Editorial: paradigms for adrenal cancer: think globally, act locally.

Adrenocortical carcinoma (ACC) is a disease that most physicians, including many endocrinologists, will rarely, if ever, treat during the course of their medical practice. The incidence of this disease is approximately one patient per million in the population worldwide (1), with the exception of regions of Brazil, where the incidence is approximately 10 times higher (2). ACC continues to carry a poor prognosis, with an overall 5-yr survival rate of less than 50% and rates of less than 20–25% for the approximately 60% of patients who present with advanced disease (3). As with most cancers, complete surgical removal at the time of diagnosis offers the best hope for rendering these patients free of disease. However, as the median size of ACCs at the time of diagnosis is still in excess of 10 cm, it is not surprising that gross or microscopic metastases are frequently present at the time of presentation. This clinical observation points out the inherent need for the development of new therapies targeting these residual cancer cells. One of the major problems in dealing with ACC as a clinical disease is the longstanding view in the field that this cancer is poorly responsive to all treatments, including both cytotoxic chemotherapy and radiotherapy. This viewpoint has arisen from historical data over the past 50 yr, including institutional case series, small clinical trials, and expert opinion. For many years, the most hotly debated question regarding therapy for ACC was regarding the role of the adrenolytic agent mitotane, which was the most “effective” treatment available, with response rates in the 25–30% range (4). Over the last few years, this reliance on historical precedent has begun to be replaced by data-driven treatment strategies. Part of the impetus for this push has come from Europe, where the availability of country-wide integrated networks for treatment has allowed a small number of centers in Italy, France, and Germany (among others) to develop specific expertise and specific treatment protocols for this rare disease. Another part of this drive comes from new understandings of the molecular mechanisms of disease and the desire to translate these data into more rational and effective treatment agents (5). As these newer studies have developed, it has become clear that ACC can, in fact, be treated, although it remains fairly resistant to many (but not all) therapies. The first example of this was the development of a chemotherapy regimen by Berruti and colleagues in Italy, who showed that a regimen of etoposide, doxorubicin, and platinum in combination with mitotane (EDP/M, also known as the Berruti regimen) could produce clinical response rates up to 50% in advanced ACC patients, although complete remissions were still rare (6). This response rate was markedly higher than rates achieved with previous chemotherapy regimens and has held up remarkably well in a reanalysis of patient data 7 yr after the initial description (7). Fueled by these findings, a large, multicenter, international clinical trial is currently underway to compare this regimen with treatment with another moderately successful regimen, streptozotocin plus mitotane (SO, also known as Sz/M or the Khan regimen) (8), to define the standard of care for chemotherapy for this disease. Until patient accrual is completed, referral to this clinical trial, known as the FIRM-ACT study (www.firm-act.org), should be first-line therapy for any patient with a new diagnosis of advanced ACC. Using the FIRM-ACT data as a baseline, it will then be possible to assess properly the systemic effects of newer, molecular targeted therapies given in addition or instead of classical cytotoxic agents (5). What, then, can be done for patients with nondisseminated ACC? This issue was recently addressed at a 2003 consensus conference on ACC held in Ann Arbor, MI (9), and is best subdivided into two distinct areas. First, what to do about patients that have isolated metastatic disease? Second, what is the role of adjuvant therapy after (presumably complete) primary tumor resection? Regarding the patients with metastatic but limited disease, the data clearly indicate that repeat surgery with the intent to cure (i.e. complete metastasectomy) is beneficial for patients (10), both in terms of survival and for improving symptoms of hormone oversecretion. For patients that are not able to tolerate surgery, radiofrequency ablation appears to offer excellent local control for isolated metastases, particularly those that are less than 5 cm in diameter (11). Additionally, although it has not been widely discussed, there is good evidence in the literature that radiation therapy (XRT) is effective at providing significant local relief from the pain of bony metastasis (12). For adjuvant therapy, the story is much less clear. The majority of the discussion at the Ann Arbor conference centered on the use of mitotane in the adjuvant setting, although irradiation was also discussed. Briefly, no recommendations were made regarding either treatment because there has not been enough data on this topic (9). In this setting, the study of Fassnacht et al. (13) in this issue of JCEM occupies an important place in addressing the role of XRT as adjuvant therapy for ACC. In the paper, the authors report retrospectively on findings in 14 patients from the German ACC registry who underwent XRT Abbreviations: ACC, Adrenocortical carcinoma; XRT, radiation therapy.