Complete surgical resection is the mainstay of treatment for ACC. Open surgical technique for adrenalectomy is recommended. Complete, en bloc, margin-negative resection should be the surgical goal [50, 51]. Lymph node dissection is recommended [52]. Resection of adjacent organs including the spleen, kidney, liver, or pancreas might be required if local invasion is present. Tumor extension into the inferior vena cava is not a contraindication to surgery, and resection can be performed by cardiopulmonary bypass. The role of laparoscopy is controversial; a number of previous studies showed that laparoscopic surgery for ACC increased the risk of local recurrence, peritoneal dissemination, and metastases [53–57], while others reported comparable results with open surgery particularly if the adrenal tumor is small [58]. Open surgery is currently the preferred approach by NCCN guidelines. Completeness of surgical resection is the most important factor that influences outcome [32, 59]. If resection is incomplete, repeated surgery for achieving clear margins should be considered.

Patients who undergo complete repeat resection of local recurrence or distant metastasis also have improved survival. One study showed that patients who had a complete second resection of local or distant recurrence had a median survival of 74 months (5-year survival, 57 %), whereas those with incomplete second resection had a median survival of 16 months (5-year survival, 0 %) [60]. Therefore surgery is still an important treatment in advanced disease when complete resection of recurrence and all metastases is feasible. Selected patients with uncontrollable symptomatic hormone excess might be candidates for debulking surgery.

The benefit of neoadjuvant systemic therapy prior to surgery for locally advanced disease is not known, and this is not considered a standard approach.

Adrenocortical carcinoma is a rare tumor; thus there are no randomized trials of adjuvant therapy. Up to 80 % of the patients experience disease recurrence after radical resection; this forms the rationale behind adjuvant therapy. The only treatment which showed benefit in terms of disease-free and overall survival in retrospective reports is mitotane. Mitotane is a derivative of the insecticide dichlorodiphenyltrichloroethane (DDT or rothane). Mitotane is metabolized to an active metabolite which leads to necrosis of the zona fasciculata and reticularis of the adrenal cortex and inhibition of adrenocortical hormone production (blocking adrenal 11-beta-hydroxylation and cholesterol side-chain cleavage) [61]. The largest series of adjuvant mitotane use after surgery compared to surgery alone in 177 patients with ACC from 8 centers in Italy and 47 centers in Germany was published recently. All patients had radical resection with a follow-up of up to 10 years. Forty-seven of the 177 patients received adjuvant mitotane after surgery, while the rest of the patients had surgery alone. Median recurrence-free survival was 42 months in the mitotane group, 10 months in the Italian control group (p < 0.001), and 25 months in the German control group (p = 0.005). Median overall survival was 110 months in the mitotane group, as compared with 52 months in the Italian control group (p = 0.01) and 67 months in the German control group (p = 0.1). Mitotane treatment had a significant advantage for recurrence-free survival in multivariate analysis [62]. The median duration of treatment was 29 months. Twenty-seven patients received 1–3 g/day and 20 patients received 3–5 g/day. Serum levels of mitotane were not assessed. Grade 3 gastrointestinal (nausea or vomiting or elevated serum GGT) or neurologic events (confusion, ataxia, vertigo) were observed in 15 and 20 % of the patients, and all occurred in patients who received the higher-dose mitotane regimen.

Adjuvant mitotane is indicated in patients with high risk of recurrence; however the definition of high risk is not uniform. This controversial topic was discussed in 2008 by an international panel of specialists for the treatment of patients with ACC. On these grounds, the panel unanimously stated that patients with potential residual disease (R1 or Rx resection) and/or Ki67 more than 10 % should be offered adjuvant mitotane, whereas adjuvant therapy was not considered mandatory in patients fulfilling all of the following criteria: stage I or II disease (based on the new European Network for the Study of Adrenal Tumors), histologically proven R0 resection, and Ki67 expressed in ≤10 % of neoplastic cells. The panel did not express a unanimous position with respect to whether or not patients with stage III ACC with R0 disease after surgery should receive adjuvant therapy in clinical routine [63]. Fassnacht et al. propose tumor size >8 cm and microscopic evidence of invasion of blood vessels or the tumor capsule as additional risk factors which require consideration of adjuvant therapy [4]. NCCN guidelines suggest that mitotane be “considered” (category 3 recommendation, with major disagreement that the intervention is appropriate) for all patients with resected low-grade or high-grade localized ACC regardless of stage or tumor size [52]. Intraoperative tumor spillage or fracture is also suggested by some authors as indication for adjuvant mitotane [64]. A large international randomized trial in 200 patients with low- to intermediate-risk resected disease [stage I to III, microscopically complete (R0) resection, Ki67 < 10 %] is currently ongoing (the ADIUVO trial, NCT00777244).

Response rates to single-agent mitotane in metastasized ACC are between 13 and 31 %. Responses are mostly partial and generally short-lived [65]. However these were early studies, mitotane doses were suboptimal, and response evaluations were not up to date. Median survival was less than 1 year. The main benefit of mitotane in patients with advanced disease is reduction in hypercortisolism symptoms. Mitotane is almost always administered in combination with cytotoxic chemotherapy in metastatic disease given the higher response rates.

Side effects including anorexia, nausea, vomiting, and diarrhea are common and can limit adjuvant mitotane use as a long-term treatment. Also monitoring for the blood level of mitotane is essential for effective treatment. Mitotane treatment starts 1 g twice daily orally and the dose is escalated up to 10 g/day. Patients metabolize mitotane to different degrees. Optimum dose of the drug can be safely and accurately delivered by monitoring the blood levels. Therefore monitoring of plasma levels of mitotane is required, and a target serum level between 14 and 20 mg/L should be achieved for obtaining optimal response and decreased toxic side effects [66].

Use of mitotane routinely induces atrophy and/or steroidogenic inhibition of the normal adrenal glands, thereby necessitating replacement therapy for cortisol deficiency; the zona glomerulosa is more resistant to the adrenolytic effect of mitotane, and aldosterone deficiency may occur after several months of therapy. Monitoring of blood sodium, potassium, creatinine, and 24-h urinary free cortisol levels is mandatory to assess adrenal insufficiency. Higher doses than the routine maintenance can be needed to avoid adrenal insufficiency. If signs or symptoms of mineralocorticoid deficiency (i.e., postural hypotension, hyperkalemia, etc.) develop, fludrocortisone should be added. Patients should also be monitored for hypogonadism and hypothyroidism. The most common side effects are fatigue, nausea, vomiting, and anorexia, but skin rash, diarrhea, lethargy, sedation, confusion, dizziness, ataxia, gynecomastia, arthralgias, leukopenia, prolonged bleeding time, hematuria, and reversible growth arrest in children also occur. Mitotane has significant drug interactions and can reduce efficacy of some calcium channel antagonists, opioids, benzodiazepines, macrolide-type antibiotics, and many other drugs [67].

There is no evidence for the role of cytotoxic chemotherapy in the adjuvant treatment of ACC. However, Fassnacht et al. from the German consortium suggest 3 cycles of 90 mg/m² cisplatin in addition to mitotane in patients with Ki67 >30 % and a large tumor thrombus in the vena cava [68].