• Massimo TerzoloEmail author
  • Arianna Ardito
  • Barbara Zaggia
  • Silvia De Francia
  • Fulvia Daffara


Mitotane (o,p’-DDD), an analog of the insecticide DDT, has been used for the treatment of advanced adrenocortical carcinoma (ACC) since the 1960s. Its use as an adjunctive postoperative measure remained more controversial. Despite being in use for many years, the rarity of ACC precluded the organization of randomized trials; thus many areas of uncertainty and controversy remain regarding the role of this old drug in the clinical management of patients with ACC.


Adrenocortical Carcinoma Zona Fasciculata Zona Reticularis Adjuvant Mitotane Objective Tumor Regression 
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  1. 1.
    Hahner S, Fassnacht M (2005) Mitotane for adrenocortical carcinoma treatment. Curr Opin Investig Drugs 6(4):386–394PubMedGoogle Scholar
  2. 2.
    Schteingart DE et al (2005) Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer 667–680CrossRefGoogle Scholar
  3. 3.
    MICROMEDEX® Healthcare Series, Copyright © 1974–2009, Thomson ReutersGoogle Scholar
  4. 4.
    Schteingart DE (2000) Conventional and novel strategies in the treatment of adrenocortical cancer. Brazilian J Med Biol Res 33:1197–1200Google Scholar
  5. 5.
    Hart MM et al (1973) The effect of isomers of DDD on the ACTH-induced steroid output, histology and ultrastructure of the dog adrenal cortex. Toxicol Appl Pharmacol 24: 127–159CrossRefGoogle Scholar
  6. 6.
    Cueto C, Brown JH (1958) The chemical fractionation of an adrenocorticolytic drug. Endocrinology 62:326–333PubMedCrossRefGoogle Scholar
  7. 7.
    Nelson AA, Woodard G (1949) Severe adrenal cortical atrophy (cytotoxic) and hepatic damage produced in dogs by feeding 2,2-bis(parachlorophenyl)-1,1-dichloroethane (DDD or TDE). Arch Pathol (Chic) 48:387–394Google Scholar
  8. 8.
    Nichols J, Hennigar G (1957) Studies on DDD, 2,2-bis (parachlorophenyl)-1,1-dichloroethane. Exp Med Surg 15:310–316PubMedGoogle Scholar
  9. 9.
    Kaminsky N et al (1962) Ultrastructure of adrenal cortex of the dog during treatment with DDD. J Natl Cancer Inst 29:127–159PubMedGoogle Scholar
  10. 10.
    Vilar O, Tullner WW (1959) Effects of o,p’DDD on histology and 17-hydroxycorticosteroid output of the dog adrenal cortex. Endocrinology 65:80–86PubMedCrossRefGoogle Scholar
  11. 11.
    Bergenstal DM et al (1960) Chemotherapy of adrenocortical cancer with o,p’DDD. Ann Intern Med 53:672Google Scholar
  12. 12.
    Hutter AM Jr, Kayhoe DE (1966) Adrenal cortical carcinoma: clinical features in 138 patients. Am J Med 41:572–580PubMedCrossRefGoogle Scholar
  13. 13.
    Lubitz JA et al (1973 Mar 5) Mitotane use in inoperable adrenal cortical carcinoma. JAMA. 223(10):1109–1112PubMedCrossRefGoogle Scholar
  14. 14.
    Hoffman DL, Mattox VR (1972 Jul) Treatment of adrenocortical carcinoma with o,p’-DDD. Med Clin North Am 56(4):999–1012PubMedGoogle Scholar
  15. 15.
    Boven E et al (1984) Complete response of metastatized adrenal cortical carcinoma with op’-DDD. Case report and literature review. Cancer 53: 26–29PubMedCrossRefGoogle Scholar
  16. 16.
    Wooten MD, King DK (1993) Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 72(11): 3145–3155PubMedCrossRefGoogle Scholar
  17. 17.
    WHO handbook for reporting results of cancer treatment WHO Offset Publication No 48. Geneva, 1979Google Scholar
  18. 18.
    Dackiw AP et al (2001) Adrenal cortical carcinoma. World J Surg 25:914–926PubMedCrossRefGoogle Scholar
  19. 19.
    Vassilopoulou-Sellin R et al (1993) Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 71(10): 3119–3123PubMedCrossRefGoogle Scholar
  20. 20.
    Wajchenberg B et al (2000) Adrenocortical carcinoma: clinical and laboratory observations. Cancer 88:711–736PubMedCrossRefGoogle Scholar
  21. 21.
    Decker RA et al (1991) Eastern Cooperative Oncology Group study 1879: mitotane and adriamycin in patients with advanced adrenocortical carcinoma. Surgery 110(6):1006–1013PubMedGoogle Scholar
  22. 22.
    Hajiar RA et al (1975) Adrenal cortical carcinoma: a study of 32 patients. Cancer 35: 549–554CrossRefGoogle Scholar
  23. 23.
    Haq MM et al (1980) Cytotoxic chemotherapy in adrenal cortical carcinoma. Cancer Treat Rep 64: 909–913PubMedGoogle Scholar
  24. 24.
    Hogan TF et al (1978) op’,DDD (mitotane) therapy for adrenal cortical carcinoma: observation on drug dosage, toxicity, and steroid replacement. Cancer 42: 2177–2181PubMedCrossRefGoogle Scholar
  25. 25.
    Venkatesh S et al (1989) Adrenal cortical carcinoma. Cancer 64: 765–769PubMedCrossRefGoogle Scholar
  26. 26.
    Grapski RT et al (1983) Cisplatin chemotherapy of adrenocortical carcinoma. Proc Am Soc Clin Oncol 2: 232Google Scholar
  27. 27.
    Luton JP et al (1990) Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 322:1195–2001PubMedCrossRefGoogle Scholar
  28. 28.
    Pommier RF, Brennan MF (1992) An eleven-year experience with adrenocortical carcinoma. Surgery 112: 963–970PubMedGoogle Scholar
  29. 29.
    Tattersall MH et al (1980) Cis-platinum treatment of metastatic adrenal carcinoma. Med J Aust 1:419–421PubMedGoogle Scholar
  30. 30.
    Bodie B et al (1989) The Cleveland Clinic experience with adrenal cortical carcinoma. J Urol 141:257–260PubMedGoogle Scholar
  31. 31.
    Williamson SK et al (2000) Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adrenocortical carcinoma: a Southwest Oncology Group Study. Cancer 88(5): 1159–1165PubMedCrossRefGoogle Scholar
  32. 32.
    Haak HR et al (1994) Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 69:947–951PubMedCrossRefGoogle Scholar
  33. 33.
    Van Slooten H et al (1984) The treatment of adrenocortical carcinoma with o,p’-DDD: prognostic implications of serum level monitoring. Eur J Cancer Clin Oncol 20:47–53PubMedCrossRefGoogle Scholar
  34. 34.
    Baudin E et al (2001) Impact of monitoring plasma 1,1-dichlorodiphenildichloroethane (o,p’DDD) levels on the treatment of patients with adrenocortical carcinoma. Cancer 92:1385–1392PubMedCrossRefGoogle Scholar
  35. 35.
    Seki M et al (1999) Changes in neoplastic cell features and sensitivity to mitotane during mitotane-induced remission in a patient with recurrent, metastatic adrenocortical carcinoma. Endocr Relat Cancer 6:529–533PubMedCrossRefGoogle Scholar
  36. 36.
    Allolio B, Fassnacht M (2006) Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 91:2027–2037PubMedCrossRefGoogle Scholar
  37. 37.
    Bates SE et al (1991) Mitotane enhances cytotoxicity of chemotherapy in cell lines expressing a multidrug resistance gene (mdr-1/Pglycoprotein) which is also expressed by adrenocortical carcinomas. J Clin Endocrinol Metab 73(1): 18–29PubMedCrossRefGoogle Scholar
  38. 38.
    Villa R et al (1999) Modulation of cytotoxic drug activity by mitotane and lonidamine in human adrenocortical carcinoma cells. Int J Oncol 14(1):133–138PubMedGoogle Scholar
  39. 39.
    Abraham J et al (2002) A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: continuous infusion doxorubicin, vincristine, and etoposide with daily mitotane as a P-glycoprotein antagonist. Cancer 94(9): 2333–2343PubMedCrossRefGoogle Scholar
  40. 40.
    Faggiano A et al (2006) Rapidly progressing high o,p’DDD doses shorten the time required to reach the therapeutic threshold with an acceptable tolerance: preliminary results. Clin Endocrinol 64:110–113CrossRefGoogle Scholar
  41. 41.
    Terzolo M et al (2000) Low-dose monitored mitotane treatment achieves the therapeutic range with manageable side effects in patients with adrenocortical cancer J Clin Endocrin Metab 86 (6): 2234–2238Google Scholar
  42. 42.
    Daffara F et al (2008) Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly. Endocr Relat Cancer 15:1043–1053PubMedCrossRefGoogle Scholar
  43. 43.
    Hague RV et al (1989) Hepatic microsomal enzyme induction and adrenal crisis due to o,p’DDD therapy for metastatic adrenocortical carcinoma. Clin Endocrinol 31:51–57CrossRefGoogle Scholar
  44. 44.
    Kasperlik-Zaluska AA (2000) Clinical results of the use of mitotane for adrenocortical carcinoma. Brazilian J Med Biol Res 33:1191–1196Google Scholar
  45. 45.
    Nader N et al (2006) Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans. J Clin Endocrinol Metab 91:2165–2170PubMedCrossRefGoogle Scholar
  46. 46.
    Allolio B et al (2004) Management of adrenocortical carcinoma. Clin Endocrinol 60:273–287CrossRefGoogle Scholar
  47. 47.
    Icard P et al (1992) Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112: 972–980PubMedGoogle Scholar
  48. 48.
    Kasperlik-Zaluska AA et al (1995) Adrenocortical carcinoma. A clinical study and treatment results of 52 patients. Cancer 75: 2587–2591PubMedCrossRefGoogle Scholar
  49. 49.
    Dickstein G et al (1998) Is there a role for low doses of mitotane (o,p’-DDD) as adjuvant therapy in adrenocortical carcinoma? J Clin Endocrinol Metab 83:3100–3103PubMedCrossRefGoogle Scholar
  50. 50.
    Schteingart DE et al (1982 Sep) Treatment of adrenal carcinomas. Arch Surg 117(9):1142–1146PubMedGoogle Scholar
  51. 51.
    Barzon L et al (1999 Apr) Comment – Is there a role for low doses of mitotane (o,p’-DDD) as adjuvant therapy in adrenocortical carcinoma? J Clin Endocrinol Metab 84(4):1488–1489PubMedCrossRefGoogle Scholar
  52. 52.
    Barzon L et al (1997 Nov–Dec) Adrenocortical carcinoma: experience in 45 patients. Oncology 54(6):490–496PubMedCrossRefGoogle Scholar
  53. 53.
    Icard P et al (2001) Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 25: 891–897PubMedCrossRefGoogle Scholar
  54. 54.
    Terzolo M (2007) Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356:2372–2380PubMedCrossRefGoogle Scholar
  55. 55.
    Bertherat J et al (2007) Adjuvant mitotane in adrenocortical carcinoma. Letter to the Editor. N Engl J Med 357:1256–1257PubMedCrossRefGoogle Scholar
  56. 56.
    Abiven G et al (2006) Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab 91:2650–2655PubMedCrossRefGoogle Scholar
  57. 57.
    Terzolo M et al (2007) Adjuvant mitotane in adrenocortical carcinoma. Letter to the editor. N Engl J Med 357:1259Google Scholar
  58. 58.
    Schteingart DE (2007) Adjuvant Mitotane Therapy of Adrenal Cancer – Use and Controversy. N Engl J Med 356:2415–2418PubMedCrossRefGoogle Scholar
  59. 59.
    Lee JE (2007) Adjuvant mitotane in adrenocortical carcinoma. Letter to the Editor. N Engl J Med 357:1256–1258CrossRefGoogle Scholar
  60. 60.
    Stojadinovic A et al (2002) Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 20:941–950PubMedCrossRefGoogle Scholar
  61. 61.
    Dickstein G et al (2007) Adjuvant Mitotane in Adrenocortical Carcinoma. Letter to the Editor. N Engl J Med 357(12):1257Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Massimo Terzolo
    • 1
    Email author
  • Arianna Ardito
    • 1
  • Barbara Zaggia
    • 1
  • Silvia De Francia
    • 2
  • Fulvia Daffara
    • 1
  1. 1.Department of Clinical and Biological Sciences, Medicina Interna 1, AOU San Luigi GonzagaUniversity of TurinOrbassanoItaly
  2. 2.Department of Clinical and Biological Sciences, Farmacologia, AOU San Luigi GonzagaUniversity of TurinOrbassanoItaly

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