Review Article| Volume 21, ISSUE 1, P1-7, February 2023

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A Systematic Review of Published Clinical Trials in the Systemic Treatment of Adrenocortical Carcinoma: An Initiative Led on Behalf of the Global Society of Rare Genitourinary Tumors

Published:October 22, 2022DOI:


      Adrenocortical carcinoma (ACC) is a very rare endocrine cancer and is associated with a poor prognosis. There is a paucity of randomized clinical trials for this rare disease. We aimed to perform a systematic review of the literature on systemic therapy options in different stages of ACC. A systematic review was performed using Pubmed and Embase databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 24 trials of systemic therapy in the treatment of ACC were identified and included in this review. Only one clinical trial in the adjuvant setting was identified, the negative phase III trial ADIUVO, which tested mitotane in low to intermediate-risk ACC patients. In the treatment of advanced ACC, cisplatin-based chemotherapy was evaluated in small and non-randomized phase II trials, and response rates ranged from 21% to 53.5%. The phase III trial FIRM-ACT compared etoposide, doxorubicin, cisplatin, and mitotane versus treatment with streptozotocin and mitotane and showed no difference in OS, but higher RR and PFS were reported with the multi-drug regimen. Six clinical trials of immunotherapy and seven studies of targeted therapy in advanced ACC were included, with modest activity and no phase 3 trials were identified. Treatment recommendations of ACC are based on retrospective and small studies with limited systemic therapy options. International and multi-center collaboration is essential to expand clinical research and improve outcomes.


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        • Sharma E
        • Dahal S
        • Sharma P
        • et al.
        The characteristics and trends in adrenocortical carcinoma: a united states population based study.
        J Clin Med Res. 2018; 10: 636-640
        • Bilimoria KY
        • Shen WT
        • Elaraj D
        • et al.
        Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors.
        Cancer. 2008; 113: 3130-3136
        • Ribeiro RC
        • Sandrini F
        • Figueiredo B
        • et al.
        An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma.
        in: Proc Natl Acad Sci U S A.98. 2001: 9330-9335
        • Else T
        • Kim AC
        • Sabolch A
        • et al.
        Adrenocortical carcinoma.
        Endocr Rev. 2014; 35: 282-326
        • Siegel RL
        • Miller KD
        • Fuchs HE
        • Jemal A.
        Cancer statistics, 2022.
        CA: Cancer J Clin. 2022; 72: 7-33
        • Page MJ
        • McKenzie JE
        • Bossuyt PM
        • et al.
        The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
        BMJ. 2021; 372: n71
        • Berruti A
        • Fassnacht M
        • Libè R
        • et al.
        First randomized trial on adjuvant mitotane in adrenocortical carcinoma patients: The Adjuvo study.
        J Clin Oncol. 2022; 40 (–1): 1
        • Decker RA
        • Elson P
        • Hogan TF
        • et al.
        Eastern cooperative oncology group study 1879: mitotane and adriamycin in patients with advanced adrenocortical carcinoma.
        Surgery. 1991; 110: 1006-1013
        • Berruti A
        • Terzolo M
        • Pia A
        • Angeli A
        • Dogliotti L.
        Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group for the Study of Adrenal Cancer.
        Cancer. 1998; 83: 2194-2200
        • Williamson SK
        • Lew D
        • Miller GJ
        • Balcerzak SP
        • Baker LH
        • Crawford ED.
        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. 2000; 88: 1159-1165
        • Baudin E
        • Docao C
        • Gicquel C
        • et al.
        Use of a topoisomerase I inhibitor (irinotecan, CPT-11) in metastatic adrenocortical carcinoma.
        Ann Oncol. 2002; 13: 1806-1809
        • Berruti A
        • Terzolo M
        • Sperone P
        • Pia A
        • S della Casa
        • Gross DJ
        • 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: 657-666
        • Sperone P
        • Ferrero A
        • Daffara F
        • et al.
        Gemcitabine plus metronomic 5-fluorouracil or capecitabine as a second-/third-line chemotherapy in advanced adrenocortical carcinoma: a multicenter phase II study.
        Endocr Relat Cancer. 2010; 17: 445-453
        • 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: 451-458
        • Fassnacht M
        • Terzolo M
        • Allolio B
        Combination chemotherapy in advanced adrenocortical carcinoma.
        New Eng J Med. 2012; 366: 2189-2197
        • Laganà M
        • Grisanti S
        • Ambrosini R
        • et al.
        Phase II study of cabazitaxel as second-third line treatment in patients with metastatic adrenocortical carcinoma.
        ESMO Open. 2022; 7100422
        • Urup T
        • Pawlak WZ
        • Petersen PM
        • Pappot H
        • Rørth M
        • Daugaard G.
        Treatment with docetaxel and cisplatin in advanced adrenocortical carcinoma, a phase II study.
        British J Cancer. 2013; 108: 1994-1997
        • le Tourneau C
        • Hoimes C
        • Zarwan 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: 111
        • Carneiro BA
        • Konda B
        • Costa RB
        • et al.
        Nivolumab in metastatic adrenocortical carcinoma: results of a phase II trial.
        J Clin Endocrinol Metab. 2019; 104: 6193-6200
        • Habra MA
        • Stephen B
        • Campbell M
        • et al.
        Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma.
        J Immunother Cancer. 2019; 7: 253
        • Raj N
        • Zheng Y
        • Kelly V
        • et al.
        PD-1 Blockade in advanced adrenocortical carcinoma.
        J Clin Oncol. 2020; 38: 71-80
        • Klein O
        • Senko C
        • Carlino MS
        • et al.
        Combination immunotherapy with ipilimumab and nivolumab in patients with advanced adrenocortical carcinoma: a subgroup analysis of CA209-538.
        Oncoimmunology. 2021; 101908771
        • Baudin E
        • Jimenez C
        • Fassnacht M
        • et al.
        EO2401, a novel microbiome-derived therapeutic vaccine for patients with adrenocortical carcinoma (ACC): Preliminary results of the SPENCER study.
        J Clin Oncol. 2022; 40 (–4596): 4596
        • Smith DC
        • Kroiss M
        • Kebebew E
        • et al.
        A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma.
        Invest New Drugs. 2020; 38: 1421-1429
        • Kroiss M
        • Quinkler M
        • Johanssen S
        • et al.
        Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial.
        J Clin Endocrinol Metab. 2012; 97: 3495-3503
        • Haluska P
        • Worden F
        • Olmos D
        • 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: 765-773
        • 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: 426-435
        • García-Donas J
        • Hernando Polo S
        • Guix M
        • et al.
        Phase II study of dovitinib in first line metastatic or (non resectable primary) adrenocortical carcinoma (ACC): SOGUG study 2011-03.
        J Cli Oncol. 2014; 32 (–4588): 4588
        • 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: 232-239
        • 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: 826-830
        • Terzolo M
        • Angeli A
        • Fassnacht M
        • et al.
        Adjuvant mitotane treatment for adrenocortical carcinoma.
        N Engl J Med. 2007; 356: 2372-2380
        • Tang Y
        • Liu Z
        • Zou Z
        • Liang J
        • Lu Y
        • Zhu Y.
        Benefits of adjuvant mitotane after resection of adrenocortical carcinoma: a systematic review and meta-analysis.
        Biomed Res Int. 2018; 20189362108
        • Gaujoux S
        • Mihai R
        • joint working group of ESES and ENSAT
        European Society of Endocrine Surgeons (ESES) and European Network for the Study of Adrenal Tumours (ENSAT) recommendations for the surgical management of adrenocortical carcinoma.
        Br J Surg. 2017; 104 (PMID: 28199015): 358-376
        • Fassnacht M
        • Assie G
        • Baudin E
        • et al.
        Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2020; 31: 1476-1490
        • Shah MH
        • Goldner WS
        • Benson AB
        • et al.
        Neuroendocrine and adrenal tumors, version 2.2021, NCCN clinical practice guidelines in oncology.
        J Nat Comprehens Cancer Network. 2021; 19: 839-868
        • Fassnacht M
        • Dekkers OM
        • Else T
        • 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.
        Euro J Endocrinol. 2018; 179: G1-46
        • Bednarski BK
        • Habra MA
        • Phan A
        • et al.
        Borderline resectable adrenal cortical carcinoma: a potential role for preoperative chemotherapy.
        World J Surg. 2014; 38: 1318-1327
        • Assié G
        • Letouzé E
        • Fassnacht M
        • et al.
        Integrated genomic characterization of adrenocortical carcinoma.
        Nat Genet. 2014; 46: 607-612
        • Zheng S
        • Cherniack AD
        • Dewal N
        • et al.
        Comprehensive pan-genomic characterization of adrenocortical carcinoma.
        Cancer Cell. 2016; 29: 723-736
        • Nazha B
        • Zhuang TZ
        • Dada HI
        • et al.
        Blood-based next-generation sequencing in adrenocortical carcinoma.
        Oncologist. 2022; 27: 462-468
      1. KEYTRUDA Highlights of prescribing information. Accessed September 30, 2022 from:

      2. LAROTRECTINIB Highlights of prescribing information. Accessed September, 30, 2022:

      3. FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. Retrieved September, 30, 2022 from:

        • Strother M
        • Hallanger Johnson J
        • Kutikov A
        A point-of-care resource to improve care of patients with adrenal mass:
        Eur Urol. 2022; 81 (AprEpub 2022 Jan 14. PMID: 35034801): 434