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Management of Patients with Adrenal Cancer: Recommendations of an International Consensus Conference

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Management of Patients with Adrenal Cancer: Recommendations of an International Consensus Conference Endocrine-Related Cancer (2005) 12 667–680 Management of patients with adrenal cancer: recommendations of an international consensus conference D E Schteingart, G M Doherty1, P G Gauger1, T J Giordano2, G D Hammer, M Korobkin3 and F P Worden Departments of Internal Medicine, Surgery1, Pathology2 and Radiology3, University of Michigan Medical School, Ann Arbor, Michigan, USA (Requests for offprints should be addressed to D E Schteingart; Email: [email protected]) Abstract Adrenocortical carcinomas are rare, highly malignant tumors that account for only 0.2% of deaths due to cancer. Given the limited number of patients seen in most medical centers with this diagnosis, series usually reported are small and clinical trials not randomized or blinded. In an attempt to answer important questions concerning the management of patients with adrenal cancer, a consensus conference was organized and held at the University of Michigan in Ann Arbor, MI, 11–13 September 2003, with the participation of an international group of physicians who had reported on the largest series of patients with this disease and who had recognized basic and clinical research expertise in adrenal cortical cancer. Totally 43 questions were addressed by the presenters and recommendations discussed in plenary and breakout sessions. Evidence for the recommendations of this conference was at the 2–4+ level and based on available literature and participants’ experience. In addition to setting up guidelines in specific areas of the diagnosis and treatment of adrenal cancer, the conference recommended and initiated the planning of an international prospective trial for treatment of patients with adrenal cancer in stages III and IV. In terms of new therapies, first trials of dendritic cell therapy in human subjects with adrenal cancer have been started, but it is too early to comment on efficacy. Different strategies of immunotherapy, including DNA vaccination are currently being tried in animal models. There are no clinical gene therapy trials for human adrenal cortical cancer. The adrenals are a preferred target for adenovirus and the results of gene therapy in preclinical studies are promising. In addition, there is evidence that histone deacetylase inhibitors can further enhance the rate of adenoviral infectivity in human adrenal cancer cells. Testing of retroviral vectors, non-viral vectors, small interfering RNA technology, and combined approaches could be performed in various laboratories. Anti-angiogenic substances have only been applied in preclinical studies. The use of these and other agents in the treatment of adrenal cancer should be hypothesis-driven and based on a thorough analysis of tumor biology. Endocrine-Related Cancer (2005) 12 667–680 Introduction attain a large size and produce localized abdominal symptoms or metastases. Occasionally children have Adrenocortical carcinomas (ACCs) are rare, highly been found to have ACC but most cases occur between malignant tumors that account for only 0.2% of deaths ages 30 and 50 (Brennan 1987). An exception to this due to cancer. Their incidence has been estimated at 2 age distribution occurs in southern Brazil, where the per million people per year. Approximately 50% of annual incidence of ACC in children is unusually high, these tumors are functioning and produce hormonal ranging from 3.4 to 4.2/million children, compared and metabolic syndromes leading to their discovery. with a worldwide incidence of 0.3/million children The other 50% are silent and discovered only when they younger than 15 (Figueiredo et al. 1999). The etiology Endocrine-Related Cancer (2005) 12 667–680 DOI:10.1677/erc. 1.01029 1351-0088/05/012–667 g 2005 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 10/02/2021 12:50:33AM via free access D E Schteingart et al.: Consensus on adrenal cancer of adrenal cancer is unknown but molecular cytoge- time was allowed for general discussion. Each day netic cloning studies in the past 5 years have described included breakout sessions at which participants were chromosomal abnormalities possibly associated with asked to formulate a consensus on the questions asked. tumorigenesis (Lynch et al. 1985, Grayson et al. 1994, This consensus became the conference preliminary re- Lin et al. 1994, Reincke et al. 1994, Miyamoto et al. commendations. Final recommendations were agreed 1996, McNicol et al. 1997, Bornstein et al. 1999). While upon at a final plenary session. genetic defects may predispose to adrenal cortical tumor formation, environmental factors have been Participants and program implicated in southern Brazil because the distribution The names of participants, their country of origin and of the tumors follows a regional rather than familial topic covered are summarized in Table 1. The mod- pattern. erators and discussants for each section are listed with There are multiple publications on the diagnosis and each category of questions. management of patients with ACC However, there is no validation or evidence-based consensus on the Consensus recommendations diagnosis, prognosis and management of patients with this disease. Given the limited number of patients seen We summarize below the topics discussed by the in most medical centers with this diagnosis, the series conference and its recommendations. The recommen- usually reported are small and clinical trials not dations are based on the assumption that upon randomized or blinded. In an attempt to answer suspicion of ACC, patients are referred to a medical important questions concerning the management of center with appropriate expertise with this disease. The patients with adrenal cancer, a consensus conference objective is to achieve definitive diagnosis including was organized and held at the University of Michigan endocrinological and oncological staging and definitive in Ann Arbor, MI, 11–13 September, 2003, with the initial surgery (open adrenalectomy) with curative participation of an international group of physicians intent. Evidence for the recommendations of this who had reported on the largest series of patients with conference was based on available literature of non- this disease and who had recognized basic and clinical randomized or observational studies and expert research expertise in ACC. This report summarizes the opinion of participants (evidence level 2–4+). Refer- main recommendations made during this conference. ences providing the background for discussion and recommendations are listed for each set of topics and when available, references are indicated for a parti- Method cular one. Each session in which a specific set of topics was discussed had two moderators and two or three A list of questions was prepared and mailed to all invited discussants. participants for evaluation. Questions were modified or reformulated and additional questions added. The final questions were grouped into ten major categories as Diagnosis follows: (i) diagnosis; (ii) prognosis; (iii) surgical treat- Moderators: Melvyn Korobkin, Milton Gross ment; (iv) adjuvant therapy; (v) radiation therapy; (vi) Lead Discussants: Franco Mantero, Martin Reincke, emergent therapies; (vii) follow-up during treatment; Oscar Bruno (viii) adrenal cancer in children; (ix) metastatic disease; and (x) data collection. Determination if a unilateral adrenal mass is cancer in a patient without known primary Data collection tumor (Arteaga et al. 1984, Copeland 1984, Farge et al. 1987, Grondal & Curstedt 1991, A literature review was carried out and relevant articles Schteingart 1992, 2000) that reported on series of patients (not single case reports) were listed. These articles addressed the topics The suspicion of ACC is raised by a combination of covered by the questions. Articles were assembled on a clinical, biochemical and radiological criteria and CD and mailed to all participants in anticipation of the finally verified by histopathology. Approximately conference. All participants were assigned a topic for 50% of ACCs are functional, and Cushing’s syndrome discussion and were expected to specifically answer with virilization is the most frequent presentation. each question pertinent to the topic. Two or three The mean tumor size of ACC is 10 cm; 95% of ACC participants were asked to address the same topic and are larger than 5 cm. The prevalence of ACC in questions. Presentations were limited to 20 min and surgical series of adrenal incidentalomas is 2% in tumors 668 Downloadedwww.endocrinology-journals.org from Bioscientifica.com at 10/02/2021 12:50:33AM via free access Endocrine-Related Cancer (2005) 12 667–680 Table 1 Participants in the International Consensus Conference Name Specialty Affiliation City/Country Ahlman, Hakan, MD. Surgery Goteborg University Goteborg, Sweden Aron, David, MD, MS Epidemiology Education Office Cleveland, OH, USA Barson, Luisa, MD Histology, microbiology University of Padova Padua, Italy Ben Josef, Edgar, MD Radiology University of Michigan Ann Arbor, MI, USA Beuschlein, Felix, MD Endocrinology Albert Ludwigs University Freiburg, Germany Bornstein, Stefan, MD Endocrinology University of Dusseldorf Dusselborf, Germany Bertagna, Xavier, MD Endocrinology Hop Cochin Paris, France Bruno, Oscar, MD Endocrinology University of Buenos Aires Buenos Aires, Argentina Campbell, Karen, MS Molecular biology Cushing Support & Pleasanton, CA, USA Research Foundation Chrousos, George, MD Endocrinology NICHD, NIH Bethesda, MD, USA Doherty, Gerard, MD Endocrine surgery
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