Combination Chemotherapy in Advanced Adrenocortical Carcinoma

The 5-year survival rate for adrenocortical carcinoma, a rare cancer with a poor prognosis, is <15% among patients with metastatic disease. 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.

For this trial [N Engl J Med. 2012;366(23):2189-2197], FIRM-ACT (First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment), the authors compared the 2 most successful regimens in patients with advanced disease. One regimen, which combined etoposide, doxorubicin, and cisplatin (EDP) with mitotane, resulted in an objective response rate of 53% in a study involving 28 patients with advanced adrenocortical carcinoma. The second regimen, which combined streptozocin with mitotane, resulted in an objective response rate of 36% in a study involving 22 patients with advanced adrenocortical carcinoma.

The goal of this investigator-initiated, randomized, controlled, open-label, parallel-group trial, which was conducted in 12 countries at 40 specialized centers for the treatment of adrenocortical carcinoma, was to establish a treatment standard for advanced disease.

The investigators randomly assigned patients with adrenocortical carcinoma to receive 1 of 2 regimens. The patients received mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin  (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy.

In both treatment schedules, mitotane was started a minimum of 1 week before the initiation of the cytotoxic treatment, with the goal of attaining a blood level of 14 mg to 20 mg per liter. Primary end point was overall survival. Secondary end points were progression-free survival, tumor response, and quality of life. Secondary objectives were to explore the effect of a blood mitotane level of 14 mg to 20 mg per liter on the clinical outcome and to determine the response to each of the two regimens as second-line therapy.

A total of 304 patients were enrolled in the study from June 2004, through October 2009. The database was closed for final analysis on December 10, 2010. At least 1 cycle of chemotherapy was administered in 148 patients in the EDP-mitotane group and 149 patients in the streptozocin-mitotane group.

An objective tumor response occurred in 35 of 151 patients in the EDP-mitotane group, compared with 14 of 153 patients in the streptozocin-mitotane group (23.2% vs 9.2%, P<.001).  Tumor progression occurred in 280 of 304 patients (92.1%). The median duration of progression-free survival was 5.0 months (95% confidence interval [CI], 3.5-6.9) in the EDP-mitotane group, compared with 2.1 months (95% CI, 2.04-2.33) in the streptococci-mitotane group (hazard ratio [HR], 0.55; 95% CI, 0.43-0.69; P<.001).

At 12 months, 26.1% of patients (95% CI, 19.0-33.1) who received first-line therapy with EDP plus mitotane were alive without disease progression, compared with 7.2% (95% CI, 3.1-11.3) who received first-line therapy with streptozocin plus mitotane.

At final analysis, 232 patients (76.3%) had died, with 211 deaths caused by progressive disease (90.9%); 18 deaths were from causes other than cancer, and 3 deaths were from unknown causes. Among patients receiving first-line therapy, there were 108 deaths in the EDP-mitotane group and 124 in the streptozocin-mitotane group; the median duration of survival was 14.8 months (95% CI, 11.3-17.1) and 12.0 months (95% CI, 10.3-13.6), respectively. Thus, EDP plus mitotane as first-line treatment reduced the risk of death by 21%, as compared with streptozocin plus mitotane (HR, 0.79; 95% CI, 0.61-1.02; P=.07) in the intention-to-treat analysis.