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A study published in the New England Journal of Medicine provides evidence for effectiveness of mitotane, a drug used in treating adrenocortical carcinoma. This tumour is rare, with an estimated worldwide incidence of two cases per million per year; conducting randomised controlled trials in the disease is therefore difficult.
Mitotane is an old drug related to the insecticide DDT that has been used in treating carcinoma for many years, but there is limited robust evidence for its efficacy. This study used retrospective analysis to clarify its effects.
The authors used the fact that for many years some specialist centres had routinely given mitotane after surgery whereas others had not. They obtained data on three groups of patients treated between 1985 and 2003 in specialist centres in Italy and Germany: one group (Italian) had received adjuvant mitotane after radical surgery and the other two groups (one from Germany and one from Italy) had not and thus became the controls. Primary outcome was recurrence-free survival in those who received mitotane compared to those who had not.
A total of 177 eligible patients was identified, 47 Italian patients who had received mitotane (study group), 55 Italian patients who had not (control group 1) and 75 German patients who had not (control group 2).
Recurrence-free survival was significantly longer in the study group compared to both control groups, at 42 months vs 10 and 25 months for groups 1 and 2 respectively. Documented recurrence in the three groups was 48.8% in the study group compared to 90.9% in control group 1 and 73.3% in control group 2.
Hazard ratios for recurrence were 2.91 (95% CI, 1.77–4.78; p<0.001) and 1.97 (95% CI, 1.21–3.20; p=0.005), respectively. There was no significant difference in efficacy between patients receiving mitotane 1–3g daily and those receiving 3–5g daily, but adverse effects were significantly more common in the high-dose group.
The authors conclude that although their study has limitations, it demonstrates a significant benefit from adjuvant treatment with mitotane after surgery for adrenocortical carcinoma.
An accompanying editorial discusses the study. The author notes the rarity of and limited effective treatments for this tumour. He comments that there is controversy over the efficacy of mitotane and that the trial data are inconclusive.
While this study is retrospective and thus has inevitable limitations, it appears to have been done as robustly as possible and therefore has credibility.
He discusses possible reasons why response to mitotane should vary, and notes that it requires metabolic activation –some tumours may not activate it due to alterations in the process involved; this raises the possibility of testing for susceptibility in advance of treatment. Overall, this trial provides the best evidence so far that the drug is beneficial and its observation that lower doses seem to be as effective as higher ones is useful.
New Engl J Med 2007;356:2372-80;2415-8