https://orcid.org/0000-0002-0835-0916
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ABSTRACT
Introduction
Surgery, followed or not by adjuvant mitotane, is the current mainstay of therapy for patients with early-stage adrenocortical carcinoma (ACC). Mitotane, either alone or in association with EDP (Etoposide-Doxorubicin-Cisplatin) combination chemotherapy, is the standard approach for patients with metastatic ACC.
Areas covered
The activity of newer cytotoxic drugs, radioligands, targeted therapies, and immunotherapy, both in preclinical and clinical studies, will be reviewed in this paper.
Expert opinion
ADIUVO trial revealed that the administration of adjuvant mitotane is not advantageous in patients with good prognosis. Future strategies are to intensify efforts in adjuvant setting in patients with high risk of relapse. In patients with advanced/metastatic disease, modern targeted therapies have shown significant cytotoxicity in preclinical studies; however, studies in ACC patients reported disappointing results so far. The absence of targeted agents specifically inhibiting the major molecular pathways of ACC growth is the main cause of the failure of these drugs. Since ACC is often antigenic but poorly immunogenic, the results of immunotherapy trials appeared inferior to those achieved in the management of patients with other malignancies. Radioligand therapy may also be a promising approach. Combination of chemotherapy plus immunotherapy could be interesting to be tested in the future.
Article highlights
Current systemic strategies in the management of patients with adrenocortical carcinoma are adjuvant mitotane to be prescribed in radically operated patients with high risk of relapse and either mitotane alone or mitotane in association with Etoposide, Doxorubicin and Cisplatin (EDP-M) in patients with advanced/metastatic disease.
ACC patients with low/intermediate risk of relapse after surgery (stage I-III, Ki67<10%) have a relatively good prognosis and may not need adjuvant mitotane.
Currently, no molecular-targeted therapy has been shown to be effective in the management of patients with pre-treated metastatic ACC.
Immunotherapy has shown better results than targeted therapy but for now very far from those obtained in other neoplasms in which this therapy is approved and in current use.
As in other neoplasms, the theragnostic approach is interesting.
This box summarizes key points contained in the article.
Abbreviations
| ACC: adrenocortical carcinoma | = | |
| CAR-T: chimeric antigen receptor T-cell therapy | = | |
| CDK: cyclin dependent kinase | = | |
| CTLA4: cytotoxic T-lymphocyte antigen 4 | = | |
| DDT: dichlorodiphenyltrichloroethane | = | |
| EDP: etoposide, doxorubicin, cisplatin | = | |
| EGFR: receptor of epidermal growth factor | = | |
| HPA-1: heparinase-1 | = | |
| HR: hazard ratio | = | |
| ICI: immune checkpoint inhibitor | = | |
| IGF: insulin-like growth factor | = | |
| IGFR: receptor of insulin-like growth factor | = | |
| mTOR: mammalian target of rapamycin | = | |
| OS: overall survival | = | |
| PD-1: programmed death protein 1 | = | |
| PDL-1: ligand of programmed death protein 1 | = | |
| PFS: progression free survival | = | |
| PS: performance status | = | |
| PRRT: peptide receptor radionuclide therapy | = | |
| RFA: radio-frequency ablation | = | |
| RFS: relapse free survival | = | |
| RRM1: ribonucleotide reductase large subunit | = | |
| SSTRs: somatostatin receptors | = | |
| TACE: trans-arterial chemoembolization | = | |
| TILs: tumor infiltrating lymphocytes | = | |
| TKI: tyrosine kinases inhibitor | = | |
| TMB: tumor mutation burden | = | |
| TMZ: temozolomide | = | |
| VEGF: vascular-endothelial growth factor | = | |
| VEGFR: receptor of vascular-endothelial growth factor | = |
Declaration of interest
A Berruti received honoraria for advisory and public speech from Novartis-AAA, Janssen, Bayer, Astellas, Amgen and research grants for ACC research from Janssen and Sanofi. S Sigala received research grants for preclinical studies from Novartis and Pharmamar. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.