Gaining Traction in the Treatment of Adrenocortical Carcinoma

With the publication of the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) (1), the year 2012 became a landmark for those involved in the treatment of patients with adrenocortical carcinoma (ACC). In just over 5 yr, this large, multinational effort accrued over 300 patients with advanced ACC for a comparison of the etoposide/doxorubicin/cis-platinum plus mitotane (EDP-M) chemotherapy regimen described by Berruti et al. (2) with the regimen of streptozotocin with mitotane proposed by Khan et al. (3). Although the trial's crossover design led to the introduction of some uncertainty in regards to effectiveness in overall survival, there was a clear advantage to EDP-M in terms of progression-free survival. Based on these data, EDP-M can now be considered the “standard-of-care” in chemotherapy for ACC, although the 25% response rate (with another 28% disease stabilization) necessitates a sober tone for the discussion. This rate is significantly lower than the approximately 50% response described previously for EDP-M (2, 4) and likely reflects the effects of a randomized, controlled trial compared with a smaller trial of carefully selected patients. It is worth mentioning that reviews of the effects of mitotane as a single agent place the response rate in a similar range (5), rendering the value of cytotoxic chemotherapy an open question. Aside from the ascertainment of these high-quality clinical data, the FIRM-ACT trial represented the realization of the goal initially expounded at the Ann Arbor (Michigan) conference in 2003 (6) of founding a clinical trials group for patients with ACC. Although the patient-based outcomes were somewhat poorer than hoped, this trial was an overwhelming success in terms of bringing together both intranational and international groups of clinical researchers focused on this rare disease. Because of the infrastructure that supported FIRM-ACT, the pace of clinical research on ACC has markedly increased, which should over time lead to the production of improved and evidence-based strategies. As a potent example of this phenomenon, one can consider the 2007 publication by Terzolo et al. (7) on the role of adjuvant mitotane for ACC. Taking advantage of large patient collections in both Italy and Germany, the authors demonstrated a striking increase in recurrence-free survival in patients treated with mitotane compared with those who did not receive this therapy. Although this study was limited by its retrospective nature and questions remain regarding mitotane's much more modest effects on survival (8), the availability of large recruited cohorts of ACC patients is paving the way for trials like this and for new efforts to assess the effects of molecular-targeted therapies (9). The same approach driving inquiries into best medical therapy for ACC has also been used to analyze optimal surgical treatments. Open adrenalectomy has traditionally been recommended for patients with ACC to provide the best (and possibly only) chance to cure the disease (6). Because laparoscopic adrenalectomy has advantages to patients such as reduced pain and shorter hospitalization, it has been proposed as an appropriate surgery for ACC. Although early studies suggested poorer outcomes with laparoscopic adrenalectomy (10, 11), two recent studies from larger and better organized cohorts indicate that outcomes are not different, particularly in patients with tumors of less than 10 cm (12, 13). However, a direct comparison of methods has not yet been undertaken, and there are significant methodological and practice-style biases in each of the studies. Thus, the optimal surgery for ACC remains an active area of debate among surgeons (14), although all agree that surgery should be performed in specialized referral centers with expertise in surgery for adrenal neoplasms, including ACC. In this issue of the JCEM, Erdogan et al. (15) report the results of a study on a different surgical question: the role of surgery at the time of first recurrence in a cohort of patients thought to be cured of their cancer. Of 350 patients from the German ACC registry who had initially undergone radical resection, 218 individuals had recurrent disease, of whom 154 were available for analysis. Eighty-six of these patients were “amenable to radical resection,” whereas 68 were not. Using an aggressive approach, the majority of the patients with localized disease (78 of 86; 91%) were treated surgically, along with 23 of 63 (36.5%) of the patients with nonresectable disease. In the big picture, 144 of 154 (94%) patients in the cohort experienced disease progression during the time of the study, meaning that even with 33 patients undergoing microscopically compete resection at their second surgery, only 10 were observed to be tumor-free at the study conclusion. As might be expected, the group of patients receiving a microscopically compete resection did better than those in whom complete resection was not possible. The only other factor found to predict survival was a longer time to first recurrence. Although 1 yr was the major dividing line, the correlation held even when subdividing patients into smaller intervals. The fact that time to first recurrence is a significant predictor of tumor behavior suggests that inherent features of the tumor predict its prognosis. Recent molecular studies to stratify ACC aggressiveness have suggested that TP53, β-catenin, or SF1 may be clinically relevant predictors (16, 17). It would have been valuable to have correlated these biomarkers to the clinical behavior observed in this manuscript. If validated, this type of data might identify patients more likely to exhibit rapid progression and shift them toward more appropriate treatment paradigms. Interestingly, the authors also show a clear survival benefit of repeat surgery, even when a surgical cure was not obtained, echoing the Italian experience from over 15 yr ago (18). Because of the retrospective nature of both studies, it was not possible to determine the basis for the observations. If solely an effect of reduced hormone activity, these same benefits could be replicated with the use of hormone receptor antagonists. The availability of mifepristone as an antagonist for the glucocorticoid receptor (19) joins blockers of the mineralocorticoid (spironolactone, eplerenone), androgen (spironolactone), and estrogen (testolactone, tamoxifen) receptors as clinically available means to medically relieve the burden of hormone hypersecretion. All in all, the data in the present study and the others mentioned indicate that we are developing the patient cohorts and clinical tools needed to critically evaluate current practice strategies for ACC. Although this approach leaves open the promise of therapeutic improvements, it also highlights the need for continued development of new therapeutic modalities to treat this deadly disease.