Context:Adrenocortical carcinoma is a rare malignant endocrine neoplasia. Studies regarding outcome and prognostic factors rely on fairly small studies. Here we summarize the experience with patients with a diagnosis of adrenocortical carcinoma from a large tertiary referral center.Objective:To identify prognostic factors in patients with adrenocortical carcinoma and evaluate adjuvant treatment strategies.Design:Patient data was collected in a retrospective single center study. Epidemiological, patient and tumor characteristics were analyzed for prognostic factors regarding overall and recurrence-free survival in Cox-regression models (multivariable and univariable).Results:391 adult patients with the diagnosis of adrenocortical carcinoma were identified. Median overall survival was 35.2 months. Cortisol production (HR=1.4, HR=1.5), tumor stage (HR stage 3=2.1 and 2.1, HR stage 4=4.8) and tumor grade (HR=2.4 and 2.0) were identified as negative prognostic factors (HR for death, HR for recurrence). Mitotane therapy increases recurrence-free survival, an effect that was significantly further improved by adjuvant radiation therapy, but did not impact overall survival. Patients with open adrenalectomy had improved overall survival.Conclusions:This study increases the evidence for adverse risk factors (cortisol production, high tumor stage and high tumor grade), and suggests the following therapy approach: Adrenocortical carcinoma patients should be treated with open adrenalectomy. Adjuvant therapy particularly mitotane therapy in conjunction with radiation should be considered in order to delay tumor recurrence.
[Show abstract][Hide abstract] ABSTRACT: ADRENOCORTICAL CARCINOMA (ACC) IS NOT ONLY A RARE AND HETEROGENEOUS DISEASE BUT ALSO ONE OF THE MOST AGGRESSIVE ENDOCRINE TUMORS. DESPITE SIGNIFICANT ADVANCES IN THE LAST DECADE, ITS PATHOGENESIS IS STILL ONLY INCOMPLETELY UNDERSTOOD AND OVERALL THERAPEUTIC MEANS ARE UNSATISFACTORY.HERE, WE PROVIDE OUR PERSONAL VIEW OF THE CURRENTLY AVAILABLE TREATMENT OPTIONS AND SUGGEST THE FOLLOWING RESEARCH EFFORTS THAT WE CONSIDER TIMELY AND NECESSARY TO IMPROVE THERAPY: (1) For better outcome in localized ACC, surgery should be restricted to experienced centers, which should then collaborate closely to address the key surgical questions (e.g. best approach and extent of surgery) in a multi-center manner. (2) For the development of better systemic therapies, it is crucial to elucidate the exact molecular mechanisms of action of mitotane. (3) A prospective trial is needed to address the role of cytotoxic drugs in the adjuvant setting in aggressive ACC (e.g. mitotane vs. mitotane + cisplatin). (4) For metastastic ACC, new regimens should be investigated as first-line therapy. (5) Several other issues (e.g. the role of radiotherapy and salvage therapies) might be answered - at least in a first step - by large retrospective multicenter studies.In conclusion, although complete understanding of ACC and cure in the majority of ACC is unrealistic within the next decade, international collaborative efforts (including multiple translational and clinical studies) should allow significant improvement of clinical outcome of this disease. To this end, it might be reasonable to expand the European Network for the Study of Adrenal Tumors (ENSAT) to a truly worldwide international network - INSAT.
European Journal of Endocrinology 04/2014; 171(1). DOI:10.1530/EJE-14-0273 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Description of novel findings about the mechanism of action of mitotane and its activity as an adjunctive postoperative measure, or for treatment of advanced adrenocortical carcinoma.
Several in-vitro studies have shown that mitotane suppresses gene transcription of different enzymatic steps of the steroidogenetic pathway. Moreover, mitotane induces CYP3A4 expression, thus accelerating the metabolic clearance of a variety of drugs including steroids. Retrospective studies provided evidence that adjunctive mitotane can prolong recurrence-free survival of treated patients. The concept of a therapeutic window of mitotane plasma concentrations was confirmed also for adjunctive treatment, but the relationship between mitotane concentration and given dose is loose. Genetic variability of the P450-dependent enzymes metabolizing mitotane may explain individual differences.
Mitotane concentration of 14-20 mg/l should be reached and maintained during treatment also in an adjunctive setting. In advanced adrenocortical carcinoma, a high-dose starting regimen should be employed when mitotane is used as monotherapy. The combination of mitotane with other drugs should consider the possibility of pharmacologic interactions due to mitotane-induced activation of drug metabolism. This concept applies also to steroid replacement in mitotane-treated patients, who need higher doses to adjust for increased steroid metabolism.
Current opinion in endocrinology, diabetes, and obesity 04/2014; 211(3). DOI:10.1097/MED.0000000000000056 · 3.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context: Adrenocortical carcinoma (ACC) is a rare malignancy with high recurrence and mortality rates. The utility, sensitivity, and effect on patient outcome of transcutaneous adrenal biopsy (TAB) for single, large, adrenal masses are unclear. Objective: This study evaluated the utility, diagnostic sensitivity, and effect on patient outcome of TAB in patients with ACC. Design and setting: We conducted a retrospective review of the electronic medical records of all ACC patients who were evaluated at the University of Michigan Health System from 1991 to 2011. We evaluated the sensitivity of TAB for tumors with the final pathological diagnosis of ACC. We compared the characteristics and survival of patients with stage I-III disease who underwent TAB with those who did not undergo TAB. Results: A total of 75 ACC patients with TAB were identified. Complications occurred in at least 11% of patients and were mainly associated with bleeding. The maximum sensitivity of the procedure in diagnosing ACC was 70%. For stage I-III patients, baseline characteristics, stage at diagnosis, and adjuvant treatment with mitotane or radiation were not significantly different between the TAB (n=36) and the non-TAB (n=254) groups. There was no significant difference in recurrence-free (P=0.7) or overall survival (P=0.7) between patients who underwent TAB and those who did not. Conclusions: TAB of single, large, adrenal masses is usually unnecessary, exposes patients to risk, but does not affect recurrence-free or overall survival.
European Journal of Endocrinology 06/2014; 170(6):829-35. DOI:10.1530/EJE-13-1033 · 4.07 Impact Factor
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