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] 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
- Mitotane is the only approved drug in the USA until now.[2]
- 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.
- Mitotane can be metabolized by adrenal mitochondria and the metabolites bind to mitochondrial proteins to inhibit mitochondrial respiration. This inhibits the adrenocortical steroidogenesis pathway.[3]
- CYP11A1 and CYP11B1 are mainly the enzymes inhibited by mitotane.[4]
- 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.
Indications
- Mitotane can be used as an adjuvant therapy. It is routinely started within 3 months after surgery.[5]
- 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. [6]
- 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.
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. 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 androgens may happen.[7]
- Aminoglutethimide is an inhibitor of CYP11A1 and CYP11B1.[8]
- Etomidate is a powerful inhibitor of CYP11B1 and CYP11B2.[9]
- 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 (anastrozole) and estrogen receptor antagonists (eg, tamoxifen and raloxifene) are other medical treatment.[10]
Target therapy
- They are pharmacological compounds with defined molecular targets.[11]
- Most of them are IGF-1R antagonists such as sunitinib.[12]
- Side effects include hyperglycemia, nausea, fatigue, and anorexia.[13]
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) - ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.