Developing treatment for adrenocortical carcinoma

Kerkhofs, Thomas M.A.; Ettaieb, M H T; Hermsen, I G C; Haak, Harm R.

doi:10.1530/erc-15-0318

Cited by 36 publications

(27 citation statements)

References 97 publications

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“…Hypercortisolism (Cushing syndrome) or mixed Cushing and virilizing syndromes are observed in the majority of these patients. Pure androgen excess is less frequent while estrogen or mineralocorticoid excess are very rare (13,18,19,20,21,22). Non-specific symptoms from an abdominal mass include abdominal discomfort (nausea, vomiting, abdominal fullness) or back pain.…”

Section: Clinical Presentationmentioning

confidence: 99%

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

Fassnacht

Dekkers

Else

et al. 2018

European Journal of Endocrinology

654

867

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Adrenocortical carcinoma (ACC) is a rare and in most cases steroid hormone-producing tumor with variable prognosis. The purpose of these guidelines is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with ACC based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions, which we judged as particularly important for the management of ACC patients and performed systematic literature searches: (A) What is needed to diagnose an ACC by histopathology? (B) Which are the best prognostic markers in ACC? (C) Is adjuvant therapy able to prevent recurrent disease or reduce mortality after radical resection? (D) What is the best treatment option for macroscopically incompletely resected, recurrent or metastatic disease? Other relevant questions were discussed within the group. Selected Recommendations: (i) We recommend that all patients with suspected and proven ACC are discussed in a multidisciplinary expert team meeting. (ii) We recommend that every patient with (suspected) ACC should undergo careful clinical assessment, detailed endocrine work-up to identify autonomous hormone excess and adrenal-focused imaging. (iii) We recommend that adrenal surgery for (suspected) ACC should be performed only by surgeons experienced in adrenal and oncological surgery aiming at a complete en bloc resection (including resection of oligo-metastatic disease). (iv) We suggest that all suspected ACC should be reviewed by an expert adrenal pathologist using the Weiss score and providing Ki67 index. (v) We suggest adjuvant mitotane treatment in patients after radical surgery that have a perceived high risk of recurrence (ENSAT stage III, or R1 resection, or Ki67 >10%). (vi) For advanced ACC not amenable to complete surgical resection, local therapeutic measures (e.g. radiation therapy, radiofrequency ablation, chemoembolization) are of particular value. However, we suggest against the routine use of adrenal surgery in case of widespread metastatic disease. In these patients, we recommend either mitotane monotherapy or mitotane, etoposide, doxorubicin and cisplatin depending on prognostic parameters. In selected patients with a good response, surgery may be subsequently considered. (vii) In patients with recurrent disease and a disease-free interval of at least 12 months, in whom a complete resection/ablation seems feasible, we recommend surgery or alternatively other local therapies. Furthermore, we offer detailed recommendations about the management of mitotane treatment and other supportive therapies. Finally, we suggest directions for future research.

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Section: Clinical Presentationmentioning

confidence: 99%

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

Fassnacht

Dekkers

Else

et al. 2018

European Journal of Endocrinology

654

867

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“…Adrenocortical carcinoma is an aggressive disease, and the stage of the tumor at diagnosis is the factor with the greatest impact on prognosis (Kerkhofs et al 2015). Fay and coworkers investigated the expression of PD-L1 in adrenocortical carcinoma tissues (Fay et al 2015).…”

Section: Adrenocortical Carcinomamentioning

confidence: 99%

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

Cunha

Marcello

Rocha-Santos

et al. 2017

Endocrine-Related Cancer

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Immune checkpoint inhibitors are agents that act by inhibiting the mechanisms of immune escape displayed by various cancers. The success of immune checkpoint inhibitors against several tumors has promoted a new treatment strategy in clinical oncology, and this has encouraged physicians to increase the number of patients who receive the immune checkpoint therapy. In the present article, we review the main concepts regarding immune checkpoint mechanisms and how cancer disrupts them to undergo immune escape. In addition, we describe the most essential concepts related to immune checkpoint inhibitors. We critically review the literature on preclinical and clinical studies of the immune checkpoint inhibitors as a treatment option for thyroid cancer, ovarian carcinoma, pancreatic adenocarcinoma, adrenocortical carcinoma and neuroendocrine tumors. We present the challenges and the opportunities of using immune checkpoint inhibitors against these endocrine malignancies, highlighting the breakthroughs and pitfalls that have recently emerged.

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“…11,12 If genomic profiling is expected to become clinically relevant in the future, the KI67 proliferation index seems the best prognostic tool currently available. 13 Regarding the targeted therapies, no study has demonstrated any benefit with agents blocking molecular pathways such as EGFR, VEGF, mTOR, IGF-1R or FGFR in advanced disease. [14][15][16][17][18] The concept that cancer cells can exploit the immune checkpoint pathway to evade the immune system and allow tumor growth has been known for decades.…”

Section: Introductionmentioning

confidence: 99%

PDL1 expression is associated with longer postoperative, survival in adrenocortical carcinoma

et al. 2019

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Adrenocortical carcinomas (ACCs) are heterogeneous cancers associated with a very poor prognosis. The improvement of prognostic tools and systemic therapy are urgently needed. Targeting the immune system using checkpoint inhibitors such as PD1/PDL1 inhibitors is an attractive novel therapeutic strategy for poor-prognosis tumors. Multiple clinical trials are ongoing, including in advanced ACC. However, PDL1 expression has been studied in ACC in only one heterogeneous series of 28 clinical samples. Here, we have retrospectively analyzed PDL1 mRNA expression in 146 clinical ACC samples and searched for correlations between expression and biological and clinicopathological data, including post-operative disease-free survival (DFS). PDL1 mRNA expression was heterogeneous across samples. "PDL1-high" tumors were not associated with the classical prognostic variables but were associated with longer DFS in both uni-and multivariate analyses. High PDL1 mRNA expression was associated with biological signs of the cytotoxic local immune response. Supervised analysis between "PDL1-high" and "PDL1-low" tumors identified a robust 370-gene signature whose ontology analysis suggested the existence in "PDL1-high" tumors of a cytotoxic T-cell response, however, associated with some degree of T-cell exhaustion. In conclusion, PDL1 mRNA expression refines the prognostication in ACC and high expression is associated with longer DFS. Clinical validation at the protein level and functional validation are required to fully understand the role of PDL1 in ACC. Reactivation of dormant tumor-infiltrating lymphocytes by PDL1-inhibitors could represent a promising strategy in "PDL1-high" ACCs, supporting the ongoing clinical trials.

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Developing treatment for adrenocortical carcinoma

Cited by 36 publications

References 97 publications

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

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

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

PDL1 expression is associated with longer postoperative, survival in adrenocortical carcinoma

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