Review
The next generation of therapies for adrenocortical cancers

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Adrenocortical carcinoma (ACC) is a rare cancer for which few treatment options have been available. Currently, the best available treatment involves combination chemotherapy with the adrenolytic drug mitotane, although the response rate remains modest. Over the past 10 years there has been renewed interest in the field owing to the recognition that targeted therapies may provide new avenues for effective treatment of this deadly disease. Molecular analyses have revealed specific signaling alterations in ACC, and advances in drug development have generated the tools to block these pathways. Although convincing evidence for the effectiveness of targeted therapies is not currently available, these studies are in progress and should shift the prognosis of this disease in the years to come.

Introduction

Adrenocortical carcinoma (ACC) is a disease with an incidence of approximately one patient per million [1], suggesting that many endocrinologists will see patients with this disease rarely, if ever. In common with many endocrine cancers it has a very poor prognosis, with an overall 5-year survival rate around 35% [2]. The poor prognosis is attributable in part to the fact that many ACCs are not detected until they are at advanced stage [3]. However, the cancer behaves aggressively even in tumors detected early, such that cases felt to represent a cure at initial surgery may recur later with metastatic disease. Therapies for ACC have been limited by the ineffectiveness of most cytotoxic chemotherapy regimes, although the adrenolytic agent mitotane produces a response in approximately 25–30% of cases [4]. With the recent explosion of new data on tumor genetics and the renewed interest in targeted signaling pathways using kinase inhibitors, there is reason for guarded optimism regarding the future of ACC treatment. In this review I will discuss the current state of therapies, provide an update on ongoing and recently completely clinical trials, and discuss how therapy for ACC is likely to evolve over the next 5–10 years.

Section snippets

Adrenocortical cancer therapy: the past

The past 50 years has seen the development of chemotherapy regimens that have been beneficial for the treatment of cancer, including diseases such as breast, colon, and hematologic malignancies. As with most endocrine cancers, the response of ACC to classical cytotoxic chemotherapy regimens was poor [5]. Progress in the field was limited by the fact that ACC is rare, and no single institution could accrue enough patients to conduct large randomized trials. Further, the fact that the care of ACC

Formation of the International ACC Working Group

In 1998 Berruti and colleagues in Italy described the use of chemotherapy with etoposide, doxorubicin, and cisplatin together with mitotane (EDP/M, the so-called ‘Berruti’ or ‘Italian’ regimen) [8]. With this combination of agents, 46% of patients achieved a partial response (PR), and 2/28 patients (7.1%) achieved a complete response (CR); these results were confirmed in a follow-up study on 72 patients, including 28 from the original study [9]. Around the same time, Khan and coworkers in

Initiation of molecular analysis of ACC

Another significant development of the past 10 years has been the advent of platform technologies. Although overexpression of insulin-like growth factor 2 (IGF2) in ACC had been known since the mid-1990s from the work of Gicquel, Le Bouc, and colleagues [23], the use of high-throughput techniques has allowed substantial refinement of this information. Adrenocortical tumor mRNA expression-profiling was first carried out by Giordano et al. in 2003 [24], and has been followed by similar studies

Combination therapy

Although the initial development of new therapies has typically been carried out using single-agent trials, past experience indicates that combination therapy is likely to provide additional benefit. This synergy may be realized by simultaneously blocking multiple pathways required for tumor growth/survival, or it may occur by the prevention of resistance to single pathway agents [90].

One of the best documented examples of receptor co-signaling involves EGFR and IGF1R [91]. It is well

Concluding remarks

Although the prognosis for patients with ACC remains guarded, data from the past 10 years have begun to show signs of progress. There is a much improved vision of the signaling pathways that drive ACC, and this is now being matched by new therapeutics that might inhibit these pathways.

In the setting of this optimism, there are important questions which remain and should continue to drive research into ACC (Box 2). First, newer technologies have enabled the identification of serum and tissue

Note added in proof

The FIRM-ACT study was published online in the New England Journal of Medicine on May 2, 2012. As noted in the text, EDP/M was found to be superior to Sz/M, with response rates of 23.2% and 9.2% respectively. Treatment recommendations remain as described in Box 1.

Glossary

Adjuvant chemotherapy
a pharmacological or immunological agent that is administered in the absence of known cancer but is presumed to act by treating residual microscopic disease.
Adrenolytic agent
an agent that acts by destroying adrenal cells.
EDP/M combination therapy
also called the ‘Berruti’ or ‘Italian’ regimen, this chemotherapy protocol for ACC combines the use of the anti-cancer chemotherapy drugs etoposide (a topoisomerase inhibitor), doxorubicin (an anthracycline) and cisplatin (a

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