Adrenocortical carcinoma medical therapy: Difference between revisions

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{{Adrenocortical carcinoma}}
{{Adrenocortical carcinoma}}
{{CMG}}; {{AE}} {{RT}}
{{CMG}}; {{AE}} {{RT}} {{MAD}}
==Overview==
==Overview==
Chemotherapy and hormonal therapy may be required in treatment of adrenocortical carcinoma.
[[Chemotherapy]] and [[Hormone therapy|hormonal therap<nowiki/>y]] may be required in the treatment of adrenocortical carcinoma. [[Mitotane]] is the only approved [[drug]] in the USA until now. [[Mitotane]] causes a destruction of the inner zones of the [[adrenal cortex]], the [[zona fasciculata]], and [[zona reticularis]]. Other drugs such as [[Ketoconazole|ketoconazole]], [[Metyrapone|metyrapone]], [[Aminoglutethimide|aminoglutethimide]], [[Etomidate]], and [[Mifepristone]] can be used also. Target therapy such as [[sunitinib]] is IGF-1R [[antagonists]] that may be effective also.  
==Medical Therapy==
==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;
Regimens typically include the drug [[mitotane]], an [[inhibitor]] of [[steroid]] synthesis and [[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]]).
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|etoposide,]] and [[mitotane]]. The [[endocrine]] [[cell]] [[toxin]] [[streptozotocin]] has also been included in some treatment protocols. [[Chemotherapy]] may be given to patients with non-resectable [[disease]], to shrink [[Tumor|the tumor]] prior to [[surgery]] ([[neoadjuvant chemotherapy]]), or in an attempt to eliminate [[microscopic]] [[residual]] [[disease]] after [[surgery]]([[adjuvant chemotherapy]]).


===Hormonal therapy===
[[Steroid]] [[synthesis]] [[Inhibitor|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 USA until now.<ref name="pmid16172199">{{cite journal| author=Schteingart DE, Doherty GM, Gauger PG, Giordano TJ, Hammer GD, Korobkin M et al.| title=Management of patients with adrenal cancer: recommendations of an international consensus conference. | journal=Endocr Relat Cancer | year= 2005 | volume= 12 | issue= 3 | pages= 667-80 | pmid=16172199 | doi=10.1677/erc.1.01029 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16172199  }}</ref>
* [[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 [[Inflammation|inflammatory]] infiltrate.
* [[Mitotane]] can be metabolized by [[adrenal]] [[Mitochondrion|mitochondria]] and the [[metabolites]] bind to [[mitochondrial]] [[proteins]] to inhibit [[mitochondrial]] [[respiration]]. This inhibits the [[adrenocortical]] [[steroidogenesis]] pathway.<ref name="pmid8453685">{{cite journal| author=Schteingart DE, Sinsheimer JE, Counsell RE, Abrams GD, McClellan N, Djanegara T et al.| title=Comparison of the adrenalytic activity of mitotane and a methylated homolog on normal adrenal cortex and adrenal cortical carcinoma. | journal=Cancer Chemother Pharmacol | year= 1993 | volume= 31 | issue= 6 | pages= 459-66 | pmid=8453685 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8453685  }}</ref>
* [[CYP11A1]] and [[CYP11B1]] are mainly the [[enzymes]] inhibited by [[mitotane]].<ref name="pmid9118466">{{cite journal| author=Cai W, Counsell RE, Schteingart DE, Sinsheimer JE, Vaz AD, Wotring LL| title=Adrenal proteins bound by a reactive intermediate of mitotane. | journal=Cancer Chemother Pharmacol | year= 1997 | volume= 39 | issue= 6 | pages= 537-40 | pmid=9118466 | doi=10.1007/s002800050610 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9118466  }}</ref>
* The usual daily [[dose]] is 5 to 15 g/d and [[Blood plasma|plasma]] levels range between 0 and 90 mg/L.
* Doses more than 20 g regularly result in [[neurological]] side effects.


Mitotane remains the only drug approved by the U.S.
===== Indications =====
* [[Mitotane]] can be used as an [[adjuvant therapy]]. It is routinely started within 3 months after [[surgery]].<ref name="pmid91184662">{{cite journal| author=Cai W, Counsell RE, Schteingart DE, Sinsheimer JE, Vaz AD, Wotring LL| title=Adrenal proteins bound by a reactive intermediate of mitotane. | journal=Cancer Chemother Pharmacol | year= 1997 | volume= 39 | issue= 6 | pages= 537-40 | pmid=9118466 | doi=10.1007/s002800050610 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9118466  }}</ref>
* [[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. <ref name="pmid22547773">{{cite journal| author=Volante M, Terzolo M, Fassnacht M, Rapa I, Germano A, Sbiera S et al.| title=Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer. | journal=Clin Cancer Res | year= 2012 | volume= 18 | issue= 12 | pages= 3452-61 | pmid=22547773 | doi=10.1158/1078-0432.CCR-11-2692 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22547773  }}</ref>
* The therapeutic [[mitotane]] level is 14 to 20 mg/L.  The most important [[prognostic]] factor is the [[mitotane]] [[plasma]] level. Monitoring of [[blood]] levels should be done.


Food and Drug Administration and European Medicine
===== Side effects =====
{| class="wikitable"
!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 [[Thyroid-stimulating hormone|TSH]], low free
[[T4]]
|Very common
|None
|}
* '''[[Ketoconazole]]''' is commonly used to control [[glucocorticoid]] excess. [[Ketoconazole]] inhibits [[CYP17A1]], [[CYP11A1]]. The usual starting [[dose]] is 200 mg twice daily and can be increased to 1200 mg/d. [[Liver enzymes]] should be monitored during treatment as it is an [[inhibitor]] of several [[hepatic]] [[enzymes]] (eg, [[CYP3A4]], [[CYP2C9]], and [[CYP1A2]]).
* '''[[Metyrapone]]''' is an [[inhibitor]] of [[steroidogenesis]] at the level of [[CYP11B1]]. 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.<ref name="pmid2852194">{{cite journal| author=Hartzband PI, Van Herle AJ, Sorger L, Cope D| title=Assessment of hypothalamic-pituitary-adrenal (HPA) axis dysfunction: comparison of ACTH stimulation, insulin-hypoglycemia and metyrapone. | journal=J Endocrinol Invest | year= 1988 | volume= 11 | issue= 11 | pages= 769-76 | pmid=2852194 | doi=10.1007/BF03350221 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2852194  }}</ref>


Executive Agency for treatment of ACC (15).  
* '''[[Aminoglutethimide]]''' is an [[inhibitor]] of [[CYP11A1]] and [[CYP11B1]].<ref name="pmid198423">{{cite journal| author=Santen RJ, Wells SA, Runić S, Gupta C, Kendall J, Rudy EB et al.| title=Adrenal suppression with aminoglutethimide. I. Differential e-fects of aminoglutethimide on glucocorticoid metabolism as a rationale for use of hydrocortisone. | journal=J Clin Endocrinol Metab | year= 1977 | volume= 45 | issue= 3 | pages= 469-79 | pmid=198423 | doi=10.1210/jcem-45-3-469 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=198423  }}</ref>
* '''[[Etomidate]]''' is a powerful [[inhibitor]] of [[CYP11B1]] and [[CYP11B2]].<ref name="pmid9768661">{{cite journal| author=Drake WM, Perry LA, Hinds CJ, Lowe DG, Reznek RH, Besser GM| title=Emergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with Cushing's syndrome and peritonitis. | journal=J Clin Endocrinol Metab | year= 1998 | volume= 83 | issue= 10 | pages= 3542-4 | pmid=9768661 | doi=10.1210/jcem.83.10.5156 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9768661  }}</ref> 
* '''[[Mifepristone]]''' is a direct [[antagonist]] used for [[glucocorticoid]] excess. Treatment can be initiated with 300 mg daily up to 1200 mg daily. 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|'''Aromatase inhibitors''']] ([[anastrozole]]) and [[Estrogen receptors|estrogen receptor]] [[antagonists]] (eg, [[tamoxifen]] and [[raloxifene]]) are other medical treatment.<ref name="pmid8473376">{{cite journal| author=Flack MR, Pyle RG, Mullen NM, Lorenzo B, Wu YW, Knazek RA et al.| title=Oral gossypol in the treatment of metastatic adrenal cancer. | journal=J Clin Endocrinol Metab | year= 1993 | volume= 76 | issue= 4 | pages= 1019-24 | pmid=8473376 | doi=10.1210/jcem.76.4.8473376 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8473376  }}</ref> 


Mitotane leads with relative specificity to a destruction of the
=== Target therapy ===
 
* They are [[pharmacological]] compounds with defined [[molecular]] targets.<ref name="pmid22837187">{{cite journal| author=Kroiss M, Quinkler M, Johanssen S, van Erp NP, Lankheet N, Pöllinger A et al.| title=Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 10 | pages= 3495-503 | pmid=22837187 | doi=10.1210/jc.2012-1419 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22837187  }}</ref>
inner zones of the adrenal cortex, the zona fasciculata, and
* Most of them are [[IGF-1 receptor|IGF-1R]] [[antagonists]] such as [[sunitinib]].<ref name="pmid25163779">{{cite journal| author=Zhang Q, Pan J, Lubet RA, Wang Y, You M| title=Targeting the insulin-like growth factor-1 receptor by picropodophyllin for lung cancer chemoprevention. | journal=Mol Carcinog | year= 2015 | volume= 54 Suppl 1 | issue=  | pages= E129-37 | pmid=25163779 | doi=10.1002/mc.22206 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25163779  }}</ref>
 
* Side effects include [[hyperglycemia]], [[nausea]], [[fatigue]], and [[anorexia]].<ref name="pmid22465830">{{cite journal| author=Naing A, LoRusso P, Fu S, Hong DS, Anderson P, Benjamin RS et al.| title=Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing's sarcoma family tumors. | journal=Clin Cancer Res | year= 2012 | volume= 18 | issue= 9 | pages= 2625-31 | pmid=22465830 | doi=10.1158/1078-0432.CCR-12-0061 | pmc=3875297 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22465830  }}</ref>
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==
==References==

Latest revision as of 19:33, 30 October 2017

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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] Mohammed Abdelwahed M.D[3]

Overview

Chemotherapy and hormonal therapy may be required in the treatment of adrenocortical carcinoma. Mitotane is the only approved drug in the USA until now. Mitotane causes a destruction of the inner zones of the adrenal cortex, the zona fasciculata, and zona reticularis. Other drugs such as ketoconazole, metyrapone, aminoglutethimide, Etomidate, and Mifepristone can be used also. Target therapy such as sunitinib is IGF-1R antagonists that may be effective also.

Medical Therapy

Chemotherapy and hormonal therapy

Regimens typically include the drug mitotane, an inhibitor of steroid synthesis and 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 non-resectable 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

Indications
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

T4

Very common None

Target 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)
  2. ↑ Schteingart DE, Doherty GM, Gauger PG, Giordano TJ, Hammer GD, Korobkin M; et al. (2005). "Management of patients with adrenal cancer: recommendations of an international consensus conference". Endocr Relat Cancer. 12 (3): 667–80. doi:10.1677/erc.1.01029. PMID 16172199.
  3. ↑ Schteingart DE, Sinsheimer JE, Counsell RE, Abrams GD, McClellan N, Djanegara T; et al. (1993). "Comparison of the adrenalytic activity of mitotane and a methylated homolog on normal adrenal cortex and adrenal cortical carcinoma". Cancer Chemother Pharmacol. 31 (6): 459–66. PMID 8453685.
  4. ↑ Cai W, Counsell RE, Schteingart DE, Sinsheimer JE, Vaz AD, Wotring LL (1997). "Adrenal proteins bound by a reactive intermediate of mitotane". Cancer Chemother Pharmacol. 39 (6): 537–40. doi:10.1007/s002800050610. PMID 9118466.
  5. ↑ Cai W, Counsell RE, Schteingart DE, Sinsheimer JE, Vaz AD, Wotring LL (1997). "Adrenal proteins bound by a reactive intermediate of mitotane". Cancer Chemother Pharmacol. 39 (6): 537–40. doi:10.1007/s002800050610. PMID 9118466.
  6. ↑ Volante M, Terzolo M, Fassnacht M, Rapa I, Germano A, Sbiera S; et al. (2012). "Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer". Clin Cancer Res. 18 (12): 3452–61. doi:10.1158/1078-0432.CCR-11-2692. PMID 22547773.
  7. ↑ Hartzband PI, Van Herle AJ, Sorger L, Cope D (1988). "Assessment of hypothalamic-pituitary-adrenal (HPA) axis dysfunction: comparison of ACTH stimulation, insulin-hypoglycemia and metyrapone". J Endocrinol Invest. 11 (11): 769–76. doi:10.1007/BF03350221. PMID 2852194.
  8. ↑ Santen RJ, Wells SA, Runić S, Gupta C, Kendall J, Rudy EB; et al. (1977). "Adrenal suppression with aminoglutethimide. I. Differential e-fects of aminoglutethimide on glucocorticoid metabolism as a rationale for use of hydrocortisone". J Clin Endocrinol Metab. 45 (3): 469–79. doi:10.1210/jcem-45-3-469. PMID 198423.
  9. ↑ Drake WM, Perry LA, Hinds CJ, Lowe DG, Reznek RH, Besser GM (1998). "Emergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with Cushing's syndrome and peritonitis". J Clin Endocrinol Metab. 83 (10): 3542–4. doi:10.1210/jcem.83.10.5156. PMID 9768661.
  10. ↑ Flack MR, Pyle RG, Mullen NM, Lorenzo B, Wu YW, Knazek RA; et al. (1993). "Oral gossypol in the treatment of metastatic adrenal cancer". J Clin Endocrinol Metab. 76 (4): 1019–24. doi:10.1210/jcem.76.4.8473376. PMID 8473376.
  11. ↑ Kroiss M, Quinkler M, Johanssen S, van Erp NP, Lankheet N, Pöllinger A; et al. (2012). "Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial". J Clin Endocrinol Metab. 97 (10): 3495–503. doi:10.1210/jc.2012-1419. PMID 22837187.
  12. ↑ Zhang Q, Pan J, Lubet RA, Wang Y, You M (2015). "Targeting the insulin-like growth factor-1 receptor by picropodophyllin for lung cancer chemoprevention". Mol Carcinog. 54 Suppl 1: E129–37. doi:10.1002/mc.22206. PMID 25163779.
  13. ↑ Naing A, LoRusso P, Fu S, Hong DS, Anderson P, Benjamin RS; et al. (2012). "Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing's sarcoma family tumors". Clin Cancer Res. 18 (9): 2625–31. doi:10.1158/1078-0432.CCR-12-0061. PMC 3875297. PMID 22465830.

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