Abstract
Although mitotane is the only approved drug for the treatment of adrenocortical carcinoma (ACC), data on monotherapy in advanced disease are still scarce. To assess the efficacy of mitotane in advanced ACC in a contemporary setting and to identify predictive factors. Multicenter cohort study of three German referral centers. One hundred twenty-seven patients with advanced ACC treated with mitotane monotherapy. Response Evaluation Criteria in Solid Tumors evaluation, progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier method, and predictive factors by Cox regression. Twenty-six patients (20.5%) experienced objective response, including three with complete remission. Overall, median PFS was 4.1 months (range 1.0 to 73) and median OS 18.5 months (range 1.3 to 220). Multivariate analysis indicated two main predictive factors: low tumor burden (<10 tumoral lesions), hazard ratio (HR) for progression of 0.51 (P = 0.002) and for death of 0.59 (P = 0.017); and initiation of mitotane at delayed advanced recurrence, HR 0.35(P < 0.001) and 0.34 (P < 0.001), respectively. Accordingly, 67% of patients with low tumor burden and mitotane initiation ≥360 days after primary diagnosis experienced a clinical benefit (stable disease >180 days). Patients who achieved mitotane levels >14 mg/L had significantly longer OS (HR 0.42; P = 0.003). At 20.5% the objective response rate was slightly lower than previously reported. However, >20% of patients experienced long-term disease control at >1 year. In general, patients with late diagnosis of advanced disease and low tumor burden might especially benefit from mitotane monotherapy, whereas patients with early advanced disease and high tumor burden are probably better candidates for combined therapy of mitotane and cytotoxic drugs.
Highlights
Adrenocortical carcinoma (ACC) is a rare and aggressive disease with dismal prognosis and limited therapeutic options in advanced tumor stages [(1, 2])
Our data seems to suggest that low tumor burden is a predictive factor for response to 241 mitotane treatment, as 71% of patients with less than 10 tumoral lesions experienced disease control for more 242 than 6 months, whereas this was the case in only 18% of patients with higher tumor load
PatientsPatients with Ki67 index ≤10 % had a better overall survival than patients with Ki67 index ≥ 20 %: With this endpoint, the effect was only visible as trend after multivariate analysis (HR 0.52; p=0.08).%. These results are in line with previous studies [24] that described Ki67 as an important prognostic marker in adrenocortical carcinoma (ACC), which appears to have less discriminative value in advanced disease (33)
Summary
Adrenocortical carcinoma (ACC) is a rare and aggressive disease with dismal prognosis and limited therapeutic options in advanced tumor stages [(1, 2]). While the interest in mitotane as a sole first-line therapy in advanced ACC has increased recently, the lack of convincing data on monotherapy has unsettled clinicians One reason for this "revival" of mitotane monotherapy comes indirectly from the FIRM-ACT trial. In 1984 van Slooten and colleagues had measured mitotane blood levels in 34 patients and found a relation 105 to the response rate [(14]) This concept was confirmed in a larger retrospective series (n=58) [(11]) and a small prospective study (n=13) [(8]). 108 In the current large cohort study we analyze 127 patients with advanced ACC treated at three German centers with the aim to provide efficacy data on mitotane monotherapy based on contemporary imaging methods and to identify for the first time predictive factors for treatment response to mitotane Since that time most authors recommend aiming at plasma mitotane levels 107 between 14 and 20 mg/l to improve response rate and to limit toxicity [(1, 2]). 108 In the current large cohort study we analyze 127 patients with advanced ACC treated at three German centers with the aim to provide efficacy data on mitotane monotherapy based on contemporary imaging methods and to identify for the first time predictive factors for treatment response to mitotane
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