Management of patients with adrenal cancer: recommendations of an international consensus conference

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.

Combination Chemotherapy in Advanced Adrenocortical Carcinoma

“…During the International Consensus Conference on adrenocortical carcinoma in 2003, 15 the first randomized phase 3 trial of treatment for this rare tumor was planned. In this trial, called the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT), we compared the two most successful regimens in patients with advanced disease.…”

Immunohistochemistry of a Proliferation Marker Ki67/MIB1 in Adrenocortical Carcinomas: Ki67/MIB1 Labeling Index Is a Predictor for Recurrence of Adrenocortical Carcinomas

“…Immunohistochemical analysis with Ki67/MIB1 has been widely performed in various human malignancies, and its role both as a diagnostic tool and as a prognostic factor has been well established [10,11]. In human ACC, a high mitotic rate has been reported to be a significant and independent marker of poor clinical courses [18], and Ki67/MIB1LI was significantly related to mitotic count [12] and other parameters of cell proliferation such as expression of DNA topoisomerase type IIa [14] and p27 [16]. Previous studies including ours reported that the cut-off values of Ki67/MIB1LI between 2.5% and 5.0% reliably differentiated ACC from adrenal adenomas [8,[12][13][14][15][16][17]20].…”

“…Complete follow-up data were available for all patients. The following data were collected for each patient: demographics, localization and size of tumors evaluated by CT and/or MRI, tumor staging at initial presentation assessed by the Sullivan modification of the McFarlane system with TNM definitions [1,18,19], hormonal data at initial presentation, disease status at the end of followup, date of last follow-up, date and cause of death, and additional therapies including administration of mitotane. The resection of the primary tumor was considered to be curative in all cases except for one case (corresponding to case 1 in Table 1), which exhibited a metastatic lesion at lung at the time of the first surgery.…”

Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection

“…The adjuvant use of mitotane (o,p 0 -DDD), an adrenolytic drug used for treating advanced ACC since the 1960s (3,4,8), has become increasingly popular after the demonstration that post-operative mitotane treatment was associated with a significantly reduced risk of recurrence and death in a large series of patients with radically operated ACC (9,10). Given its retrospective nature, however, this study could not provide a definitive demonstration of the efficacy of mitotane in the adjuvant setting (11,12).…”

“…Surgery is the mainstay of therapy and complete surgical removal of ACC is the most important prognostic factor for longterm survival together with stage. Recurrence after apparently complete resection is frequent and may be found in up to 70-85% of patients with high proliferation index or locally advanced disease (3,4,5,6,7), an observation suggesting that adjuvant treatment concepts have a major role in ACC management.…”