Mitotane Delays Relapse in Adrenocortical Cancer

TURIN, Italy, June 6 -- Mitotane (Lysodren), a controversial derivative of the insecticide DDT, delays relapse in cases of radically resected adrenal carcinoma, researchers here say.

Recurrence rates for patients treated with the drug as an adjuvant were between a third and half as high as among patients who were simply watched after surgery, according to Massimo Terzolo, M.D., of the University of Turin.

The finding, based on a retrospective review of 177 cases in centers in Italy and Germany, "should renew interest" in adjuvant therapy for the disease, Dr. Terzolo and colleagues reported in the June 7 issue of the New England Journal of Medicine.

They did, however, acknowledge that a prospective randomized trial is required to confirm the results.

Adrenocortical carcinoma is a rare cancer "characterized by a dismal prognosis," the researchers said. Indeed, no more than 38% of patients live for more than five years after diagnosis, even though most cancers are resectable.

The problem is that up to 75% of patients suffer a relapse even after radical resection. Investigators have tried using mitotane, which selectively targets and destroys adrenal cells, but results from clinical trials, most of them small, have been mixed. That's left physicians without clear guidance.

To fill the gap, Dr. Terzolo and colleagues reviewed outcomes for 102 patients who had radical resection in eight Italian centers between 1985 and 2005. Four of the centers routinely used mitotane as adjuvant therapy and four did not, creating a treatment group of 47 patients and a control group of 55.

They also reviewed outcomes of 75 patients in 47 centers in Germany, which did not use mitotane, as a second control group.

The researchers found:

• Recurrence was seen in 23 patients in the mitotane group, or 48.9%, compared with 50 (90.9%) in the Italian controls and 55 (73.3%) in the German controls.
• Median relapse-free survival was 42 months for mitotane patients, compared with 10 months for the Italian controls and 25 months for the Germans. The differences were significant at P<0.001 and P=0.005, respectively.
• After adjustment for age, sex and tumor stage, the hazard ratio for recurrence among the Italian controls was 3.79, with a 95% confidence interval from 2.27 to 6.32.
• The equivalent figure for the German controls was 2.93, with a 95% confidence interval from 1.74 to 4.94.

Patients in the control groups were also more likely to die, with hazard ratios of 2.47 for the Italians and 1.96 for the Germans, the researchers found.

While the study is retrospective, it is carefully done and "credible," according to David Schteingart, M.D., of the University of Michigan, writing in an accompanying editorial.

He pointed out that "a limitation of mitotane therapy has been its

marked toxicity at daily doses exceeding 6 g. Doses sufficient to achieve 'therapeutic' levels of 16 ?g per milliliter are usually associated with undesirable toxicity. An important finding in the study by Terzolo et al. is that favorable outcomes were achieved with relatively low doses of mitotane-1 to 3 g per day was sufficient to produce the desired effect with reduced toxic effects."

In the absence of prospective randomized trials-unlikely given the rarity of the disease-the study is "the best evidence to date" that the use of adjuvant mitotane offers a benefit to patients, Dr. Schteingart said.

"It should make the therapeutic choice of using the drug more acceptable," he concluded.