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Adjuvant Therapy for Adrenal Cancer

Mitotane prolonged recurrence-free survival following radical resection.

Adrenocortical carcinoma is a very rare epithelial cancer: In the U.S., only one to two cases per million individuals are seen annually. A relatively high percentage of such patients develop metastatic disease within 1 year to 3 years of complete surgical resection. Systemic therapies generally do not affect survival, although some patients respond to mitotane (a derivative of dichlorodiphenyltrichloroethane, better known as the insecticide DDT). Keeping in mind the rarity of adrenocortical carcinoma and the consequent difficulty in conducting prospective randomized trials, investigators explored the use of adjuvant mitotane by assessing the outcomes of its routine use in some academic centers in Italy; the rest were designated as control centers. A second control group consisted of patients in Germany who were treated with surgery only.

This retrospective analysis included 177 patients who underwent curative-intent resection of adrenocortical carcinoma at 8 centers in Italy and 47 centers in Germany from 1985 to 2005. Adjuvant mitotane was administered to 47 patients at 4 of the Italian centers. The investigators compared recurrence-free survival of patients who received adjuvant mitotane with that of those who underwent surgery alone. Secondary endpoints included overall survival and adverse events associated with mitotane use.

Baseline features in the mitotane group and the Italian control group (control group I) were similar, whereas the German patients (control group II) were slightly older and had a higher incidence of stage I or II adrenocortical carcinoma than did patients in the mitotane group. Median follow-up was 57 months in the mitotane group and 68 and 43 months in the two control groups, respectively. Of the 47 patients who received mitotane, 20 received 3 to 5 g daily and 27 received 1 to 3 g daily. Median recurrence-free survival was significantly prolonged in the mitotane group compared with the two control groups (42 months vs. 10 and 25 months, respectively). Results of multivariate analysis showed that mitotane treatment conferred a significant advantage for recurrence-free survival. Adverse events associated with mitotane were mostly grade 1 or 2, but 13% of patients required temporary dose reductions.

Comment: Previous studies of adjuvant mitotane have provided a mixed picture, with some results supportive and others suggesting limited benefit. An editorialist notes that the observed variability in therapeutic benefit of adjuvant mitotane therapy might be explained partly by pharmacogenomic differences among patients. Given the rarity of the disease, we might never fully characterize the role of this agent. In this study, mitotane’s benefits generally were observed with relatively low doses; thus, its tolerability could provide a rationale for use in high-risk patients.

— Robert Dreicer, MD, MS, FACP

Published in Journal Watch Oncology and Hematology June 6, 2007

Citation(s):

Terzolo M et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 2007 Jun 7; 356:2372-80.

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• Medline abstract (Free)

Schteingart DE. Adjuvant mitotane therapy of adrenal cancer — Use and controversy. N Engl J Med 2007 Jun 7; 356:2415-8.

• Original article (Subscription may be required)
• Medline abstract (Free)