by ecancer reporter Clare Sansom

Adrenocortical carcinoma is a rare, aggressive tumour that originates in the adrenal glands above the kidneys.

It is most commonly diagnosed in young children and in adults in their thirties, it is often not detected until it has become metastatic, and only about 15% of patients diagnosed with metastatic disease live for five years after diagnosis.

The only drug currently approved for the treatment of adrenocortical carcinoma is mitotane, which directly suppresses the function of the adrenal cortex.

Combinations of this drug with other chemotherapeutic agents have been tested retrospectively and in small Phase II trials. The First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) was set up to compare the two drug combinations identified in these trials as being the most promising treatments for advanced disease.

These combined mitotane with, firstly, a combination of etoposide, doxorubicin, and cisplatin (known as EDP) and, secondly, streptozocin alone.

The results of the FIRM-ACT trial have now been reported by a large study group led by Martin Wassnacht at the University Hospital of Würzburg, Würzburg, Germany. This was a Phase III randomised, open-label, parallel group trial involving forty study centres in twelve countries.

A total of 304 adult patients diagnosed with advanced adrenocortical carcinoma who had no previous history of cancer and who had not been treated with drugs other than mitotane were assigned to receive either EDP or streptozocin plus mitotane. Patients whose disease progressed on their initial study drug combination were moved to the alternative regimen as second-line therapy in two parallel phase II trials incorporated into the basic study design. The primary end point was overall survival.

A total of 297 patients received at least one cycle of drugs in either regimen, and 185 patients whose tumours progressed received at least one cycle of a second-line therapy. A total of 35 of 151 patients in the EDP-mitotane study group had an objective tumour response, compared with 14 of 153 patients in the streptozocin group (23.2% vs. 9.2%, p<0.001).

There was also a significant difference in favour of the EDP-mitoxin group in progression-free survival, with a median progression-free survival time of 5.0 months in that group compared to 2.1 months with streptozocin-mitotane ((hazard ratio, 0.55; 95% confidence interval, 0.43-0.69; p<0.001). However, the small difference in overall survival was not statistically significant (14.8 months for EDP-mitotane compared to 12.0 months for streptozocin-mitotane, p = 0.07).

The efficacy of the two regimens as second-line therapy was broadly similar to their efficacy as first-line therapy; the median progression-free survival for EDP-mitotane was 5.2 months compared to 2.2 months for streptozocin-mitotane.

The safety profiles of the two regimens were also similar; 58.1% of patients randomized to receive EDP-mitotane and 41.6% of those randomized to receive streptozocin-mitotane had at least one serious adverse event during first-line therapy. The most common serious adverse events were bone marrow toxicity in the EDP-mitotane group and gastrointestinal toxicity in the streptozocin-mitotane group.

The study authors concluded that the EDP can be preferred over streptozocin in combination with mitotane as a treatment for advanced adrenocortical carcinoma because of its improved response rate and progression-free survival and comparable side effect profiles.

However, neither treatment regimen provided a significant improvement in overall survival, showing that further treatment options are still needed for this aggressive tumour. A further conclusion was that that the trial had proved that phase III trials in rare cancers are feasible, despite a lack of pharmaceutical company interest in these diseases.

Reference

Fassnacht, M., Terzolo, M., Allolio, B. and 34 others, for the FIRM-ACT study group (2012). Combination Chemotherapy in Advanced Adrenocortical Carcinoma. N. Engl. J. Med., published online ahead of print 2 May 2012. doi: 10.1056/NEJMoa1200966