Adrenocortical carcinoma medical therapy

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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

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).

Hormonal therapy

Steroid synthesis inhibitors such as aminoglutethimide may be used in a palliative manner to reduce the symptoms of hormonal syndromes.

1. Mitotane

Mitotane remains the only drug approved by the U.S.

Food and Drug Administration and European Medicine

Executive Agency for treatment of ACC (15).

Mitotane leads with relative specificity to a destruction of the

inner zones of the adrenal cortex, the zona fasciculata, and

zona reticularis.

mitotane leads to cell death, most likely via necrosis, and is followed by the emergence of a dense inflammatory infiltrate (283).

mitotane can be extracted in the adrenal gland and further

metabolized (284).

Active metabolites produced by adrenal mitochondria, in turn, covalently bind to mitochondrial proteins hypothesized to inhibit mitochondrial respiration (285).

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.

30% 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

  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)

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