Does Adjuvant Mitotane Impact Cure Rates in Adrenocortical Carcinoma? Insights From the ICARO-GETTHI/SEEN Registry

CONTEXT: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with a high risk of postoperative recurrence. Although adjuvant mitotane is commonly used, its potential for achieving cure rather than simply postponing inevitable recurrence remains uncertain. OBJECTIVE: This study investigates whether mitotane impacts ACC recurrence patterns by preventing or delaying recurrence. METHODS: This retrospective analysis used data from the ICARO-GETTHI/SEEN registry, which includes 36 Spanish hospitals. Recurrence in nonmetastatic ACC patients after resection was analyzed using Cox models, flexible longitudinal models, and mixture cure models to evaluate the impact of mitotane. RESULTS: Among 244 patients, 133 (52%) received adjuvant mitotane, with therapeutic levels monitored in 84%. Findings suggest a possible "cure fraction" with a 32.5% estimated 30-year cure rate (95% CI, 23.4%-45.0%). Cox regression indicated a 39% reduced recurrence risk (HR 0.61; 95% CI, 0.39-0.95) for mitotane-treated patients, with effects diminishing over 24 months. Mixture cure models suggest mitotane primarily delays rather than prevents recurrence. Effect modification analysis showed significant benefit in male patients (HR 0.33; 95% CI, 0.16-0.69), younger patients, tumors with higher Ki-67% (modeled as a continuous variable), and those with venous invasion (HR 0.47; 95% CI, 0.27-0.82), with potential synergy when combined with radiotherapy. CONCLUSION: This study underscores the intriguing possibility that adjuvant mitotane delays recurrence, yet questions remain as to its curative capacity. The early benefit suggests a cytostatic effect, but certain subgroups-especially males, younger individuals, and those with high-risk tumors-may experience a more durable outcome. Further research is needed to explore mitotane's curative potential in ACC management.