Annals of Surgical Oncology

, Volume 25, Issue 12, pp 3453–3459 | Cite as

Adjuvant and Neoadjuvant Therapy, Treatment for Advanced Disease, and Genetic Considerations for Adrenocortical Carcinoma: An Update from the SSO Endocrine and Head and Neck Disease Site Working Group

  • Paxton V. DicksonEmail author
  • Lawrence Kim
  • Tina W. F. Yen
  • Anthony Yang
  • Elizabeth G. Grubbs
  • Dhavel Patel
  • Carmen C. Solórzano
Endocrine Tumors


This is the second of a two-part review on adrenocortical carcinoma (ACC) management. While margin-negative resection provides the only potential cure for ACC, recurrence rates remain high. Furthermore, many patients present with locally advanced, unresectable tumors and/or diffuse metastases. As a result, selecting patients for adjuvant therapy and understanding systemic therapy options for advanced ACC is important. Herein, we detail the current literature supporting the use of adjuvant mitotane therapy, consideration of adjuvant radiation therapy, and utility of cytotoxic chemotherapy in patients with advanced disease. Ongoing investigation into molecular targeted agents, immunotherapy, and inhibitors of steroidogenesis for the treatment of ACC are also highlighted. Lastly, the importance of genetic counseling in patients with ACC is addressed as up to 10% of patients will have an identifiable hereditary syndrome.



None of the authors has any financial disclosures related to this work.


  1. 1.
    Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007;356(23):2372–2380.CrossRefGoogle Scholar
  2. 2.
    Berruti A, Grisanti S, Pulzer A, et al. Long-term outcomes of adjuvant mitotane therapy in patients with radically resected adrenocortical carcinoma. J Clin Endocrinol Metab. 2017;102(4):1358–1365.CrossRefGoogle Scholar
  3. 3.
    Else T, Williams AR, Sabolch A, Jolly S, Miller BS, Hammer GD. Adjuvant therapies and patient and tumor characteristics associated with survival of adult patients with adrenocortical carcinoma. J Clin Endocrinol Metab. 2014;99(2):455–461.CrossRefGoogle Scholar
  4. 4.
    Grubbs EG, Callender GG, Xing Y, et al. Recurrence of adrenal cortical carcinoma following resection: surgery alone can achieve results equal to surgery plus mitotane. Ann Surg Oncol. 2010;17(1):263–270.CrossRefGoogle Scholar
  5. 5.
    Postlewait LM, Ethun CG, Tran TB, et al. Outcomes of adjuvant mitotane after resection of adrenocortical carcinoma: a 13-institution study by the US adrenocortical carcinoma group. J Am Coll Surg. 2016;222(4):480–490.CrossRefGoogle Scholar
  6. 6.
    Haak HR, Hermans J, van de Velde CJ, et al. Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer. 1994;69(5):947–951.CrossRefGoogle Scholar
  7. 7.
    van Slooten H, Moolenaar AJ, van Seters AP, Smeenk D. The treatment of adrenocortical carcinoma with o,p’-DDD: prognostic implications of serum level monitoring. Eur J Cancer Clin Oncol. 1984;20(1):47–53.CrossRefGoogle Scholar
  8. 8.
    Schteingart DE, Doherty GM, Gauger PG, et al. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer. 2005;12(3):667–680.CrossRefGoogle Scholar
  9. 9.
    Miller BS, Else T. AACE adrenal scientific committee. Personalized care of patients with adrenocortical carcinoma: a comprehensive approach. Endocr Pract. 2017;23(6):705–715.CrossRefGoogle Scholar
  10. 10.
    Puglisi S, Perotti P, Pia A, Reimondo G, Terzolo M. Adrenocortical Carcinoma with Hypercortisolism. Endocrinol Metab Clin North Am. 2018;47(2):395–407.CrossRefGoogle Scholar
  11. 11.
    Allolio B, Hahner S, Weismann D, Fassnacht M. Management of adrenocortical carcinoma. Clin Endocrinol (Oxf). 2004;60(3):273–287.CrossRefGoogle Scholar
  12. 12.
    Fassnacht M, Hahner S, Polat B, et al. Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma. J Clin Endocrinol Metab. 2006;91(11):4501–4504.CrossRefGoogle Scholar
  13. 13.
    Sabolch A, Else T, Griffith KA, et al. Adjuvant radiation therapy improves local control after surgical resection in patients with localized adrenocortical carcinoma. Int J Radiat Oncol Biol Phys. 2015;92(2):252–259.CrossRefGoogle Scholar
  14. 14.
    Hoff AO, Berruti A. 5th international ACC symposium: future and current therapeutic trials in adrenocortical Carcinoma. Horm Cancer. 2016;7(1):29–35.CrossRefGoogle Scholar
  15. 15.
    Bednarski BK, Habra MA, Phan A, et al. Borderline resectable adrenal cortical carcinoma: a potential role for preoperative chemotherapy. World J Surg. 2014;38(6):1318–1327.CrossRefGoogle Scholar
  16. 16.
    Berruti A, Terzolo M, Sperone P, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005;12(3):657–666.CrossRefGoogle Scholar
  17. 17.
    Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012;366(23):2189–2197.CrossRefGoogle Scholar
  18. 18.
    Fassnacht M, Berruti A, Baudin E, et al. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol. 2015;16(4):426–435.CrossRefGoogle Scholar
  19. 19.
    Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–723.CrossRefGoogle Scholar
  20. 20.
    Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–1833.CrossRefGoogle Scholar
  21. 21.
    Wolfgang GH, MacDonald JR, Vernetti LA, Pegg DG, Robertson DG. Biochemical alterations in guinea pig adrenal cortex following administration of PD 132301-2, an inhibitor of acyl-CoA:cholesterol acyltransferase. Life Sci. 1995;56(13):1089–1093.CrossRefGoogle Scholar
  22. 22.
    de Krijger RE, Bertherat J. 5th International ACC symposium: classification of adrenocortical cancers from pathology to integrated genomics: real advances or lost in translation? Horm Cancer. 2016;7(1):3–8.CrossRefGoogle Scholar
  23. 23.
    Assie G, Jouinot A, Bertherat J. The ‘omics’ of adrenocortical tumours for personalized medicine. Nat Rev Endocrinol. 2014;10(4):215–228.CrossRefGoogle Scholar
  24. 24.
    Zheng S, Cherniack AD, Dewal N, et al. Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell. 2016;29(5):723–736.CrossRefGoogle Scholar
  25. 25.
    de Reynies A, Assie G, Rickman DS, et al. Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. J Clin Oncol. 2009;27(7):1108–1115.CrossRefGoogle Scholar
  26. 26.
    Lerario AM, Moraitis A, Hammer GD. Genetics and epigenetics of adrenocortical tumors. Mol Cell Endocrinol. 2014;386(1-2):67–84.CrossRefGoogle Scholar
  27. 27.
    Angelousi A, Zilbermint M, Berthon A, Espiard S, Stratakis CA. Diagnosis and Management of Hereditary Adrenal Cancer. Recent Results Cancer Res. 2016;205:125-147.CrossRefGoogle Scholar
  28. 28.
    Petr EJ, Else T. Genetic predisposition to endocrine tumors: diagnosis, surveillance and challenges in care. Semin Oncol. 2016;43(5):582–590.CrossRefGoogle Scholar
  29. 29.
    Bachinski LL, Olufemi SE, Zhou X, et al. Genetic mapping of a third Li-Fraumeni syndrome predisposition locus to human chromosome 1q23. Cancer Res. 2005;65(2):427–431.PubMedGoogle Scholar
  30. 30.
    Raymond VM, Else T, Everett JN, Long JM, Gruber SB, Hammer GD. Prevalence of germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma. J Clin Endocrinol Metab. 2013;98(1):119–125.CrossRefGoogle Scholar
  31. 31.
    Palmero EI, Achatz MI, Ashton-Prolla P, Olivier M, Hainaut P. Tumor protein 53 mutations and inherited cancer: beyond Li-Fraumeni syndrome. Curr Opin Oncol. 2010;22(1):64–69.CrossRefGoogle Scholar
  32. 32.
    Libe R, Groussin L, Tissier F, et al. Somatic TP53 mutations are relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity. Clin Cancer Res. 2007;13(3):844–850.CrossRefGoogle Scholar
  33. 33.
    Chompret A, Abel A, Stoppa-Lyonnet D, et al. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet. 2001;38(1):43–47.CrossRefGoogle Scholar
  34. 34.
    Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol. 2013;31(24):3012–3018.CrossRefGoogle Scholar
  35. 35.
    Liu Y, Chew MH, Goh XW, et al. Systematic study on genetic and epimutational profile of a cohort of Amsterdam criteria-defined Lynch Syndrome in Singapore. PLoS One. 2014;9(4):e94170.CrossRefGoogle Scholar
  36. 36.
    Challis BG, Kandasamy N, Powlson AS, et al. Familial adrenocortical carcinoma in association with lynch syndrome. J Clin Endocrinol Metab. 2016;101(6):2269–2272.CrossRefGoogle Scholar
  37. 37.
    Schaefer S, Shipotko M, Meyer S, et al. Natural course of small adrenal lesions in multiple endocrine neoplasia type 1: an endoscopic ultrasound imaging study. Eur J Endocrinol. 2008;158(5):699–704.CrossRefGoogle Scholar
  38. 38.
    Gatta-Cherifi B, Chabre O, Murat A, et al. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d’etude des Tumeurs Endocrines database. Eur J Endocrinol. 2012;166(2):269–279.CrossRefGoogle Scholar
  39. 39.
    Else T, Rodriguez-Galindo C. 5th International ACC symposium: hereditary predisposition to childhood ACC and the associated molecular phenotype: 5th international ACC symposium session: not just for kids! Horm Cancer. 2016;7(1):36–39.CrossRefGoogle Scholar
  40. 40.
    Custodio G, Parise GA, Kiesel Filho N, et al. Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J Clin Oncol. 2013;31(20):2619–2626.CrossRefGoogle Scholar
  41. 41.
    Villani A, Shore A, Wasserman JD, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016;17(9):1295–1305.CrossRefGoogle Scholar
  42. 42.
    Villani A, Tabori U, Schiffman J, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. 2011;12(6):559–567.CrossRefGoogle Scholar
  43. 43.
    Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990–3011.CrossRefGoogle Scholar
  44. 44.
    O’Sullivan C, Edgerly M, Velarde M, et al. The VEGF inhibitor axitinib has limited effectiveness as a therapy for adrenocortical cancer. J Clin Endocrinol Metab. 2014;99(4):1291–1297.CrossRefGoogle Scholar
  45. 45.
    Berruti A, Sperone P, Ferrero A, et al. Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma. Eur J Endocrinol. 2012;166(3):451–458.CrossRefGoogle Scholar
  46. 46.
    Wortmann S, Quinkler M, Ritter C, et al. Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma. Eur J Endocrinol. 2010;162(2):349–356.CrossRefGoogle Scholar
  47. 47.
    Quinkler M, Hahner S, Wortmann S, et al. Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. J Clin Endocrinol Metab. 2008;93(6):2057–2062.CrossRefGoogle Scholar
  48. 48.
    Naing A, Lorusso P, Fu S, et al. Insulin growth factor receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic adrenocortical carcinoma. Br J Cancer. 2013;108(4):826–830.CrossRefGoogle Scholar
  49. 49.
    Lerario AM, Worden FP, Ramm CA, et al. The combination of insulin-like growth factor receptor 1 (IGF1R) antibody cixutumumab and mitotane as a first-line therapy for patients with recurrent/metastatic adrenocortical carcinoma: a multi-institutional NCI-sponsored trial. Horm Cancer. 2014;5(4):232–239.CrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2018

Authors and Affiliations

  • Paxton V. Dickson
    • 1
    Email author
  • Lawrence Kim
    • 2
  • Tina W. F. Yen
    • 3
  • Anthony Yang
    • 4
  • Elizabeth G. Grubbs
    • 5
  • Dhavel Patel
    • 6
  • Carmen C. Solórzano
    • 7
  1. 1.Division of Surgical Oncology, Department of SurgeryUniversity of Tennessee Health Science CenterMemphisUSA
  2. 2.Division of Surgical Oncology and Endocrine SurgeryUniversity of North CarolinaChapel HillUSA
  3. 3.Division of Surgical OncologyMedical College of WisconsinMilwaukeeUSA
  4. 4.Department of Surgery, Division of Surgical OncologyNorthwestern University Feinberg School of MedicineChicagoUSA
  5. 5.University of Texas MD Anderson Cancer CenterHoustonUSA
  6. 6.Endocrine Oncology BranchNational Institutes of HealthBethesdaUSA
  7. 7.Division of Surgical Oncology and Endocrine SurgeryVanderbilt UniversityNashvilleUSA

Personalised recommendations