NEW STANDARD OF CARE FOR ADVANCED ADRENOCORTICAL CARCINOMA

May 4, 2012 — A new standard of treatment might have been established for advanced adrenocortical carcinoma. In the first phase 3 randomized trial evaluating treatment for this rare disease, an international team of researchers found that one regimen was superior to another.

The First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT), published online May 2 in the New England Journal of Medicine, showed more benefit from mitotane combined with etoposide, doxorubicin, and cisplatin (EDP-M) than from mitotane plus streptozocin.

Patients who received EDP-M as first-line therapy had a significantly higher response rate than those who received mitotane plus streptozocin (23.2% vs 9.2%; P < .001). They also had a longer median progression-free survival (5.0 vs 2.1 months; hazard ratio [HR], 0.55).

Despite these benefits, there was no significant difference in overall survival between the 2 groups. First-line therapy with EDP-M did not translate into a significantly improved rate of overall survival, compared with mitotane plus streptozocin (14.8 vs 12.0 months; P = .07).

Although the primary end point of overall survival was not met, lead author Martin Fassnacht, MD, is convinced that EDP-M will be the new standard of care for patients with advanced adrenocortical carcinoma requiring cytotoxic therapy.

"There might be several reasons why the significant effects on response and progression-free survival did not translate to a significant overall survival difference," said Dr. Fassnacht, who is from the Department of Internal Medicine and Endocrinology at the University Hospital of Würzburg in Germany.

Interestingly, EDP-M was also very effective as second-line therapy, which "most likely attenuated the EDP-mitotane advantage in first-line therapy and affected the overall survival analysis," he told Medscape Medical News. "Furthermore, a post hoc analysis of the 119 patients not receiving second-line therapy for a variety of reasons clearly suggests that EDP plus mitotane should become first-line treatment."

In that analysis, median survival in 67 patients receiving EDP-M was 17.1 months and in 52 patients receiving mitotane plus streptozocin was 4.7 months. Dr. Fassnacht pointed out that this improved efficacy did not cause more adverse events or a poorer quality of life.

"There are no doubts that we need better treatment options for the future," he said. "One major achievement of the FIRM-ACT study was to establish an international network that is able to perform what was thought 10 years ago to be impossible — a randomized trial in this rare disease without support from pharmaceutical companies."

It is hoped that "this network will pave the way to better treatment options in the future," he added.

Improved Progression-Free Survival and Response Rates

Adrenocortical carcinoma is a rare heterogeneous neoplasm with an incompletely understood pathogenesis and a poor prognosis. Its incidence is estimated to be 0.7 to 2.0 cases per million population per year. Among patients with metastatic disease, 5-year survival is less than 15%. The authors note that mitotane is the only pharmaceutical agent approved for this disease; it is used in the adjuvant setting and for advanced disease. Its efficacy, however, has never been demonstrated in a randomized trial.

FIRM-ACT was designed to compare the 2 most successful treatment regimens as first-line treatment in patients with advanced disease.

In one previous study (Cancer. 1998;83:2194-2200), EDP-M resulted in an objective response rate of 53%. In another (Ann Oncol. 2000;11:1281-1287), mitotane plus streptozocin resulted in an objective response rate of 36%.

In FIRM-ACT, 304 patients with advanced adrenocortical carcinoma were randomized to 1 of the 2 regimens; those with disease progression received the alternate treatment combination as a second-line therapy. The primary end point was overall survival; secondary end points included progression-free survival, tumor response, and quality of life.

Enrollment took place from June 2004 to October 2009, and the database closed for final analysis in December 2010.

A response was achieved by 35 of 151 patients in the EDP-M group and by 14 of 53 patients in the mitotane plus streptozocin group. Of the responders, 2 patients receiving EDP-M achieved a complete response and 4 became disease free with surgery after achieving a partial response. In comparison, 1 patient receiving mitotane plus streptozocin achieved a complete response and 2 became disease free with surgery after achieving a partial response.

Tumor progression occurred in 280 patients (92.1%). At 12 months, 26.1% of patients who received first-line EDP-M were alive without disease progression, compared with 7.2% of patients who received first-line mitotane plus streptozocin.

Of the 232 patients who died (108 in the EDP-M group and 124 in the mitotane plus streptozocin group), 211 died from progressive disease. As a first-line therapy, EDP-M reduced the mortality risk by 21% (HR, 0.79) in the intent-to-treat analysis.

Efficacy as second-line therapy was similar to that of first-line therapy in the 2 regimens. Median progression-free survival for second-line EDP-M was 5.6 months and for second-line mitotane plus streptozocin was 2.2 months.

Just the Beginning

Even though the study did not show a difference in overall survival, it did demonstrate treatment superiority for EDP-M, said Willie Underwood III, MD, MPH, MSci, from the Department of Urology and the Office of Cancer Health Disparities Research at Roswell Park Cancer Institute in Buffalo, New York.

"In many cancer trials, survival difference is often only 2 or 3 months," he told Medscape Medical News when approached for independent comment. "Quality of life and progression-free survival are important goals; sometimes you have to make a tradeoff between quantity and quality."

He pointed out that mitotane has been used without "any real objective studies to back up what we were doing. We can't practice evidence-based medicine without the evidence.... This study finally gives us that."

Dr. Underwood sees this study as a first step to improving the treatment of this rare tumor. "We have to do better understanding this disease and how to develop better treatment for it," he said. "Ideally, we will be able to diagnose it early enough so that we can treat it at an early stage."

The study was supported by grants from the German Ministry of Education and Research, the Italian Ministry of University and Research, the Institut Gustave-Roussy Clinical Research Unit, and the Cortical and Medullary Endocrine Tumors Network of the French Institut National du Cancer. A nested study within FIRM-ACT was funded by HRA Pharma.

N Engl J Med. Published online May 2, 2012. Abstract