Adrenocortical carcinoma medical therapy: Difference between revisions

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Revision as of 17:56, 21 September 2017

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]

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

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 drug metabolizing 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 and titrated 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)

Template:WikiDoc Sources

[G&G-1] 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)

[1]

@@ Line 5: / Line 5: @@
 Chemotherapy and hormonal therapy may be required in treatment of adrenocortical carcinoma.
 ==Medical Therapy==
-===Chemotherapy===
+===Chemotherapy and hormonal therapy===
 Regimens typically include the drug [[mitotane]], an inhibitor of [[steroid]] synthesis which is toxic to cells of the [[adrenal cortex]],<ref name="G&G">{{cite book |author=Laurence L. Brunton, editor-in-chief;
 John S. Lazo and Keith L. Parker, Associate Editors |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition |publisher=The McGraw-Hill Companies, Inc. |location=United States of America |year=2006 |pages= |isbn=0-07-142280-3 |oclc= |doi= }}</ref> 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]]).
-===Hormonal therapy===
+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.
-'''''1. Mitotane'''''
+==== '''''Mitotane''''' ====
+Mitotane is the only approved drug in the U.S. until now.  (15)
-Mitotane remains the only drug approved by the U.S.
+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).
-Food and Drug Administration and European Medicine
+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.
-Executive Agency for treatment of ACC (15).
+CYP11A1 and CYP11B1 are mainly the enzymes got inhibited by mitotane. (286, 287).
-Mitotane leads with relative specificity to a destruction of the
+The usual daily dose is 5 to 15 g/d and plasma levels range between 0 and 90 mg/L.
-inner zones of the adrenal cortex, the zona fasciculata, and
+Doses more than 20 g regularly result in neurological side effects. (288).
-zona reticularis.
+===== 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.
-mitotane leads to cell death, most likely via necrosis, and is followed by the emergence of a dense inflammatory infiltrate (283).
+===== Side effects =====
+* '''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 drug metabolizing 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.
-mitotane can be extracted in the adrenal gland and further
+* '''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 and titrated 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).
-metabolized (284).
+=== Target therapy ===
+* They are pharmacological compounds with defined molecular targets.  (304).
-Active metabolites produced by adrenal mitochondria, in turn, covalently bind to mitochondrial proteins hypothesized to inhibit mitochondrial respiration (285).
+* Most of them are IGF-1R antagonists such as sunitinib (315).
+* Side effects include hyperglycemia, nausea, fatigue, and anorexia (317).
-mitotane metabolites inhibit several enzymes in the adrenocortical steroidogenesis pathway, mainly at the level of the cholesterol side-chain cleavage enzymes
-CYP11A1 and CYP11B1 (286, 287).
-a usual daily dose of 5 to 15 g/d, plasma levels
-range between 0 and 90 mg/L.
-Doses greater than 20 g regularly result in neurological side effects, which are reversible with normalization of plasma levels (288).
-'''''a.   Mitotane for adjuvant therapy.'''''
-routinely started within 3 months after surgery.
-mitotane was significantly more successful in preventing the growth of xenotransplants when given early at the time of tumor cell inoculation rather than late at the time of visible
-tumor growth (282).
-Median overall survival was significant only in comparison with one of the control groups (110 vs 52 and 67 months) (290).
-'''''b. Mitotane for recurrent and advanced disease.'''''
-% of patients show stable disease or partial remission after treatment with mitotane.
-one-third of patients will have a response to mitotane,
-The most important prognostic factor is the mitotane plasma level (295). the therapeutic mitotane level to be 14 to 20 mg/L
-(296).  On the molecular level, ''RRM1'' expression has been found to be inversely correlated with mitotane response. Low ''RRM1'' expression was a predictor of response to mitotane therapy with prolonged tumor-free survival (298).
-'''''c. Mitotane management.'''''
-The dose is initiated at 1 g
-twice daily and increased every 4 to 7 days by 0.5 to 1 g/d
-until a daily dose of 5 to 7 g is reached.Alow-dose loading
-protocol has also been described,
-appropriate monitoring of blood levels is key and readily available in most countries.
-After the initial loading phase, the mitotane
-dose is titrated to a blood level of 14 to 20 mg/L.
-Side effect and surveillance , don't forget
-several inhibitors of steroidogenesis as well as direct hormone receptor antagonists can be used to control hormone secretion in functioning tumors.
-Adjunct therapy to control side effects with nonspecific pharmacotherapy, such as the use of drugs to prevent osteoporosis, antihyperglycemic drugs, or antihypertensive drugs, may be necessary as well.
-patients need to be regularly evaluated for adrenal insufficiency and should be regarded as adrenal-insufficient in times of physical stress
-Ketoconazole and metyrapone are commonly
-used to control glucocorticoid excess.
-Ketoconazole inhibits CYP17A1, CYP11A1, and to some extent CYP11B1 (320).
-The usual starting dose is 200 mg twice daily and can be increased to 1200 mg/d.
-During treatment with ketoconazole, liver enzymes need to be carefully watched. Because it is an inhibitor of several hepatic drugmetabolizing enzymes (eg, CYP3A4, CYP2C9, and
-CYP1A2)
-Another powerful inhibitor of steroidogenesis at the level
-of CYP11B1 is metyrapone (321), and 250 mg twice daily
-is the usual starting dose and can be increased to 2 to 3 g/d
-in 250-mg intervals. Due to the inhibition of CYP11B1, a
-relative increase in adrenal androgens may occur, possibly
-worsening symptoms related to hyperandrogenemia.
-Aminoglutethimide is an inhibitor of CYP11A1 and CYP11B1 and was initially introduced as an antiepileptic medication (322, 323).
-etomidate is a powerful inhibitor of CYP11B1 and CYP11B2 (324, 325). For this effect, it can be used in the inpatient setting. Some centers have experience with a steady low-dose perfusor, which is a last-resort option. Steady infusion can be safe because doses used are only 1/10 of the anesthetic dose (2–3 vs 20–30 mg/h).
-A direct antagonist used for glucocorticoid excess is
-mifepristone. Treatment can be initiated with 300 mg
-daily and titrated up to 1200 mg daily. Overt adrenal
-insufficiency is rare under treatment with mifepristone
-(326). However, neither ACTH nor glucocorticoid levels
-can be used to guide therapy.
-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. This effect can be further controlled with the addition of spironolactone or eplerenone.
-Spironolactone can also be used to control androgen
-effects in women with androgen-secreting tumors and
-mineralocorticoid effects in patients with mineralocorticoid-
-secreting tumors. Dosesmayneed to be as high as 200
-to 400 mg/d. For the rare cases of male patients with gynecomastia,
-aromatase inhibitors (eg, anastrozole and
-letrozole) as well as estrogen receptor antagonists (eg, tamoxifen
-and raloxifene) can be used.
-Cytotoxic
-Suramin,
-had been found to induce adrenal insufficiency in
-humans and to have adrenolytic activity in animal experiments,
-where it led to inflammatory changes of the adrenal
-cortex (310, 311).
-Another compound
-that had been evaluated as a single agent is gossypol,
-a natural phenol from the cotton plant. An initial
-study suggested a response rate of 14%, but the results of
-repeat studies are pending (314).
-The overall response to chemotherapeutic regimens is 30%
-and 50%, when counting stable disease as a response.
-However, the response is invariably transient and shortlived
-(6–18 months).
-there is criticism regarding whether chemotherapy without mitotane may be more successful.
-Target therapy
-Target therapy refers to
-pharmacological compounds with defined molecular targets,
-such as receptors or intracellular enzymes.
-The most data for targeted therapy exist for the
-IGF-1R antagonists. These studies had been initiated with
-great hopes and were based on the knowledge that children
-with BWS have higher levels of IGF-2. Drugs targeting
-the IGF-1R system are currently being tried in phase 1 and
-phase 2 trials in several tumor entities (315).
-Treatment-related toxicities were generally
-mild and mainly included hyperglycemia, nausea, fatigue,
-and anorexia
-Another phase 2 study used IMCA12 (cixutumab), a fully humanized
-IGF-1R antibody
-cixutumab in combination with temsirolimus (317).
-A study using the multikinase inhibitor sunitinib led to
-stable disease in 5 of 35 patients (304).
-unfortunately, none of the
-studies so far have shown definitive effectiveness that
-would make any of the substances a good candidate for
-further exploration or routine use in ACC therapy.
 ==References==