adjuvant mitotane for adrenocortical cancer working through uncertainty

The Journal of Clinical Endocrinology & Metabolism recently published a commentary by Huang and Fojo (1) offering a skeptical view on the efficacy of mitotane as an adjunctive postsurgical measure in patients with adrenocortical cancer (ACC). Their commentary focused on outlining the limitations of our recent study which indicated that adjuvant mitotane may prolong recurrence-free survival (RFS) in patients with radically resected ACC (2). However, we do not agree with several of their conclusions and believe that it is of interest to present our view for a balanced and comprehensive coverage of this important matter. Inprinciple,weagreewithHuangandFojothatourstudysuffers from the important limitation of a retrospective analysis; thus our investigation should be considered as hypothesis generating and certainly does not provide conclusive evidence. This problem has been clearly acknowledged in the paper, and we cautiously concluded that our study should renew interest in adjuvant therapy, whereas prospective, randomized trials will be needed to confirm the efficacyof adjuvantmitotane treatment (2).However, the rarity of ACC precluded organization of a randomized trial either in an adjuvantsettingor inpatientswithadvancedACC(3).Nonetheless, mitotane has been used for treating patients with ACC since the 1960s and is the only drug approved for ACC by the U.S. Food and Drug Administration and the European Medicines Evaluation Agency (4). In this scenario, a study including all consecutive patients treated postoperatively with mitotane in some centers and all consecutive patients left untreated after operation in other centers is thebestway toobtainexplorativedataon theefficacyofadjuvant mitotane, provided that the two groups are comparable. In our study, in fact, mitotane was recommended on the basis of the treatmentpolicyof thecenter, independentof thecharacteristicsofeither the tumorsor thepatients, and this is amajoradvantageminimizing selection bias as compared with other studies that had less clear treatment assignments (5). The major criticism of Huang and Fojo (1) is that we did not demonstrate any benefit on overall survival (OS) for patients treated adjuvantly. However, this is not correct because the hazard ratio of death of the German cohort of nontreated patients was nonsignificantly higher than mitotane-treated patients in univariate analysis, but the difference became significant in multivariate analysis after adjusting for imbalances in prognostic factors (the German cohort included more patients with stage I and II ACC than the Italian cohort of mitotane-treated patients). Even when we accept that the effect of adjuvant mitotane on OS was less impressive than on RFS, we disagree that prolonging a disease-free status is not a clinically meaningful objective even without extending significantly duration of life. In addition, there is a long-standing debate on the most appropriate endpoint for adjuvant trials, and both OS and RFS have been suggested. Analysis of RFS has the advantage of needing a shorter follow-up and being directly related to the treatment tested. The most important disadvantage of RFS is its close relationship to the frequency and quality of evaluation. Bias in follow-up or ascertainment of outcome in observational retrospective series is well recognized, and we have acknowledged this potential limit of our study. However, the follow-up procedures were highly comparable among the different centers and included imaging evaluation of the chest and abdomen every 6 months until disease progression or the end of the study period (2). Even if survival has to be considered as the reference end-point, it may not be a direct result of the study drug because it may be strongly influenced by subsequent treatments and oncologists are increasingly considering RFS as a valid surrogate for OS (6). However, this relationship has never been demonstrated specifically in ACC patients. Another criticism is derived from an ill-conceived reanalysis of our data. Huang and Fojo (1) aimed at demonstrating that the time interval between ACC recurrence and death is higher in patients treated adjuvantly than patients left untreated after surgery. Thus, they assumed important differences in tumor biology of the different cohorts. This conclusion comes from subtracting median time to recurrence from median survival observed in th