Mitotane-containing Regimens Explored for a Rare Tumor

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Response rates and progression-free survival rates were significantly better among patients with advanced adrenocortical carcinoma receiving mitotane (Lysodren) plus EDP (etoposide, doxorubicin, and cisplatin) than in patients receiving mitotane with streptozocin (Zanosar), according to results of a randomized, controlled, open-label, parallel-group trial. The study included 340 patients in 12 countries at 40 specialized centers for the treatment of adrenocortical carcinoma, a rare cancer with a poor prognosis and few treatment options. It was funded by the Swedish Research Council and others.

“Mitotane is the only drug approved for the treatment of adrenocortical carcinoma and is used both as adjuvant therapy and for advanced disease, although its efficacy has never been shown in a randomized trial,” the investigators reported in The New England Journal of Medicine. “The experience with other antineoplastic drugs for the treatment of this disease is even more limited.”

The current study, the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) is the first randomized phase III trial in this rare tumor, and compared “the two most successful regimens in patients with advanced disease,” the investigators noted. The regimen combining EDP with mitotane had produced an objective response rate of 53% in a 28-patient study, and the regimen combining streptozocin with mitotane had produced an objective response rate of 36% in a 22-patient study.

Study Data

In the FIRM-ACT trial, patients receiving first-line EDP and mitotane had a significantly higher response rate than those given first-line streptozocin plus mitotane (23.2% vs 9.2%, P < .001) and longer median progression-free survival (5.0 vs 2.1 months), the researchers reported.

Tumor progression was seen in 280 (92.1%) of 304 patients, the authors noted. At 12 months, 26.1% of patients who received first-line therapy including EDP were alive without disease progression, compared to 7.2% who received first-line therapy including streptozocin plus mitotane.

At final analysis, 232 patients (76.3%) had died, 108 in the EDP group and 124 in the streptozocin group. The median duration of survival was 14.8 months in the EDP group and 12.0 months in the streptozocin group. “Thus, EDP plus mitotane as first-line treatment reduced the risk of death by 21%, as compared with streptozocin plus mitotane,” the researchers noted.

“The efficacy of both regimens as second-line therapy was similar to their efficacy as first-line therapy,” the authors stated. “Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP–mitotane group and 2.2 months in the streptozocin–mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 months) than with streptozocin plus mitotane (4.7 months),” the researchers wrote.

Survival Remains Dismal

During first-line treatment, serious adverse events occurred among 86 patients (58.1%) in the EDP group and 62 patients (41.6%) in the streptozocin group. Bone marrow toxicity, infection, and cardiovascular or thromboembolic events were the most common serious adverse events in the EDP group. In the streptozocin group, the most common serious adverse events were gastrointestinal disorder, impaired liver function, and fatigue or general health deterioration.

The authors noted that despite findings suggesting that EDP plus mitotane had superior antitumor efficacy compared to streptozocin plus mitotane, “the overall survival rates in our study remained dismal. First-line therapy with EDP plus mitotane did not translate into a significant improvement in overall survival.” The poor overall survival rates, they added, confirm “the need for improved treatment options.” ■


1. Fassnacht MF, Terzolo M, Allolio B, et al: Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 366:2189-2197, 2012.