Adrenocortical carcinoma

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7 regimens on this page 10 variants on this page

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Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ESMO-EURACAN

• 2020: Fassnacht et al. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

• 2012: Berruti et al. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

NCCN

• NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Neuroendocrine and Adrenal Tumors.

Adjuvant therapy

Mitotane monotherapy

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

Regimen variant #1, target trough 14-20

Study	Dates of enrollment	Evidence
Wängberg et al. 2010	1979-2007	Phase 2

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

Preceding treatment

• Adrenalectomy

Chemotherapy

• Mitotane (Lysodren) 2000 mg/day PO (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

Regimen variant #2, target trough over 14

Study	Dates of enrollment	Evidence
Haak et al. 1994	1959-1992	Phase 2

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."

Preceding treatment

• Adrenalectomy

Chemotherapy

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

Supportive therapy

• One of the following:
  • Hydrocortisone (Cortef) 30 to 120 mg/day PO
  • Fludrocortisone (Florinef) 0.1 to 0.4 mg/day PO
• 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"

Regimen variant #3, no target trough

Study	Dates of enrollment	Evidence
Luton et al. 1990	1963-1987	Non-randomized

This is included for historic context.

Preceding treatment

• Adrenalectomy

Chemotherapy

• Mitotane (Lysodren)

References

1. Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, Laudat MH, Louvel A, Chapuis Y, Blondeau P, Bonnin A, Bricaire H. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med. 1990 Apr 26;322(17):1195-201. link to original article PubMed
2. Retrospective: 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
3. 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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed content property of HemOnc.org
4. Retrospective: 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
5. 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 link to PMC article PubMed
6. 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. link to original article dosing details in manuscript have been reviewed by our editors PubMed
7. ADIUVO: Terzolo M, Fassnacht M, Perotti P, Libé R, Kastelan D, Lacroix A, Arlt W, Haak HR, Loli P, Decoudier B, Lasolle H, Quinkler M, Haissaguerre M, Chabre O, Caron P, Stigliano A, Giordano R, Zatelli MC, Bancos I, Fragoso MCBV, Canu L, Luconi M, Puglisi S, Basile V, Reimondo G, Kroiss M, Megerle F, Hahner S, Kimpel O, Dusek T, Nölting S, Bourdeau I, Chortis V, Ettaieb MH, Cosentini D, Grisanti S, Baudin E, Berchialla P, Bovis F, Sormani MP, Bruzzi P, Beuschlein F, Bertherat J, Berruti A. Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study. Lancet Diabetes Endocrinol. 2023 Oct;11(10):720-730. Epub 2023 Aug 21. link to original article link to PMC article PubMed NCT00777244

Mitotane & Streptozocin

Regimen

Study	Dates of enrollment	Evidence
Khan et al. 2000	1980-2000	Phase 2

Preceding treatment

• Adrenalectomy

Chemotherapy

• Mitotane (Lysodren) as follows:
  • Cycle 2 onwards: 1000 to 4000 mg/day PO; daily dose is taken in 2 to 3 divided doses per day
• 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 therapy

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

5-day course, then 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 dosing details in manuscript have been reviewed by our editors PubMed

Recurrent, locally advanced, or metastatic disease

Cisplatin & Mitotane

Regimen

Study	Dates of enrollment	Evidence
Bukowski et al. 1993	1984-1990	Phase 2

Note: Table 1 in the original paper states that the good risk group was given 1000 mg/m² of cisplatin; this is almost certainly an error.

Chemotherapy

• Cisplatin (Platinol) by the following risk-based criteria:
  • Good risk: 100 mg/m² IV once on day 1
  • Poor risk: 75 mg/m² IV once on day 1
• Mitotane (Lysodren) 1000 mg PO four times per day on days 1 to 21

21-day cycle for 26 cycles (18 months)

References

1. Bukowski RM, Wolfe M, Levine HS, Crawford DE, Stephens RL, Gaynor E, Harker WG. Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study. J Clin Oncol. 1993 Jan;11(1):161-5. link to original article dosing details in manuscript have been reviewed by our editors PubMed

Doxorubicin monotherapy

Regimen

Study	Dates of enrollment	Evidence
Decker et al. 1991 (ECOG E1879)	1979-1986	Non-randomized

Note: Dosing instructions here are from the 2009 review article.

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1

21-day cycles

References

1. ECOG E1879: Decker RA, Elson P, Hogan TF, Citrin DL, Westring DW, Banerjee TK, Gilchrist KW, Horton J. Eastern Cooperative Oncology Group study 1879: mitotane and adriamycin in patients with advanced adrenocortical carcinoma. Surgery. 1991 Dec;110(6):1006-13. link to original article dosing details in abstract have been reviewed by our editors PubMed

Mitotane monotherapy

Regimen

Study	Dates of enrollment	Evidence
Lubitz et al. 1973	1965-06 to 1969-01	Non-randomized

Note: Dosing instructions here are from the 2009 review article.

Chemotherapy

• Mitotane (Lysodren) 1000 to 2000 mg/day PO (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").

Continued indefinitely

Dose and schedule modifications

• Target mitotane drug level is 10 to 14 mg/L.

References

1. Lubitz JA, Freeman L, Okun R. Mitotane use in inoperable adrenal cortical carcinoma. JAMA. 1973 Mar 5;223(10):1109-12. link to original article PubMed
2. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed

Mitotane & EDP

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

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fassnacht et al. 2012 (FIRM-ACT)	2004-2009	Phase 3 (E-esc)	Mitotane & Streptozocin	Might have superior OS (primary endpoint) Median OS: 14.8 vs 12 mo (HR 0.79, 95% CI 0.61-1.02)

Note: 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 therapy

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

28-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence
Berruti et al. 1998	1993-1997	Phase 2
Berruti et al. 2005	1993-2003	Phase 2

Chemotherapy

• Mitotane (Lysodren) 1000 mg/day PO (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 1 or 2 & 9 (2 doses per cycle)

28-day cycle for up to 6 cycles

References

1. Berruti A, Terzolo M, Pia A, Angeli A, Dogliotti L; Italian Group for the Study of Adrenal Cancer. Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Cancer. 1998 Nov 15;83(10):2194-200. link to original article PubMed
2. 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 dosing details in manuscript have been reviewed by our editors PubMed
3. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00094497

Mitotane & Streptozocin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fassnacht et al. 2012 (FIRM-ACT)	2004-2009	Phase 3 (E-de-esc)	Mitotane & EDP	Might have inferior OS (primary endpoint)

Note: 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)
• 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 therapy

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

21-day cycles

Dose and schedule modifications

• Target mitotane trough of 14 to 20 mg/L

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00094497