Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Current Oncology Reports
Published in: Current Oncology Reports 3/2019

01-03-2019 | Adrenocortical Carcinoma | Genitourinary Cancers (DP Petrylak and JW Kim, Section Editors)

Management of Adrenocortical Carcinoma

Authors: Sina Jasim, Mouhammed Amir Habra

Published in: Current Oncology Reports | Issue 3/2019

Login to get access

Abstract

Purpose of Review

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy typically with poor prognosis. This review aims to summarize the current knowledge regarding the clinical management of ACC.

Recent Findings

Surgery remains the cornerstone for localized ACC management. In more advanced cases, debulking surgery when feasible can help with hormonal control and may allow the initiation of systemic therapy. Over the last few years, our understanding of ACC molecular pathogenesis has expanded with no significant change in treatment options. Platinum-based chemotherapy is the gold standard in metastatic ACC despite suboptimal efficacy. Tyrosine kinase inhibitor use did not result in meaningful benefit in ACC patients. Multiple clinical trials are currently exploring the role of immunotherapy in ACC.

Summary

Despite the remarkable improvement in our understanding of the molecular signature and pathways in ACC, this knowledge did not yield a major breakthrough in management of advanced ACC. Multi-institutional and international collaborations are needed to identify promising treatments and new therapeutic targets to improve the care of ACC patients.
Literature
1.
Else T, et al. Adrenocortical carcinoma. Endocr Rev. 2014;35(2):282–326.PubMed
2.
Kebebew E, et al. Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress? World J Surg. 2006;30(5):872–8.PubMed
3.
Datta J, Roses RE. Surgical management of adrenocortical carcinoma: an evidence-based approach. Surg Oncol Clin N Am. 2016;25(1):153–70.PubMed
4.
Fassnacht M, et al. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer. 2009;115(2):243–50.PubMed
5.
Ayala-Ramirez M, et al. Adrenocortical carcinoma: clinical outcomes and prognosis of 330 patients at a tertiary care center. Eur J Endocrinol. 2013;169(6):891–9.PubMedPubMedCentral
6.
Michalkiewicz E, et al. Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol. 2004;22(5):838–45.PubMed
7.
Asare EA, et al. A novel staging system for adrenocortical carcinoma better predicts survival in patients with stage I/II disease. Surgery. 2014;156(6):1378–85 discussion 1385–6.PubMed
8.
Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol. 2017;17(4):233–47.PubMed
9.
Berruti A, et al. Prognostic role of overt hypercortisolism in completely operated patients with adrenocortical cancer. Eur Urol. 2014;65(4):832–8.PubMed
10.
Jouinot A, Bertherat J. Management of endocrine disease: adrenocortical carcinoma: differentiating the good from the poor prognosis tumors. Eur J Endocrinol. 2018;178(5):R215–30.PubMed
11.
•• Beuschlein F, et al. Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab. 2015;100(3):841–9 This work established the significance of Ki67 as a prognostic marker after localized ACC resction and this is now an adopted test by many centers with clinical use to classify ACC patients and determine adjuvant therapy and trial participation. PubMed
12.
13.
Miller BS, Else T, Committee AAS. Personalized care of patients with adrenocortical carcinoma: a comprehensive approach. Endocr Pract. 2017;23(6):705–15.PubMed
14.
Assie G, et al. Integrated genomic characterization of adrenocortical carcinoma. Nat Genet. 2014;46(6):607–12.PubMed
15.
•• Zheng S, et al. Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell. 2016;29(5):723–36 A comprehensive genomic analysis that identified 3 ACC subtypes with different outcomes and molecular signature. It also illustrated the underlying pathways and mutations in ACC. PubMedPubMedCentral
16.
Libe R, et al. Somatic TP53 mutations are relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity. Clin Cancer Res. 2007;13(3):844–50.PubMed
17.
Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst. 2000;92(18):1472–89.PubMed
18.
Lehmann T, Wrzesinski T. The molecular basis of adrenocortical cancer. Cancer Gene Ther. 2012;205(4):131–7.
19.
Giordano TJ, et al. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol. 2003;162(2):521–31.PubMedPubMedCentral
20.
Varghese J, Habra MA. Update on adrenocortical carcinoma management and future directions. Curr Opin Endocrinol Diabetes Obes. 2017;24(3):208–14.PubMed
21.
Kim AC, et al. Targeted disruption of beta-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex. Development. 2008;135(15):2593–602.PubMed
22.
Mazzuco TL, et al. Genetic aspects of adrenocortical tumours and hyperplasias. Clin Endocrinol. 2012;77(1):1–10.
23.
Gaujoux S, et al. beta-Catenin activation is associated with specific clinical and pathologic characteristics and a poor outcome in adrenocortical carcinoma. Clin Cancer Res. 2011;17(2):328–36.PubMed
24.
•• Phan LM, et al. Hepatocyte growth factor/cmet pathway activation enhances cancer hallmarks in adrenocortical carcinoma. Cancer Res. 2015;75(19):4131–42 This study explored the roles and contribution of HGF and cMET to ACC resistance to traditional therapy. It also provided preclinical data about the usefulness of targeting cMET as potential ACC therapy. PubMedPubMedCentral
25.
Dong G, et al. Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. Cancer Res. 2001;61(15):5911–8.PubMed
26.
Saucier C, et al. The Shc adaptor protein is critical for VEGF induction by Met/HGF and ErbB2 receptors and for early onset of tumor angiogenesis. Proc Natl Acad Sci U S A. 2004;101(8):2345–50.PubMedPubMedCentral
27.
Ando K, et al. Polo-like kinase 1 (Plk1) inhibits p53 function by physical interaction and phosphorylation. J Biol Chem. 2004;279(24):25549–61.PubMed
28.
Bourdeau I, MacKenzie-Feder J, Lacroix A. Recent advances in adrenocortical carcinoma in adults. Curr Opin Endocrinol Diabetes Obes. 2013;20(3):192–7.PubMed
29.
• Fassnacht M, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the study of adrenal tumors. Eur J Endocrinol. 2018; This is a recent comprehensive clinical practice guidelines in managing ACC.
30.
Claps M, et al. Adding metyrapone to chemotherapy plus mitotane for Cushing’s syndrome due to advanced adrenocortical carcinoma. Endocrine. 2018;61(1):169–72.PubMed
31.
Castinetti F, et al. Merits and pitfalls of mifepristone in Cushing’s syndrome. Eur J Endocrinol. 2009;160(6):1003–10.PubMed
32.
Seccia TM, et al. Aldosterone-producing adrenocortical carcinoma: an unusual cause of Conn’s syndrome with an ominous clinical course. Endocr Relat Cancer. 2005;12(1):149–59.PubMed
33.
Moreno S, et al. Feminizing adreno-cortical carcinomas in male adults. A dire prognosis. Three cases in a series of 801 adrenalectomies and review of the literature. Ann Endocrinol (Paris). 2006;67(1):32–8.
34.
Donatini G, et al. Long-term survival after adrenalectomy for stage I/II adrenocortical carcinoma (ACC): a retrospective comparative cohort study of laparoscopic versus open approach. Ann Surg Oncol. 2014;21(1):284–91.PubMed
35.
Lombardi CP, et al. Open versus endoscopic adrenalectomy in the treatment of localized (stage I/II) adrenocortical carcinoma: results of a multiinstitutional Italian survey. Surgery. 2012;152(6):1158–64.PubMed
36.
Cooper AB, et al. Does laparoscopic adrenalectomy jeopardize oncologic outcomes for patients with adrenocortical carcinoma? Surg Endosc. 2013;27(11):4026–32.PubMed
37.
Gonzalez RJ, et al. Laparoscopic resection of adrenal cortical carcinoma: a cautionary note. Surgery. 2005;138(6):1078–85 discussion 1085–6.PubMed
38.
Miller BS, et al. Resection of adrenocortical carcinoma is less complete and local recurrence occurs sooner and more often after laparoscopic adrenalectomy than after open adrenalectomy. Surgery. 2012;152(6):1150–7.PubMed
39.
Fassnacht M, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the study of adrenal tumors. Eur J Endocrinol. 2016;175(2):G1–G34.PubMed
40.
Kulke MH, et al. Neuroendocrine tumors. J Natl Compr Cancer Netw. 2012;10(6):724–64.
41.
Gaujoux S, Brennan MF. Recommendation for standardized surgical management of primary adrenocortical carcinoma. Surgery. 2012;152(1):123–32.PubMed
42.
Reibetanz J, et al. Impact of lymphadenectomy on the oncologic outcome of patients with adrenocortical carcinoma. Ann Surg. 2012;255(2):363–9.PubMed
43.
Gerry JM, et al. Lymphadenectomy for adrenocortical carcinoma: is there a therapeutic benefit? Ann Surg Oncol. 2016;23(Suppl 5):708–13.PubMedPubMedCentral
44.
Bednarski BK, et al. Borderline resectable adrenal cortical carcinoma: a potential role for preoperative chemotherapy. World J Surg. 2014;38(6):1318–27.PubMed
45.
Hermsen IG, et al. Surgery in adrenocortical carcinoma: Importance of national cooperation and centralized surgery. Surgery. 2012;152(1):50–6.PubMed
46.
Tang Y, et al. Benefits of adjuvant mitotane after resection of adrenocortical carcinoma: a systematic review and meta-analysis. Biomed Res Int. 2018;2018:9362108.PubMedPubMedCentral
47.
• Berruti A, et al. Long-term outcomes of adjuvant mitotane therapy in patients with radically resected adrenocortical carcinoma. J Clin Endocrinol Metab. 2017;102(4):1358–65 This retrospective study has long follow up and found an improved recurrence free survival in patients treated with adjuvant mitotane after surgery. PubMed
48.
Srougi V, et al. Adjuvant radiotherapy for the primary treatment of adrenocortical carcinoma: Are we offering the best? Int Braz J Urol. 2017;43(5):841–8.PubMedPubMedCentral
49.
•• Nelson DW, et al. Adjuvant radiation is associated with improved survival for select patients with non-metastatic adrenocortical carcinoma. Ann Surg Oncol. 2018;25(7):2060–6 Recent retrospective data analysis that found survival benefit with adjuvant radiation therapy only in ACC patients who had positive resection margins. PubMed
50.
Livhits M, et al. Surgery is associated with improved survival for adrenocortical cancer, even in metastatic disease. Surgery. 2014;156(6):1531–40 discussion 1540–1.PubMedPubMedCentral
51.
Fay AP, et al. Adrenocortical carcinoma: the management of metastatic disease. Crit Rev Oncol Hematol. 2014;92(2):123–32.PubMedPubMedCentral
52.
Gaujoux S, et al. European Society of Endocrine Surgeons (ESES) and European Network for the Study of Adrenal Tumors (ENSAT) recommendations for the surgical management of adrenocortical carcinoma. Br J Surg. 2017;104(4):358–76.PubMed
53.
Wang S, et al. Primary site surgery for metastatic adrenocortical carcinoma improves survival outcomes: an analysis of a population-based database. Onco Targets Ther. 2017;10:5311–5.PubMedPubMedCentral
54.
Megerle F, et al. Mitotane monotherapy in patients with advanced adrenocortical carcinoma. J Clin Endocrinol Metab. 2018;103(4):1686–95.PubMed
55.
Hermsen IG, et al. Plasma concentrations of o,p'DDD, o,p'DDA, and o,p'DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study. J Clin Endocrinol Metab. 2011;96(6):1844–51.PubMed
56.
Fassnacht M, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012;366(23):2189–97.PubMed
57.
• Henning JEK, et al. Gemcitabine-based chemotherapy in adrenocortical carcinoma: a multicenter study of efficacy and predictive factors. J Clin Endocrinol Metab. 2017;102(11):4323–32 This study showed a limited clinical benefit of gemcitabine-based chemotherapy in patients with advanced ACC. PubMed
58.
Lerario AM, 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):232–9.PubMedPubMedCentral
59.
Naing A, 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):826–30.PubMedPubMedCentral
60.
Haluska P, et al. Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother Pharmacol. 2010;65(4):765–73.PubMed
61.
Jones RL, et al. Phase I study of intermittent oral dosing of the insulin-like growth factor-1 and insulin receptors inhibitor OSI-906 in patients with advanced solid tumors. Clin Cancer Res. 2015;21(4):693–700.PubMed
62.
•• Fassnacht M, et al. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomized, phase 3 study. Lancet Oncol. 2015;16(4):426–35 This double-blind, randomized, multicenter phase III study did not find a significant improvement in clinical outcomes in ACC patients who received linsitinib vs. placebo. The study was terminated early because of lack of efficacy. PubMed
63.
Xu YZ, et al. Significance of heparanase-1 and vascular endothelial growth factor in adrenocortical carcinoma angiogenesis: potential for therapy. Endocrine. 2011;40(3):445–51.PubMed
64.
Rosen LS. Inhibitors of the vascular endothelial growth factor receptor. Hematol Oncol Clin North Am. 2002;16(5):1173–87.PubMed
65.
Wortmann S, et al. Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma. Eur J Endocrinol. 2010;162(2):349–56.PubMed
66.
Butler C, Butler WM, Rizvi AA. Sustained remission with the kinase inhibitor sorafenib in stage IV metastatic adrenocortical carcinoma. Endocr Pract. 2010;16(3):441–5.PubMed
67.
Berruti 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):451–8.PubMed
68.
Kroiss M, et al. Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial. J Clin Endocrinol Metab. 2012;97(10):3495–503.PubMed
69.
Gaccia-Donas J, e.a., Phase II study of dovitinib in first line metastatic or (nonresectable primary) adrenocortical carcinoma (ACC). 2014. SOGUG study 2011–03. JCO 2014. 32(5 s):Suppl; abstr 4588.
70.
O’Sullivan C, et al. The VEGF inhibitor axitinib has limited effectiveness as a therapy for adrenocortical cancer. J Clin Endocrinol Metab. 2014;99(4):1291–7.PubMedPubMedCentral
71.
Adam P, et al. Epidermal growth factor receptor in adrenocortical tumors: analysis of gene sequence, protein expression and correlation with clinical outcome. Mod Pathol. 2010;23(12):1596–604.PubMed
72.
Samnotra V, V.-S.R, Fojo AT, Oh WK, LaRocca RV, Ernstoff MS, et al. A phase II trial of gefitinib monotherapy in patients with unresectable adrenocortical carcinoma (ACC). ASCO Meeting Abstracts 2007. 2007;25(18_suppl):15527.
73.
Quinkler M, et al. Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. J Clin Endocrinol Metab. 2008;93(6):2057–62.PubMed
74.
De Martino MC, et al. The role of mTOR inhibitors in the inhibition of growth and cortisol secretion in human adrenocortical carcinoma cells. Endocr Relat Cancer. 2012;19(3):351–64.PubMed
75.
Ganesan P, et al. Phase I clinical trial of lenalidomide in combination with temsirolimus in patients with advanced cancer. Investig New Drugs. 2013;31(6):1505–13.
76.
Wagle N, et al. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. 2014;4(5):546–53.PubMedPubMedCentral
77.
Krishnamurthy N, Kurzrock R. Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treat Rev. 2018;62:50–60.PubMed
78.
Maharjan R, et al. Comprehensive analysis of CTNNB1 in adrenocortical carcinomas: Identification of novel mutations and correlation to survival. Sci Rep. 2018;8(1):8610.PubMedPubMedCentral
79.
Leal LF, et al. Inhibition of the Tcf/beta-catenin complex increases apoptosis and impairs adrenocortical tumor cell proliferation and adrenal steroidogenesis. Oncotarget. 2015;6(40):43016–32.PubMedPubMedCentral
80.
Tissier F, et al. Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res. 2005;65(17):7622–7.PubMed
81.
• Fay AP, et al. Programmed death ligand-1 expression in adrenocortical carcinoma: an exploratory biomarker study. J Immunother Cancer. 2015;3:3 This study is the first to formally explore the expression of select immune markers in ACC.PubMedPubMedCentral
82.
Jain M, et al. Interleukin-13 receptor alpha2 is a novel therapeutic target for human adrenocortical carcinoma. Cancer. 2012;118(22):5698–708.PubMedPubMedCentral
83.
Liu-Chittenden Y, et al. Phase I trial of systemic intravenous infusion of interleukin-13-pseudomonas exotoxin in patients with metastatic adrenocortical carcinoma. Cancer Med. 2015;4(7):1060–8.PubMedPubMedCentral
84.
• Le Tourneau C, et al. Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial. J Immunother Cancer. 2018;6(1):111 A phase Ib trial on the use of the immuntherapy agent, avelumab, a monoclonal antibody that targets PD-L1, in ACC. The response rate was 6% and half of the study participants received mitotane. PubMedPubMedCentral
85.
Ludimila Cavalcante, B.A.C., Ricardo Lima Barros Costa, Young Kwang Chae, Alfred Rademaker, Francis J. Giles, Preliminary results from a phase II study of nivolumab for patients with metastatic adrenocortical carcinoma J Clin Oncol 35, no. 7_suppl (March 12,017) 96–96, 2017.
86.
Kreissl MC, et al. [(1)(2)(3)I]Iodometomidate imaging in adrenocortical carcinoma. J Clin Endocrinol Metab. 2013;98(7):2755–64.PubMed
87.
Hahner S, et al. [123 I]Iodometomidate for molecular imaging of adrenocortical cytochrome P450 family 11B enzymes. J Clin Endocrinol Metab. 2008;93(6):2358–65.PubMed
88.
Hahner S, et al. [131I]iodometomidate for targeted radionuclide therapy of advanced adrenocortical carcinoma. J Clin Endocrinol Metab. 2012;97(3):914–22.PubMed
89.
Milgrom SA, Goodman KA. The role of radiation therapy in the management of adrenal carcinoma and adrenal metastases. J Surg Oncol. 2012;106(5):647–50.PubMed
90.
Glover AR, et al. Current management options for recurrent adrenocortical carcinoma. Onco Targets Ther. 2013;6:635–43.PubMedPubMedCentral
91.
Wood BJ, et al. Radiofrequency ablation of adrenal tumors and adrenocortical carcinoma metastases. Cancer. 2003;97(3):554–60.PubMedPubMedCentral
Metadata
Title
Management of Adrenocortical Carcinoma
Authors
Sina Jasim
Mouhammed Amir Habra
Publication date
01-03-2019
Publisher
Springer US
Published in
Current Oncology Reports / Issue 3/2019
Print ISSN: 1523-3790
Electronic ISSN: 1534-6269
DOI
https://doi.org/10.1007/s11912-019-0773-7

Other articles of this Issue 3/2019

Current Oncology Reports 3/2019 Go to the issue

Head and Neck Cancers (EY Hanna, Section Editor)

Sinonasal Undifferentiated Carcinoma

Lung Cancer (H Borghaei, Section Editor)

Emerging Targeted Therapies for the Treatment of Non-small Cell Lung Cancer

Genitourinary Cancers (DP Petrylak and JW Kim, Section Editors)

Clinical and Genomic Considerations for Variant Histology in Bladder Cancer

Lymphomas (MR Smith, Section Editor)

How Recent Advances in Biology of Waldenström’s Macroglobulinemia May Affect Therapy Strategy

Genitourinary Cancers (DP Petrylak and JW Kim, Section Editors)

Current Status and Future Direction of Immunotherapy in Urothelial Carcinoma

Evolving Therapies (RM Bukowski, Section Editor)

Angiopoietin-1 and Angiopoietin-2 Inhibitors: Clinical Development
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits