Adrenocortical carcinoma

Section editor
	Jeena M. Varghese, MBBS Houston, TX LinkedIn

7 regimens on this page 10 variants on this page

Guidelines

NCCN

• NCCN Guidelines - Neuroendocrine Tumors

Adjuvant therapy

Mitotane monotherapy

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There is limited and controversial clinical trial information about adjuvant mitotane use. See the references for additional case series and expert recommendation articles.

Variant #1

Study	Evidence
Wängberg et al. 2010	Phase II

Patients started on adjuvant mitotane within 4 weeks of their surgical resection.

Chemotherapy

• Mitotane (Lysodren) 2000 mg PO per day (frequency not specified, such as whether the total daily dose was divided into a few doses throughout the day); within the first 2 to 3 months, dose was adjusted to achieve a target therapeutic drug level of 14 to 20 mg/L

2 to 3-year course

Variant #2

Study	Evidence
Haak et al. 1994	Phase II

Haak et al. 1994 concluded that "mitotane treatment in adrenocortical carcinoma is effective only when high serum levels [trough of at least 14 mg/L] can be achieved."

Chemotherapy

• Mitotane (Lysodren) 1000 to 2000 mg PO QID (total dose per day: 4000 to 8000 mg), with target mitotane trough of above 14 mg/L

Supportive medications

• Hydrocortisone (Cortef) 30 to 120 mg per day or Fludrocortisone (Florinef) 0.1 to 0.4 mg per day
• Metoclopramide (Reglan) prn "gastrointestinal side-effects"
• Loperamide (Imodium) prn "gastrointestinal side-effects"

2-year course "if resection was judged to be complete or for 1 year after apparent disappearance of the tumour"

References

1. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, Taylor SH, Hess KR, Schultz PN, Samaan NA. Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer. 1993 May 15;71(10):3119-23. link to original article PubMed
2. Haak HR, Hermans J, van de Velde CJ, Lentjes EG, Goslings BM, Fleuren GJ, Krans HM. Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer. 1994 May;69(5):947-51. contains verified protocol link to PMC article PubMed content property of HemOnc.org
3. Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P, Grossrubatscher E, Reimondo G, Bollito E, Papotti M, Saeger W, Hahner S, Koschker AC, Arvat E, Ambrosi B, Loli P, Lombardi G, Mannelli M, Bruzzi P, Mantero F, Allolio B, Dogliotti L, Berruti A. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007 Jun 7;356(23):2372-80. link to original article PubMed
4. Veytsman I, Nieman L, Fojo T. Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J Clin Oncol. 2009 Sep 20;27(27):4619-29. Epub 2009 Aug 10. link to original article link to PMC article PubMed
5. Wängberg B, Khorram-Manesh A, Jansson S, Nilsson B, Nilsson O, Jakobsson CE, Lindstedt S, Odén A, Ahlman H. The long-term survival in adrenocortical carcinoma with active surgical management and use of monitored mitotane. Endocr Relat Cancer. 2010 Feb 18;17(1):265-72. Print 2010 Mar. link to original article contains verified protocol PubMed

Mitotane & Streptozocin

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Regimen

Study	Evidence
Khan et al. 2010	Phase II

Induction course

• Streptozocin (Zanosar) 1000 mg IV once per day on days 1 to 5

5-day course, followed by main regimen

Main regimen

• Mitotane (Lysodren) 1000 to 4000 mg/day PO; daily dose is taken in 2 to 3 divided doses per day
• Streptozocin (Zanosar) 2000 mg IV once per day on days 1 to 5

Supportive medications

• 5-HT3 antagonists prior to streptozocin
• Hydrocortisone (Cortef) 25 to 100 mg/day

21-day cycles; duration of therapy not clearly specified

References

1. Khan TS, Imam H, Juhlin C, Skogseid B, Gröndal S, Tibblin S, Wilander E, Oberg K, Eriksson B. Streptozocin and o,p'DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use. Ann Oncol. 2000 Oct;11(10):1281-7. link to original article contains verified protocol PubMed

Recurrent, locally advanced, or metastatic disease

Mitotane monotherapy

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Regimen

Study	Evidence
Veytsman et al. 2009	Review

Chemotherapy

• Mitotane (Lysodren) 1000 to 2000 mg PO per day (frequency not specified), then increase dose by 1000 to 2000 mg every 1 to 2 weeks to the maximum tolerated dose, not to exceed 6000 mg ("never greater than 6 to 10 g/d").
  • Target mitotane drug level is 10 to 14 mg/L.

References

1. Review: Veytsman I, Nieman L, Fojo T. Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J Clin Oncol. 2009 Sep 20;27(27):4619-29. Epub 2009 Aug 10. link to original article contains verified protocol link to PMC article PubMed

Mitotane & EDP

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Mitotane & EDP: Mitotane, Etoposide, Doxorubicin, Platinol (Cisplatin)

Variant #1

Study	Evidence	Comparator	Efficacy
Fassnacht et al. 2012 (FIRM-ACT)	Phase III	Mitotane & Streptozocin	Superior PFS

Mitotane is started at least 1 week before the other chemotherapy; the rest of the therapy is as described below.

Chemotherapy

• Mitotane (Lysodren) on days 1 to 28, with target mitotane trough of 14 to 20 mg/L (initial dose and frequency not specified)
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 2 to 4
• Doxorubicin (Adriamycin) 40 mg/m² IV once on day 1
• Cisplatin (Platinol) 40 mg/m² IV once per day on days 3 & 4

Supportive medications

• Glucocorticoid replacement was recommended in all patients except those with persistent Cushing's syndrome.

28-day cycles

Variant #2

Study	Evidence
Berruti et al. 2005	Phase II

Chemotherapy

• Mitotane (Lysodren) 1000 mg PO per day (frequency not specified, such as whether the total daily dose was divided into a few doses throughout the day) on days 1 to 28; then dose is increased as tolerated up to 4000 mg/day or maximum tolerated dose
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 5 to 7
• Doxorubicin (Adriamycin) 20 mg/m² IV once per day on days 1 & 8
• Cisplatin (Platinol) 40 mg/m² IV once per day on days 2 & 9

28-day cycle for up to 6 cycles

References

1. Berruti A, Terzolo M, Sperone P, Pia A, Della Casa S, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005 Sep;12(3):657-66. link to original article contains verified protocol PubMed
2. FIRM-ACT: Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboulleux S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la Fouchardière C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink H, Sender M, Edgerly M, Kenn W, Fojo T, Müller HH, Skogseid B; FIRM-ACT Study Group. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun 7;366(23):2189-97. Epub 2012 May 2. link to original article contains verified protocol PubMed

Mitotane & Streptozocin

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Regimen

Study	Evidence	Comparator	Efficacy
Fassnacht et al. 2012 (FIRM-ACT)	Phase III	Mitotane & EDP	Inferior PFS

Mitotane is started at least 1 week before the other chemotherapy; the rest of the therapy is as described below.

Chemotherapy

• Mitotane (Lysodren) PO on days 1 to 21 (initial dose and frequency not specified)
  • Target mitotane trough of 14 to 20 mg/L
• Streptozocin (Zanosar) as follows:
  • Cycle 1: 1000 mg IV once per day on days 1 to 5
  • Cycle 2 onwards: 2000 mg IV once on day 1

Supportive medications

• Glucocorticoid replacement was recommended in all patients except those with persistent Cushing's syndrome.

21-day cycles

References

1. Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboulleux S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la Fouchardière C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink H, Sender M, Edgerly M, Kenn W, Fojo T, Müller HH, Skogseid B; FIRM-ACT Study Group. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun 7;366(23):2189-97. Epub 2012 May 2. link to original article contains verified protocol PubMed

Placebo

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Regimen

Study	Evidence	Comparator	Efficacy
Fassnacht et al. 2015	Phase III (C)	Linsitinib	Seems not superior

No active antineoplastic treatment.

References

1. Fassnacht M, Berruti A, Baudin E, Demeure MJ, Gilbert J, Haak H, Kroiss M, Quinn DI, Hesseltine E, Ronchi CL, Terzolo M, Choueiri TK, Poondru S, Fleege T, Rorig R, Chen J, Stephens AW, Worden F, Hammer GD. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol. 2015 Apr;16(4):426-35. Epub 2015 Mar 18. link to original article PubMed