Gaining Traction in the Treatment of Adrenocortical Carcinoma
Lawrence S. Kirschner
Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210
W ith the publication of the First International Ran- domized Trial in Locally Advanced and Meta- static 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 com- parison 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 uncer- tainty 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 dis- cussion. This rate is significantly lower than the approx- imately 50% response described previously for EDP-M (2, 4) and likely reflects the effects of a randomized, con- trolled trial compared with a smaller trial of carefully se- lected 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 clin- ical data, the FIRM-ACT trial represented the realization of the goal initially expounded at the Ann Arbor (Mich- igan) 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 re- searchers focused on this rare disease. Because of the in- frastructure that supported FIRM-ACT, the pace of clin- ical 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 con- sider 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 sur- vival 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 re- main 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 ther- apies (9).
The same approach driving inquiries into best medical therapy for ACC has also been used to analyze optimal surgical treatments. Open adrenalectomy has tradition- ally 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 out- comes are not different, particularly in patients with tu- mors of less than 10 cm (12, 13). However, a direct com- parison of methods has not yet been undertaken, and there
Abbreviations: ACC, Adrenocortical carcinoma; EDP-M, etoposide/doxorubicin/cis-plati- num plus mitotane.
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 pa- tients from the German ACC registry who had initially undergone radical resection, 218 individuals had recur- rent disease, of whom 154 were available for analysis. Eighty-six of these patients were “amenable to radical re- section,” whereas 68 were not. Using an aggressive ap- proach, 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 mi- croscopically 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 fea- tures of the tumor predict its prognosis. Recent molecular studies to stratify ACC aggressiveness have suggested that TP53, ß-catenin, or SF1 may be clinically relevant predic- tors (16, 17). It would have been valuable to have corre- lated these biomarkers to the clinical behavior observed in this manuscript. If validated, this type of data might iden- tify 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 ac- tivity, these same benefits could be replicated with the use of hormone receptor antagonists. The availability of mife- pristone as an antagonist for the glucocorticoid receptor (19) joins blockers of the mineralocorticoid (spironolac- tone, eplerenone), androgen (spironolactone), and estro-
gen (testolactone, tamoxifen) receptors as clinically avail- able 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 co- horts and clinical tools needed to critically evaluate cur- rent 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.
Acknowledgments
Address all correspondence and requests for reprints to: Lawrence S. Kirschner, 420 West 12th Avenue, Tzagournis Re- search Facility 544, Columbus, Ohio 43210. E-mail: Lawrence. Kirschner@osumc.edu. This work was supported in part by National Institutes of Health Grant 3 P30 CA016058 to The Ohio State Uni- versity Comprehensive Cancer Center (to L.S.K.).
Disclosure Summary: The author is serving on an advisory board for Corcept, which is the commercial producer of mife- pristone/Korlym for Cushing syndrome.
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