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Endocrinology and Diabetes Unit
Department of Medicine
University of Wuerzburg
Adrenocortical carcinoma (ACC) is a rare neoplasm with poor prognosis.(1) The incidence is approximately one to two per million per year,(2) leading to 0.2% of cancer deaths.(3) MacFarlane reported that patients with untreated ACC have a median survival of three months.(4) In treated ACC, overall five-year survival rates range from 20% to 60% in different series. In about 60% of cases an excess of adrenal steroid hormones is clinically present (mostly as Cushing’s syndrome or virilisation), but in some cases autonomous hormone secretion is only laboratory-detectable. The detection of elevated hormone levels is important, as this can serve as a reliable tumour marker for follow-up examination. Patients with nonfunctioning ACC usually present symptoms related to the local mass (eg, abdominal fullness and indigestion), or the adrenal tumour is observed incidentally by imaging. Tumour size at presentation (mean diameter at diagnosis >10cm) is one of the most important indicators of malignancy.(5)
Due to poor survival rates and low incidence of ACC, the treatment of patients with ACC has never been adequately standardised. This limits the choice of therapy to personal experience and data from uncontrolled trials. Complete tumour removal offers, by far, the best chance for long-term survival, and therefore surgery is the treatment of choice in stage I–III ACC. However, despite tumour resection for cure, most patients eventually develop local recurrence or distant metastases.
This article summarises data currently available on drugs used for ACC therapy. Since mitotane, the only adrenal- specific drug, is relatively unknown outside the field of endocrinology, the characteristics of this drug will be detailed.
Treatment in advanced ACC
More than 40 years ago Bergenstal et al reported the first successful use of mitotane in patients with metastatic ACC.(6) Mitotane, or 1,1-dichloro-2(2-chlorophenyl)-2- (3-chlorophenyl)ethane, is an isomer of the insecticide 3,3′-DDD (dichlorodiphenyl dichloroethane) and a chemical congener of the insecticide DDT (dichlorodiphenyl trichloroethane). Mitotane is an adrenolytic compound with specific activity on the adrenal cortex,(7) and its therapeutic effects depend on intra-adrenal metabolic transformation.
During the last decades mitotane has been widely employed in the medical treatment of ACC. It was approved by the EMEA (European Agency for the Evaluation of Medicinal Products) at the beginning of 2004, which makes its administration in Europe easier. It is given orally as tablets (Lysodren; HRA Pharma) up to a daily dosage of 12g/day. It is difficult to appraise its efficacy critically, particularly in early studies that were performed before the era of modern imaging techniques. Despite the great heterogeneity of these studies, mitotane appears to have some activity in inducing objective tumour regressions. The overall response rate is approximately 25%, which is similar to that of most chemotherapeutic regimens used in this disease (see below). Mitotane treatment can also control hormone secretion in most patients with functioning ACC.
The main drawbacks of this agent are its toxicity and that it appears to have only a narrow therapeutic index. While it has been shown that blood levels of >14mg/l are required to induce tumour regression,(8,9) side-effects are frequent when the blood levels exceed 20mg/l.(10) Moreover, mitotane has a long half-life, and drug concentrations in serum are not closely correlated to the drug dose.(11) Thus, drug monitoring is important and may also improve quality of life during mitotane treatment, by avoiding overtreatment. Side-effects are mainly gastrointestinal (eg, diarrhoea, nausea or anorexia) or involve the central nervous system (eg, lethargy, somnolence, ataxia, dizziness or confusion). Importantly, due to its adrenolytic activity, mitotane treatment induces adrenal insufficiency. Inadequately treated adrenal insufficiency enhances mitotane-induced side-effects and reduces mitotane tolerance.(12) Since mitotane increases metabolic clearance of glucocorticoids, high-dose glucocorticoid replacement (preferably hydrocortisone) is needed. In addition, mitotane therapy frequently increases hepatic gamma-glutamyl transaminase levels, although in most cases withdrawal of the drug is not necessary. Serious hepatotoxicity has been described. Mitotane also increases serum cholesterol and influences platelet aggregation response. Finally, mitotane induces several endocrine abnormalities (eg, hypogonadism and thyroid dysfunction).
Cisplatin is the most widely used drug, either alone or in combination with other agents.(13) However, several other drugs have been tested in single cases or small case series. The prospective chemotherapeutic studies that employed standardised criteria of response and encompassed more than 20 patients with advanced ACC are listed in Table 1. Due to overlapping confidence intervals, the relative efficacy of the different regimens is difficult to estimate, and therefore there is no worldwide consensus on the optimal treatment of advanced ACC. Despite this lack of clear evidence, the “International Consensus Conference on Adrenal Cancer”, held in Ann Arbor (USA) in September 2003, recommended the use of the combination of etoposide, doxorubicin, cisplatin and mitotane (EDP–M) or streptozocin and mitotane (Sz–M) until more reliable data become available. The latter regimen led to an objective response rate of 36% (eight of 22 patients) and a median survival of 16 months.(14) The most encouraging results to date were observed by Berruti et al using EDP–M.(15) These authors have recently updated their results in abstract form (including 66 patients). The overall response rate was 49%, with a median survival time of 28 months. To establish a standard therapy for advanced ACC, the COllaborative group for Adrenocortical Carcinoma Treatment (CO-ACT) recently launched an international phase III trial aiming at the randomisation of more than 300 patients with advanced ACC. The primary objective of FIRM-ACT (First International Randomized trial in Metastatic and locally advanced Adrenocortical Carcinoma Treatment) is to compare the first-line treatment (EDP–M vs Sz–M) with the endpoint survival. Patient recruitment began in July 2004 and is open for seven years (see Resources).
Suramin, an antitrypanosomal agent, may induce transient remission in a few patients,(16) but its use is limited by significant toxicity.(17) Gossypol, a plant toxin from cotton seed oil, induced a partial remission in three out of 18 patients (17%) with metastatic ACC.(18)
Since hormone excess (in particular hyper-cortisolism) is associated with poor quality of life and an increased risk of complications, it is essential that patients do not suffer from Cushing’s syndrome. Adrenostatic drugs (eg, metyrapone, ketoconazole, etomidate, aminoglutethimide) may be required in addition to mitotane to control endocrine activity.
Adjuvant treatment in ACC
Due to the high rate of locoregional or metastatic recurrence after seemingly curative resection, adjuvant treatment options are clearly needed. The role of mitotane as adjuvant therapy after complete surgical removal of ACC remains a matter of debate. Several retrospective studies have demonstrated favourable results; however, in some series, adjuvant mitotane was associated with a poorer outcome. As an alternative to mitotane, or in combination, postoperative radiation of the tumour bed may have a role as adjuvant treatment. As third option, some centres administer cytotoxic chemotherapy in an adjuvant setting. Only future randomised trials will determine the efficacy of any adjuvant treatment. The CO-ACT group is planning such a trial, but patient recruitment is not due to start before the end of 2005.
Treatment of patients with ACC is still challenging for all healthcare providers. Mitotane, the most widely used drug, should be part of the first-line treatment in advanced ACC (either alone or in combination with EDP or Sz). Due to its toxicity (including a wide range of endocrine abnormalities), an experienced endocrinologist should supervise the treatment.
The value of an adjuvant treatment remains to be determined. Only large prospective multicentre trials comparing different treatment options will lead to systematic progress in the management of ACC. The FIRM-ACT trial is the first attempt to establish a standard therapy, and virtually all patients with advanced ACC should be included in that.
Prof Britt Skogseid (Uppsala, Sweden)
International Study Coordinator:
Dr Martin Fassnacht (Wuerzburg, Germany)
Dr Eric Baudin (Villejuif, France)
Prof Bruno Allolio (Wuerzburg, Germany)
Prof Paul Stewart (Birmingham, UK)
Dr Harm Haak (Eindhoven, The Netherlands)