Toxicity of adjuvant mitotane treatment is poorly known; thus, our aim was to assess prospectively the unwanted effects of adjuvant mitotane treatment and correlate the findings with mitotane concentrations. Seventeen consecutive patients who were treated with mitotane after radical resection of adrenocortical cancer (ACC) from 1999 to 2005 underwent physical examination, routine laboratory evaluation, monitoring of mitotane concentrations, and a hormonal work-up at baseline and every 3 months till ACC relapse or study end (December 2007). Mitotane toxicity was graded using NCI CTCAE criteria. All biochemical measurements were performed at our center and plasma mitotane was measured by an in-house HPLC assay. All the patients reached mitotane concentrations O14 mg/l and none of them discontinued definitively mitotane for toxicity; 14 patients maintained consistently elevated mitotane concentrations despite tapering of the drug. Side effects occurred in all patients but were manageable with palliative treatment and adjustment of hormone replacement therapy. Mitotane affected adrenal steroidogenesis with a more remarkable inhibition of cortisol and DHEAS than aldosterone. Mitotane induced either perturbation of thyroid function mimicking central hypothyroidism or, in male patients, inhibition of testosterone secretion. The discrepancy between salivary and serum cortisol, as well as between total and free testosterone, is due to the mitotane-induced increase in hormone-binding proteins which complicates interpretation of hormone measurements. A low-dose monitored regimen of mitotane is tolerable and able to maintain elevated drug concentrations in the long term. Mitotane exerts a complex effect on the endocrine system that may require multiple hormone replacement therapy.

The mENSAT classification and GRAS parameters (Grade, R status, Age and Symptoms) were found to best stratify the prognosis of patients with advanced ACC.

Context: Mitotane plasma concentrations R14 mg/l have been shown to predict tumor response and better survival in patients with advanced adrenocortical carcinoma (ACC). A correlation between mitotane concentrations and patient outcome has not been demonstrated in an adjuvant setting. Objective: To compare recurrence-free survival (RFS) in patients who reached and maintained mitotane concentrations R14 mg/l vs patients who did not. Design and setting: Retrospective analysis at six referral European centers. Patients: Patients with ACC who were radically resected between 1995 and 2009 and were treated adjuvantly with mitotane targeting concentrations of 14-20 mg/l. Main outcome measures: RFS (primary) and overall survival (secondary). Results: Of the 122 patients included, 63 patients (52%) reached and maintained during a median follow-up of 36 months the target mitotane concentrations (group 1) and 59 patients (48%) did not (group 2). ACC recurrence was observed in 22 patients of group 1 (35%) and 36 patients in group 2 (61%). In multivariable analysis, the maintenance of target mitotane concentrations was associated with a significantly prolonged RFS (hazard ratio (HR) of recurrence: 0.418, 0.22-0.79; PZ0.007), while the risk of death was not significantly altered (HR: 0.59, PZ0.20). Grades 3-4 toxicity was observed in 11 patients (9%) and was managed with temporary mitotane discontinuation. None of the patients discontinued mitotane definitively for toxicity. Conclusions: Mitotane concentrations R14 mg/l predict response to adjuvant treatment being associated with a prolonged RFS. A monitored adjuvant mitotane treatment may benefit patients after radical removal of ACC.

BACKGROUND: \ud \ud Although there is consensus that laparoscopy is the standard of care for the resection of benign adrenal tumours, there is controversy regarding the role of laparoscopy for the resection of adrenocortical cancer (ACC).\ud \ud OBJECTIVE: \ud \ud The aim of the present study was to review the ACC database of the San Luigi Hospital to compare the oncologic effectiveness of open adrenalectomy (OA) versus laparoscopic adrenalectomy (LA) in the treatment of patients with stage I and II ACC.\ud \ud DESIGN, SETTING, AND PARTICIPANTS: \ud \ud We performed a retrospective analysis involving 43 patients with stage I and II ACC who had undergone radical surgery.\ud \ud INTERVENTION: \ud \ud The patients were stratified into two groups according to the surgical procedure. The "open group" consisted of patients treated with OA; the "lap group" consisted of patients treated with LA.\ud \ud MEASUREMENTS: \ud \ud Oncologic effectiveness of the procedures was tested comparing the recurrence-free survival of patients treated with OA versus LA. Secondary outcome measures were differences in terms of type of recurrence and overall survival.\ud \ud RESULTS AND LIMITATIONS: \ud \ud The open group consisted of 25 patients and the lap group of 18 patients. The two groups were comparable in terms of demographic data. The median follow-up was 38 mo in the open group and 30 mo in the lap group. Recurrence rate was 64% in the open group and 50% in the lap group. The median recurrence-free survival was 18 mo in the open group and 23 in the lap group (p=0.8). No differences in terms of pattern of recurrences were recorded. During follow-up, 28% of the open group patients and 5% of the lap group patients died. No differences in terms of survival time were noted (p=0.3).\ud \ud CONCLUSIONS: \ud \ud The present findings provide interesting evidence that OA and LA may be comparable in terms of recurrence-free survival for patients with stage I and II ACC when the principles of surgical oncology are respected

Adrenocortical carcinoma (ACC) is a rare neoplasm characterized by poor prognosis. First-line systemic treatments in advanced disease include mitotane, either alone or in combination with chemotherapy. Studies evaluating second-line therapy options have obtained disappointing results. This trial assessed the activity and toxicity of gemcitabine plus metronomic fluoropyrimidines in heavily pretreated advanced ACC patients. From 1998 to 2008, 28 patients with advanced ACC progressing after mitotane plus one or two systemic chemotherapy lines were enrolled. They received a combination of i.v. gemcitabine (800 mg/m 2 , on days 1 and 8, every 21 days) and i.v. 5-fluorouracil protracted infusion (200 mg/m 2 /daily without interruption until progression) in the first six patients, or oral capecitabine (1500 mg/daily) in the subsequent patients. Mitotane administration was maintained in all cases. The rate of non-progressing patients after 4 months of treatment was 46.3%. A complete response was observed in 1 patient (3.5%); 1 patient (3.5%) obtained a partial regression, 11 patients (39.3%) obtained a disease stabilization and 15 patients (53.7%) progressed. Treatment was well tolerated, with grade III and IV toxicities consisting of leukopenia in six patients (21.4%), thrombocytopenia in one patient (3.5%), and mucositis in one patient (3.5%). Median time to progression and overall survival in the patient population were 5.3 (range: 1-43) and 9.8 months (range: 3-73) respectively. Gemcitabine plus metronomic fluoropyrimidines is a well-tolerated and moderately active regimen in heavily pretreated ACC patients.