Adrenocortical carcinoma: The management of metastatic disease
Introduction
Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy of the adrenal cortex with an annual US incidence around 1–2 cases per million population [1], [2]. Notably, given reliance of incidence data on NCI surveys from the 1970s as well as the challenge in proper histopathologic diagnosis, the true incidence may be underestimated.
ACC can occur at any age, but there is a bimodal distribution with a first peak at childhood (1–6 years old) and the second peak in the fourth to fifth decade of life [3]. The Surveillance Epidemiology End Results (SEER) data reports an incidence of 0.3 per million in children younger than 15 years. Notably, there is up to 18-fold higher incidence of cases in children in southern Brazil due to environmental and genetic risk factors which have been identified [4]. In this population, germline mutations of the TP53 tumor suppressor gene (R337H) have been detected in 34% of the patients [5]. In addition to the above demographics, women have a higher incidence compared to men of about 2:1 with studies showing proliferative effects of estrogen on ACC cells, although not establishing this as a clear cause for the higher female incidence [6], [7].
Sporadic ACC is a heterogeneous neoplasm with a poorly understood molecular pathogenesis [8]. The relationship between ACC tumorigenesis and familial hereditary syndromes has provided some insights into the molecular biology of this disease (Table 1) [9]. Chromosome imbalances (losses and gains) in specific loci of DNA have been reported with impact on several genes such as TP53, insulin-like growth factor type II (IGF-2), steroidogenic factor 1(SF1) and β-catenin. Given their roles, these genes have been identified as potential candidates for targeted therapies [10], [11], [12].
Overall, ACC carries a poor prognosis with the most important prognostic factors being the tumor stage at time of diagnosis. Unfortunately, with the absence of specific cancer-related early symptoms about 70% of patients are diagnosed with stage III or IV disease. In a European series of patients, the 5-year survival rates were 60% for stage I, 58% for stage II, 24% for stage III, and 0% for stage IV. Importantly, the median survival for metastatic disease (stage IV) at the time of diagnosis is less than a year [13].
ACC management often requires a multidisciplinary approach, frequently involving a medical oncologist, an endocrine surgeon, an endocrinologist and several other disciplines. Surgical resection remains the cornerstone of the treatment and represents the only curative option for patients with early stage ACC. However, around 80% of these patients will present local or distant recurrence after a complete resection [14]. With regard to recurrent or advanced disease, ACC is modestly responsive to standard cytotoxic chemotherapies, although various combinations have shown clear palliative benefit. Radiation and ablative techniques have been utilized with variable benefit depending on the clinical scenario.
The above realities highlight the fact that effective systemic treatments for advanced disease are lacking. The pipeline for novel drug development and testing in clinical trials has been limited. The goal of this manuscript is to review the advances in the therapy of advanced ACC. With the recent evolution of new technologies producing genetic data and the molecular characterization of multiple solid tumors described by The Cancer Genome Atlas, we will also focus on the potential of targeted signaling pathways and personalized therapies.
Section snippets
Evidence acquisition
A systematic review of the MEDLINE databases was performed on September 2013. The search was conducted using the keywords “general surgery”, “therapeutics”, “mitotane”, “radiotherapy”, “biological markers”, “oncogenes”, “tumor suppressor genes”, “drug therapy” and “adrenocortical carcinoma”. In total, 266 abstracts were identified. Articles about advanced disease were manually selected. Full text of potentially relevant studies (97 articles) were carefully examined by the authors and considered
Surgery
In patients with advanced disease, surgery remains an important consideration when complete resection of the primary tumor and all metastases is feasible. In contrast, cytoreductive debulking surgery should be carried out in selected patients with severe hormone excess that is refractory to medical management [15], [16].
Despite aggressive surgical intervention, local recurrences are frequent. Salvage resections may be considered especially if more than 12 months have been elapsed from the
Future directions
Advanced ACC is a very aggressive disease and its management is challenging. During the past 10 years collaborative efforts have been made to improve the ACC treatment. Although multidisciplinary approaches may result in long-term disease control and survival, conventional chemotherapy is not curative and targeted therapies did not yield so far any noticeable results. The combination of mitotane plus EDP offers the best approach to extension of survival based on a rigorous and large study.
Conflict of interest
Toni K. Choueiri: Consultancy: Pfizer, Novartis; Advisory board: Pfizer, Novartis, Aveo, GlaxoSmithKline, Exelixis; Research: Pfizer; No Speakers bureau. All remaining authors have declared no conflict of interest for this work.
Reviewers
Neeraj Agarwal, MD, Assistant Professor of Medicine, Huntsman Cancer Institute at the Unviersity of Utah, Internal Medicine/Medical Oncology, 2000 Circle of Hope, Ste 2123, Salt Lake City, Utah 84112, United States.
Laurence Albiges, MD, PhD, Assistant Professor, Institut Gustave Roussy, 114 rue Edouard Vaillant, VILLEJUIF, 94805, France.
Carlos Barrios, MD, Professor, PUCRS School of Medicine, Medicine, Padre Chagas 66/203, Porto Alegre, RS 90 570 080, Brazil.
Acknowledgement
André P. Fay receives a scholarship from CAPES-CNPq – Brazil.
André P. Fay is a medical oncologist. Since July 2013, Andre is working with clinical and translational research in the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute/Harvard Medical School under Dr. Toni Choueiri's mentoring. Recently, he was selected to receive the MERIT Award of American Society of Clinical Oncology (GU ASCO Symposium 2014) with the research project: PD-L1 expression in non-clear cell renal cell carcinoma. Toni Choueiri is the clinical director and
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Spindle and Kinetochore-Associated Complex is Associated With Poor Prognosis in Adrenocortical Carcinoma
2022, Journal of Surgical ResearchCitation Excerpt :It is an aggressive cancer that occurs in both children and adults.5 When identified in the early stages, ACC may be eligible for surgical removal; however, metastasis often occurs before diagnosis.6 Thus, biomarkers are needed for the early diagnosis, prognostic prediction, and development of new treatment approaches for ACC.7,8
Label-free impedimetric immunosensor based on arginine-functionalized gold nanoparticles for detection of DHEAS, a biomarker of pediatric adrenocortical carcinoma
2019, Biosensors and BioelectronicsCitation Excerpt :This mutation is directly associated to a specific dysfunction of p53 protein (DiGiammarino et al., 2002), which is involved in DNA repair mechanisms (Fett-Conte and Salles, 2002). Considering the absence of specific cancer-related early symptoms, approximately 70% of patients are diagnosed with pACC at advanced stages, in which the chances of cure are really small (Fay et al., 2014). For instance, the average survival rate for a metastatic disease at the time of diagnosis is less than a year (Ayala-Ramirez et al., 2013).
A phase II trial of cytoreduction and hyperthermic intraperitoneal chemotherapy for recurrent adrenocortical carcinoma
2018, Journal of Surgical ResearchCitation Excerpt :Systemic chemotherapy (e.g., etoposide, doxorubicin, cisplatin, and mitotane) offers modest benefit in progression-free survival (PFS) but no benefit in overall survival.1,4 Targeted molecular therapy with tyrosine kinase (i.e., imatinib, sunitinib), angiogenesis (i.e., bevacizumab), and mTOR (i.e., everolimus) inhibitors also provide no demonstrable survival benefit.5 Metastasectomy for recurrent and/or metastatic ACC has been reported previously as safe and associated with improved PFS and overall survival.
Bone metastasis located on foot as a clinical presentation of an adrenocortical carcinoma
2018, Endocrinologia, Diabetes y NutricionEfficacy of metyrapone for symptoms of adrenocortical carcinoma
2023, BMJ Supportive and Palliative Care
André P. Fay is a medical oncologist. Since July 2013, Andre is working with clinical and translational research in the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute/Harvard Medical School under Dr. Toni Choueiri's mentoring. Recently, he was selected to receive the MERIT Award of American Society of Clinical Oncology (GU ASCO Symposium 2014) with the research project: PD-L1 expression in non-clear cell renal cell carcinoma. Toni Choueiri is the clinical director and Kidney cancer Center director of the Lank Center of Genitourinary oncology and has contributions as a researcher, clinician and mentor of many oncology trainees. His research interests include the development of novel agents and biomarkers in genitourinary cancers, with a particular focus in renal cell carcinoma. Dr. Choueiri is currently the overall primary investigator in several phase I, II and III studies of novel agents and combinations using both clinical and correlative tissue-based endpoints.