathway of adrenocortical steroidogenesis (blocking the cholesterol side-chain cleavage enzymes CYP11A1 and CYP11B1). The anti-neoplastic effect of mitotane correlates to its plasma levels, with optimal clinical responses observed when the level is kept within a therapeutic target of 14-20 mg/L, although even lower levels (>8 mg/L) have been associated with improved outcomes (1,2). Mitotane induces cytochrome P4503A4 (CYP3A4), which leads to possible drug interactions when coadministered with steroids, calcium channel antagonists, macrolides and certain statins such as simvastatin and atorvastatin (use of mitotane lowers the levels of these drugs) (1,7).
The use of mitotane is limited by gastrointestinal adverse effects such as nausea and vomiting, liver toxicity, neuromuscular manifestations, and hypercholesterolemia. In general, toxicity is correlated with plasma levels of >20 mg/L (2). Mitotane increases total cholesterol, LDL-c as well as high-density lipoprotein cholesterol (HDL-c) levels. Total cholesterol levels may increase by as much as 68%, mainly due to an increase
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of LDL-c (4). This effect is mediated by activation of the HMG-CoA reductase, a rate- limiting enzyme in cholesterol synthesis, which leads to a down regulation of LDL receptors (3,4,8). We observed a rise of 74% and 83% for total cholesterol and LDL-c level, respectively, despite the use of potent lipid-lowering therapy. This exacerbated cholesterol increase may be related to our patient having a background of probable FH and thus already decreased LDL receptor activity. Despite 2 local recurrences within a 7 year-period, the course of ACC in our patient’s case has fortunately been better than average. This fact, together with her relatively young age and the absence of evidence of recurrence in the preceding 2 years, led to consideration of ways to manage her resistant hypercholesterolemia in order to reduce cardiovascular risk.
Two fully human monoclonal antibodies that block PCSK9 have been recently approved for the treatment of hypercholesterolemia; evolocumab and alirocumab (6). PCSK9 is an enzyme with an important role in lipid metabolism and is mainly expressed in the liver and intestine. It binds to the LDL receptor and the LDL particle at the surface of the liver cell. This complex is then subject to lysis in intracellular lysosomes, leading to premature termination of LDL receptor recycling to the cell surface and an increase of plasma LDL-c levels. Inhibition of PCSK9 by monoclonal antibodies results in more LDL receptors recycling to the cell surface in order to bind LDL particles and thus decrease of circulating LDL-c (9,10).
Evolocumab lowers LDL-c level by ~60% when added to statin treatment with or without ezetimibe (9) and is associated with a significant reduction of cardiovascular events in patients with established cardiovascular disease (10). Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use
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of evolocumab as adjunct treatment to diet for adult patients with primary hypercholesterolemia (heterozygous FH or non-familial) or mixed dyslipidemia (a) in combination with other lipid-lowering therapies (eg, statins, ezetimibe) when LDL-c goals are not reached, or (b) alone, when statin is not tolerated or is contraindicated. Evolocumab is also indicated in adults and in adolescents aged over 12 years with homozygous FH. Evolocumab is administered s.c. at a dose of 140 mg every 2 weeks, or 420 mg every 4 weeks. The drug is generally well tolerated with mild injection site reactions being the most frequent adverse event (10).
In conclusion, we present the case of a patient with probable FH and mitotane- related resistant hypercholesterolemia, in whom the administration of evolocumab led to modest reductions of LDL-c levels (by 36%) following increase of mitotane dose and achievement of therapeutic plasma levels. Despite this, LDL-c levels remained unacceptably high and other treatment options should be considered, such as LDL apheresis. Treatment with evolocumab should be considered in patients who develop mitotane-related hypercholesterolemia that cannot be managed with conventional lipid-lowering treatment.
Conflict of interest
EDT has has participated in educational and research activities sponsored by Eli Lilly, Novo Nordisk, Novartis, Rafarm, Petsiavas and Laboratoires SMB.
EL has participated in educational, research and advisory activities sponsored by Astra-Zeneca, MSD, Eli Lilly, Bayer, Amgen, Sanofi-Aventis, Boehringer-Ingelheim, Novartis, Novo Nordisk, Servier, Galenica, ELPEN and Valeant.
ZG has received travel grants and/or participated in research activities sponsored by Astra-Zeneca, Eli Lilly, Sanofi-Aventis, Novartis, Novo Nordisk, Janssen, ELPEN, and Petsiavas SA.
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ST has received lecture honoraria or travel grants from, and/or participated in advisory boards of Astra-Zeneca, Boehringer-Ingelheim, Eli Lilly, ELPEN, Galenica, MSD, Novartis, NovoNordisk, Sanofi-Aventis, Roche, Medtronic, Janssen and Laboratoires SMB.
Author Contribution Statement
All authors were involved in the patient’s care. EDT drafted the manuscript. EL, ZG and ST critically revised and contributed to the final version of the manuscript. All authors have approved the final article.
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Mitotane is used as a treatment for functional or nonfunctional adrenocortical carcinoma. Hypercholesterolemia is a common adverse effect of mitotane therapy. Evolocumab may be useful in the management of mitotane induced hypercholesterolemia.
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