Treatment

The target plasma concentration is generally attainable with a dose of 4–6 g day.

Note: When the control of an associated Cushing syndrome is urgently required, it may be necessary to initiate the treatment at higher doses (4–6 g per day) which may be increased more rapidly (weekly).

There is a wide range of side effects related to this drug [5, 6]:

Gastrointestinal upsets (38–54 % of patients): anorexia, nausea, vomiting, diarrhoea
Hepatic signs (25–47 %): increased transaminases and gamma-glutamyl transferase
Neurologic signs (27–39 %): dysarthria, ataxia, confusion, dizziness, paresthesia
Gynecomastia (18 %) and impotence
Skin manifestations (10 %)
Others: lipid profile disorders, mild neutropenia (between 1,000 and 1,500/mm³), acute depression, ocular (diplopia, blurred vision), genitourinary (haematuria, hemorrhagic cystitis, albuminuria), cardiovascular signs (hypertension, orthostatic hypotension), generalized pain, hyperthermia

It is important to remember that a substantial percentage of patients taking mitotane will develop the adrenal insufficiency syndrome. Therefore, patients should be closely monitored to prevent or detect this event, and early substitution with corticosteroids should be initiated whenever indicated. Monitoring includes measuring the serum adrenocorticotropic hormone (ACTH), thyroid hormones, testosterone, electrolytes and lipids levels. Urinary free cortisol is also estimated and abnormalities corrected.

27.2.2 Chemotherapy

A randomized study comparing the combination of mitotane with EDP (etoposide, doxorubicin and cisplatin) and the combination of mitotane with streptozocin (streptozotocin) has shown that the former carries better rates of response and progression-free survival as a first-line therapy, but they have similar rates of toxic events and no significant difference in the overall survival [7].

27.3 EBRT

The efficacy of adjuvant radiotherapy in reducing the high rate of local recurrence in ACC has been shown by a large population-based German study [8]. Recently, the effectiveness of radiation therapy has been reported in the management of metastatic ACC for both palliation and preventing complications of large metastases [9]. However, EBRT did not improve the disease-free and overall survival, and reoperation remains the most effective therapeutic option for recurrent adrenocortical carcinoma [10].

27.4 Others

Radiofrequency ablation may be used in patients with a low tumour volume (<5 cm) who are also poor candidates for surgery. It may also be useful in some patients with metastatic ACC.

Follow-up After Surgery

As mentioned above, ACC is a very aggressive tumour with a high propensity to recur after surgical resection. Therefore, close follow-up is necessary since a recurrence diagnosed at an early stage will generally be amenable to further surgical treatment. The follow-up includes clinical assessment and the use of imaging such as abdominal and chest CT-scans every 3 months for the first 2 years after surgery, then every 6–12 months for at least 5 years. PET scans can be used as an alternative to CT scanning.

In symptomatic patients, isotope bone scans are indicated to rule out bony metastases. Moreover 3-monthly measurements of the hormone levels are necessary for patients with functional tumours to detect early tumour recurrence [11].

Management of Recurrent ACC

Certain criteria are proposed to clinically determine the aggressiveness of an ACC recurrence and to further adjust the treatment [12, 13]:

The speed of symptoms exacerbation
The time elapsed from surgical resection
The lactate dehydrogenase (LDH) level at onset of the recurrence

Rapidly aggravating symptoms, or a short interval of recurrence of less than 6 months, or LDH levels of more than 1,000 units/L must be regarded as poor prognostic factors.

In keeping with the principles of other surgical malignancies, the management depends on the type of recurrence, that is, whether local or systemic (distant).

a. Repeat Surgery

Repeat surgery is the cornerstone for an isolated local recurrence and will consist of a second ‘complete’ resection. In this setting open surgery is recommended as opposed to the laparoscopic approach. If the tumour is unresectable, neoadjuvant combined chemotherapy should be initiated with the aim of rendering the tumour amenable to surgery for a second time [11].

b. EBRT

The use of radiotherapy for recurrent ACC is controversial and different studies have reported conflicting results.

c. Radiofrequency Ablation Therapy

This U/S-guided percutaneous therapy has been shown by several studies to be a valuable tool in selected patients with recurrent ACC, either alone, or in combination with surgery [12].

d. Mitotane

Mitotane is the cornerstone for managing systemic recurrences (metastases) of ACC. Its specific indications are as follows:

A low tumour volume and slow progressive disease, or patient’s unfitness for chemotherapy when mitotane may be given alone.
A high tumour volume, or rapidly progressive disease: Mitotane should be combined with chemotherapy, either with EDP (etoposide-doxorubicin-cisplatin), or with streptozocine [14, 15].

To date no effective salvage therapy has evolved for advanced cases after failure of the above-mentioned therapies. Studies have shown no objective response with combinations of bevacizumab with capecitabine [16], paclitaxel with sorafenib [17] or docetaxel with cisplatin [18] and more supportive data are awaited for the role of gemcitabine combined with metronomic¹ fluoropyrimidines such as 5-fluorouracil or capecitabine [19].

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