Adrenocortical carcinoma

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Last updated on 2024-09-06:7 regimens on this page
10 variants on this page
=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 EuroPMC
*2012: Berruti et al. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
==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)
2- to 3-year course
====Dose and schedule modifications====
*Within the first 2 to 3 months, dose was adjusted to achieve a target therapeutic drug level of 14 to 20 mg/L
===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)
====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"
====Dose and schedule modifications====
*Target mitotane trough of above 14 mg/L
===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) at varying dosages
===References===
# 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 EuroPMC
# 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 EuroPMC
# 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 EuroPMC content property of HemOnc.org
# 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 EuroPMC
# 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 EuroPMC
# 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 EuroPMC
#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 EuroPMC 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===
# 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 EuroPMC
=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===
#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 EuroPMC
==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; Decker et al. 1991 was not available for review.
====Chemotherapy====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
21-day cycles
===References===
#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 EuroPMC
==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) 
Continued indefinitely
====Dose and schedule modifications====
*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===
# 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 EuroPMC
# 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 EuroPMC
==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 longer 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) PO on days 1 to 28 (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
====Dose and schedule modifications====
*Target mitotane trough of 14 to 20 mg/L
===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===
#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 EuroPMC
# 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 EuroPMC
# 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 EuroPMC 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 shorter 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===
# 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 EuroPMC NCT00094497
Category:Adrenocortical carcinoma regimens
Category:Disease-specific pages
Category:Endocrine cancers