Adjuvant Therapies and Patient and Tumor Characteristics Associated With Survival of Adult Patients With Adrenocortical Carcinoma

1Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Hospital and Health Systems, Ann Arbor, MI, USA.
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 12/2013; 99(2). DOI: 10.1210/jc.2013-2856
Source: PubMed


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.

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    ABSTRACT: Adrenocortical carcinoma (ACC) is a malignant endocrine tumour. The rarity of the disease has stymied therapeutic development. Age distribution shows two peaks: the first and fifth decades of life, with children and women more frequently affected. Although 60-70% of ACCs are biochemically found to overproduce hormones, it is not clinically apparent in many cases. If present, endocrine symptoms include signs of hypercortisolaemia, virilisation or gynaecomastia. ACC carries a poor prognosis, and a cure can be achieved only by complete surgical resection. Mitotane is used both as an adjuvant treatment and also in non-operative patients. The role of radio- and chemotherapy is still controversial. The post-operative disease free survival is low and oscillates around 30% due to high tumour recurrence rate. The diagnosis is based on tumour histological assessment with the use of the Weiss score, however urinary steroid profiling (if available) can serve to differentiate between ACC and other adrenal tumours. Conventional prognostic markers in ACC include stage and grade of disease, and, as currently reported, the presence of hypercortisolaemia. Molecular analysis has had a significant impact on the understanding of the pathogenetic mechanism of ACC development and the evaluation of prognostic and predictive markers, among which alterations of the IGF system, the Wnt pathway, p53 and molecules involved in cancer cell invasion properties and angiogenesis seem to be very promising. We here summarise our own experience related to the management of ACC and present a literature overview. We have not aimed to include a detailed summary of the molecular alterations biology described in ACC, as this has already been addressed in other papers. (Endokrynol Pol 2014; 65 (6): 492-512).
    Endokrynologia Polska 01/2014; 65(6):492-512. DOI:10.5603/EP.2014.0069 · 0.99 Impact Factor
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    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
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    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
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