Adrenocortical carcinoma medical therapy: Difference between revisions
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Steroid synthesis inhibitors such as [[aminoglutethimide]] may be used in a palliative manner to reduce the symptoms of hormonal syndromes. The overall response to chemotherapeutic regimens is 30% and 50%. | Steroid synthesis inhibitors such as [[aminoglutethimide]] may be used in a palliative manner to reduce the symptoms of hormonal syndromes. The overall response to chemotherapeutic regimens is 30% and 50%. | ||
Mitotane causes a destruction of the inner zones of the adrenal cortex, the zona fasciculata, and zona reticularis. It is followed by the emergence of a dense inflammatory infiltrate (283). | ==== '''''[[Mitotane]]''''' ==== | ||
* Mitotane is the only approved drug in the U.S. until now. (15) | |||
Mitotane can be metabolized by adrenal mitochondria and the metabolites bind to mitochondrial proteins to inhibit mitochondrial respiration. 285 284This inhibits the adrenocortical steroidogenesis pathway. | * Mitotane causes a destruction of the inner zones of the adrenal cortex, the [[zona fasciculata]], and zona reticularis. It is followed by the emergence of a dense inflammatory infiltrate (283). | ||
* Mitotane can be metabolized by adrenal [[Mitochondrion|mitochondria]] and the metabolites bind to mitochondrial [[proteins]] to inhibit mitochondrial respiration. 285 284This inhibits the adrenocortical [[steroidogenesis]] pathway. | |||
CYP11A1 and CYP11B1 are mainly the enzymes got inhibited by mitotane. (286, 287). | * [[CYP11A1]] and [[CYP11B1]] are mainly the [[enzymes]] got inhibited by [[mitotane]]. (286, 287). | ||
* The usual daily dose is 5 to 15 g/d and plasma levels range between 0 and 90 mg/L. | |||
The usual daily dose is 5 to 15 g/d and plasma levels range between 0 and 90 mg/L. | * Doses more than 20 g regularly result in neurological side effects. (288). | ||
Doses more than 20 g regularly result in neurological side effects. (288). | |||
===== Indications ===== | ===== Indications ===== | ||
* Mitotane can be used as an adjuvant therapy. It is routinely started within 3 months after surgery.(290) | * [[Mitotane]] can be used as an adjuvant therapy. It is routinely started within 3 months after surgery.(290) | ||
* Mitotane can be used for recurrent and advanced cases as 30% of patients showed stable disease after treatment with mitotane. | * [[Mitotane]] can be used for recurrent and advanced cases as 30% of patients showed stable disease after treatment with [[mitotane]]. | ||
* One-third of patients will respond to mitotane. Low ''RRM1'' expression was a predictor of response to mitotane therapy with prolonged tumor-free survival (298) | * One-third of patients will respond to [[mitotane]]. Low ''RRM1'' expression was a predictor of response to [[mitotane]] therapy with prolonged [[tumor]]-free survival. (298) | ||
* The therapeutic mitotane level is 14 to 20 mg/L (296). The most important prognostic factor is the mitotane plasma level (295). Monitoring of blood levels should be done. | * The therapeutic [[mitotane]] level is 14 to 20 mg/L (296). The most important prognostic factor is the mitotane plasma level (295). Monitoring of blood levels should be done. | ||
===== Side effects ===== | ===== Side effects ===== | ||
| Line 35: | Line 31: | ||
!Treatment | !Treatment | ||
|- | |- | ||
|Nausea, vomiting, diarrhea | |[[Nausea]], [[vomiting]], and [[diarrhea]] | ||
|Very common | |Very common | ||
|Supportive therapy | |Supportive therapy | ||
|- | |- | ||
|Drug-induced hepatitis | |Drug-induced [[hepatitis]] | ||
|Rare | |Rare | ||
|Stop mitotane | |Stop [[mitotane]] | ||
|- | |- | ||
|Adrenal insufficiency | |[[Adrenal insufficiency]] | ||
|Very common | |Very common | ||
|Start hydrocortisone with | |Start [[hydrocortisone]] with | ||
mitotane and may use | [[mitotane]] and may use [[fludrocortisone]] | ||
|- | |- | ||
|Hypogonadism | |[[Hypogonadism]] | ||
|Common | |Common | ||
|Initiate testosterone replacement | |Initiate [[testosterone]] replacement | ||
|- | |- | ||
|Hypothyroidism | |[[Hypothyroidism]] | ||
|Common | |Common | ||
|Initiate thyroid hormone replacement | |Initiate [[thyroid hormone]] replacement | ||
|- | |- | ||
|Increased SHBG, | |Increased [[SHBG]], low [[Thyroid-stimulating hormone|TSH]], low free | ||
T4 | [[T4]] | ||
|Very common | |Very common | ||
|None | |None | ||
|} | |} | ||
* '''Ketoconazole''' is commonly used to control glucocorticoid excess. Ketoconazole inhibits CYP17A1, CYP11A1. (320)The usual starting dose is 200 mg twice daily and can be increased to 1200 mg/d. Liver enzymes should be monitored during treatment. Because it is an inhibitor of several hepatic | * '''[[Ketoconazole]]''' is commonly used to control [[glucocorticoid]] excess. Ketoconazole inhibits [[CYP17A1]], [[CYP11A1]]. (320)The usual starting dose is 200 mg twice daily and can be increased to 1200 mg/d. [[Liver enzymes]] should be monitored during treatment. Because it is an inhibitor of several [[hepatic]] [[enzymes]] (eg, [[CYP3A4]], [[CYP2C9]], and [[CYP1A2]]) | ||
* '''Metyrapone''' is an inhibitor of steroidogenesis at the level of CYP11B1. (321)The usual starting dose is 250 mg twice daily and can be increased to 2 to 3 g/d in 250-mg intervals. An increase of adrenal androgens may happen. | * '''[[Metyrapone]]''' is an inhibitor of [[steroidogenesis]] at the level of [[CYP11B1]]. (321)The usual starting dose is 250 mg twice daily and can be increased to 2 to 3 g/d in 250-mg intervals. An increase of [[Adrenal gland|adrenal]] [[androgens]] may happen. | ||
* '''Aminoglutethimide''' is an inhibitor of CYP11A1 and CYP11B1. (322, 323). | * '''[[Aminoglutethimide]]''' is an inhibitor of [[CYP11A1]] and [[CYP11B1]]. (322, 323). | ||
* '''Etomidate''' is a powerful inhibitor of CYP11B1 and CYP11B2 (324, 325). | * '''[[Etomidate]]''' is a powerful inhibitor of [[CYP11B1]] and [[CYP11B2]] (324, 325). | ||
* '''Mifepristone''' is a direct antagonist used for glucocorticoid excess. Treatment can be initiated with 300 mg daily | * '''[[Mifepristone]]''' is a direct antagonist used for [[glucocorticoid]] excess. Treatment can be initiated with 300 mg daily up to 1200 mg daily. (326)The most common side effects are [[hypokalemia]] and [[hypertension]] due to the direct effects of the very high [[cortisol]] levels on the [[renal]] [[mineralocorticoid]] receptors. | ||
* '''Spironolactone''' can also be used as an androgen antagonist in women with androgen-secreting tumors. Doses range from 200 to 400 mg/d. | * '''[[Spironolactone]]''' can also be used as an [[androgen antagonist]] in women with androgen-secreting [[tumors]]. Doses range from 200 to 400 mg/d. | ||
* '''Aromatase''' | * [[Aromatase inhibitors|'''Aromatase inhibitors''']] ([[anastrozole]]) and [[Estrogen receptors|estrogen receptor]] [[antagonists]] (eg, [[tamoxifen]] and [[raloxifene]]) are other medical treatment. (314). | ||
=== Target therapy === | === Target therapy === | ||
* They are pharmacological compounds with defined molecular targets. (304). | * They are pharmacological compounds with defined [[molecular]] targets. (304). | ||
* Most of them are IGF-1R antagonists such as sunitinib (315). | * Most of them are IGF-1R [[antagonists]] such as [[sunitinib]] (315). | ||
* Side effects include hyperglycemia, nausea, fatigue, and anorexia (317). | * Side effects include [[hyperglycemia]], [[nausea]], [[fatigue]], and [[anorexia]] (317). | ||
==References== | ==References== | ||
Revision as of 19:55, 24 September 2017
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Adrenocortical carcinoma Microchapters |
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Adrenocortical carcinoma medical therapy On the Web |
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Risk calculators and risk factors for Adrenocortical carcinoma medical therapy |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Mohammed Abdelwahed M.D[3]
Overview
Chemotherapy and hormonal therapy may be required in treatment of adrenocortical carcinoma.
Medical Therapy
Chemotherapy and hormonal therapy
Regimens typically include the drug mitotane, an inhibitor of steroid synthesis which is toxic to cells of the adrenal cortex,[1] as well as standard cytotoxic drugs. One widely used regimen consists of cisplatin, doxorubicin, etoposide and mitotane. The endocrine cell toxin streptozotocin has also been included in some treatment protocols. Chemotherapy may be given to patients with unresectable disease, to shrink the tumor prior to surgery (neoadjuvant chemotherapy), or in an attempt to eliminate microscopic residual disease after surgery (adjuvant chemotherapy).
Steroid synthesis inhibitors such as aminoglutethimide may be used in a palliative manner to reduce the symptoms of hormonal syndromes. The overall response to chemotherapeutic regimens is 30% and 50%.
Mitotane
- Mitotane is the only approved drug in the U.S. until now. (15)
- Mitotane causes a destruction of the inner zones of the adrenal cortex, the zona fasciculata, and zona reticularis. It is followed by the emergence of a dense inflammatory infiltrate (283).
- Mitotane can be metabolized by adrenal mitochondria and the metabolites bind to mitochondrial proteins to inhibit mitochondrial respiration. 285 284This inhibits the adrenocortical steroidogenesis pathway.
- CYP11A1 and CYP11B1 are mainly the enzymes got inhibited by mitotane. (286, 287).
- The usual daily dose is 5 to 15 g/d and plasma levels range between 0 and 90 mg/L.
- Doses more than 20 g regularly result in neurological side effects. (288).
Indications
- Mitotane can be used as an adjuvant therapy. It is routinely started within 3 months after surgery.(290)
- Mitotane can be used for recurrent and advanced cases as 30% of patients showed stable disease after treatment with mitotane.
- One-third of patients will respond to mitotane. Low RRM1 expression was a predictor of response to mitotane therapy with prolonged tumor-free survival. (298)
- The therapeutic mitotane level is 14 to 20 mg/L (296). The most important prognostic factor is the mitotane plasma level (295). Monitoring of blood levels should be done.
Side effects
| Side effect | Frequency | Treatment |
|---|---|---|
| Nausea, vomiting, and diarrhea | Very common | Supportive therapy |
| Drug-induced hepatitis | Rare | Stop mitotane |
| Adrenal insufficiency | Very common | Start hydrocortisone with
mitotane and may use fludrocortisone |
| Hypogonadism | Common | Initiate testosterone replacement |
| Hypothyroidism | Common | Initiate thyroid hormone replacement |
| Increased SHBG, low TSH, low free | Very common | None |
- Ketoconazole is commonly used to control glucocorticoid excess. Ketoconazole inhibits CYP17A1, CYP11A1. (320)The usual starting dose is 200 mg twice daily and can be increased to 1200 mg/d. Liver enzymes should be monitored during treatment. Because it is an inhibitor of several hepatic enzymes (eg, CYP3A4, CYP2C9, and CYP1A2)
- Metyrapone is an inhibitor of steroidogenesis at the level of CYP11B1. (321)The usual starting dose is 250 mg twice daily and can be increased to 2 to 3 g/d in 250-mg intervals. An increase of adrenal androgens may happen.
- Aminoglutethimide is an inhibitor of CYP11A1 and CYP11B1. (322, 323).
- Etomidate is a powerful inhibitor of CYP11B1 and CYP11B2 (324, 325).
- Mifepristone is a direct antagonist used for glucocorticoid excess. Treatment can be initiated with 300 mg daily up to 1200 mg daily. (326)The most common side effects are hypokalemia and hypertension due to the direct effects of the very high cortisol levels on the renal mineralocorticoid receptors.
- Spironolactone can also be used as an androgen antagonist in women with androgen-secreting tumors. Doses range from 200 to 400 mg/d.
- Aromatase inhibitors (anastrozole) and estrogen receptor antagonists (eg, tamoxifen and raloxifene) are other medical treatment. (314).
Target therapy
- They are pharmacological compounds with defined molecular targets. (304).
- Most of them are IGF-1R antagonists such as sunitinib (315).
- Side effects include hyperglycemia, nausea, fatigue, and anorexia (317).
References
- ↑ Laurence L. Brunton, editor-in-chief;
John S. Lazo and Keith L. Parker, Associate Editors (2006). Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition. United States of America: The McGraw-Hill Companies, Inc. ISBN 0-07-142280-3. line feed character in
|author=at position 38 (help)